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Sample records for aeruginosa pulmonary infection

  1. [A case of pulmonary infection caused by Pseudomonas aeruginosa with anorexia nervosa].

    PubMed

    Ugajin, Motoi; Miwa, Seiichi; Suda, Takafumi; Shirai, Masahiro; Hayakawa, Hiroshi; Chida, Kingo

    2009-12-01

    A 19-year-old woman with anorexia nervosa (body weight 25 kg) was admitted to our hospital, showing a cavitary shadow in the left upper lung field on a chest radiograph film. We diagnosed a pulmonary abscess caused by Pseudomonas aeruginosa. A few days later, exacerbation, including enlargement of the cavitary shadow, ipsilateral pleural effusion and bilateral infiltrations, were observed. Finally, by using antibiotics such as Doripenem (DRPM) and Ciprofloxacin (CPFX), we were able to treat the disease by bronchoscopic and thoracic drainage. This case suggests we should take carefully treat anorexia nervosa patients with pulmonary infection. PMID:20058691

  2. Screening of Lactobacillus spp. for the prevention of Pseudomonas aeruginosa pulmonary infections

    PubMed Central

    2014-01-01

    Background Pseudomonas aeruginosa is an opportunistic pathogen that significantly increases morbidity and mortality in nosocomial infections and cystic fibrosis patients. Its pathogenicity especially relies on the production of virulence factors or resistances to many antibiotics. Since multiplication of antibiotic resistance can lead to therapeutic impasses, it becomes necessary to develop new tools for fighting P. aeruginosa infections. The use of probiotics is one of the ways currently being explored. Probiotics are microorganisms that exert a positive effect on the host’s health and some of them are known to possess antibacterial activities. Since most of their effects have been shown in the digestive tract, experimental data compatible with the respiratory environment are strongly needed. The main goal of this study was then to test the capacity of lactobacilli to inhibit major virulence factors (elastolytic activity and biofilm formation) associated with P. aeruginosa pathogenicity. Results Sixty-seven lactobacilli were isolated from the oral cavities of healthy volunteers. These isolates together with 20 lactobacilli isolated from raw milks, were tested for their capacity to decrease biofilm formation and activity of the elastase produced by P. aeruginosa PAO1. Ten isolates, particularly efficient, were accurately identified using a polyphasic approach (API 50 CHL, mass-spectrometry and 16S/rpoA/pheS genes sequencing) and typed by pulsed-field gel electrophoresis (PFGE). The 8 remaining strains belonging to the L. fermentum (6), L. zeae (1) and L. paracasei (1) species were sensitive to all antibiotics tested with the exception of the intrinsic resistance to vancomycin. The strains were all able to grow in artificial saliva. Conclusion Eight strains belonging to L. fermentum, L. zeae and L. paracasei species harbouring anti-elastase and anti-biofilm properties are potential probiotics for fighting P. aeruginosa pulmonary infections. However, further

  3. Macrophage dysfunction and susceptibility to pulmonary Pseudomonas aeruginosa infection in surfactant protein C-deficient mice.

    PubMed

    Glasser, Stephan W; Senft, Albert P; Whitsett, Jeffrey A; Maxfield, Melissa D; Ross, Gary F; Richardson, Theresa R; Prows, Daniel R; Xu, Yan; Korfhagen, Thomas R

    2008-07-01

    To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc-/-) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc-/- mice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc-/- mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc-/- mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc-/- mice relative to Sftpc+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc-/- mice following infection. Phagocytic activity of alveolar macrophages from Sftpc-/- mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc-/- mice. Alveolar macrophages from Sftpc-/- mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses. PMID:18566429

  4. Heterogeneity of pulmonary endothelial cyclic nucleotide response to Pseudomonas aeruginosa ExoY infection.

    PubMed

    Morrow, K A; Seifert, R; Kaever, V; Britain, A L; Sayner, S L; Ochoa, C D; Cioffi, E A; Frank, D W; Rich, T C; Stevens, T

    2015-11-15

    Here, we tested the hypothesis that a promiscuous bacterial cyclase synthesizes purine and pyrimidine cyclic nucleotides in the pulmonary endothelium. To test this hypothesis, pulmonary endothelial cells were infected with a strain of the Gram-negative bacterium Pseudomonas aeruginosa that introduces only exoenzyme Y (PA103 ΔexoUexoT::Tc pUCPexoY; ExoY(+)) via a type III secretion system. Purine and pyrimidine cyclic nucleotides were simultaneously detected using mass spectrometry. Pulmonary artery (PAECs) and pulmonary microvascular (PMVECs) endothelial cells both possess basal levels of four different cyclic nucleotides in the following rank order: cAMP > cUMP ≈ cGMP ≈ cCMP. Endothelial gap formation was induced in a time-dependent manner following ExoY(+) intoxication. In PAECs, intercellular gaps formed within 2 h and progressively increased in size up to 6 h, when the experiment was terminated. cGMP concentrations increased within 1 h postinfection, whereas cAMP and cUMP concentrations increased within 3 h, and cCMP concentrations increased within 4 h postinfection. In PMVECs, intercellular gaps did not form until 4 h postinfection. Only cGMP and cUMP concentrations increased at 3 and 6 h postinfection, respectively. PAECs generated higher cyclic nucleotide levels than PMVECs, and the cyclic nucleotide levels increased earlier in response to ExoY(+) intoxication. Heterogeneity of the cyclic nucleotide signature in response to P. aeruginosa infection exists between PAECs and PMVECs, suggesting the intracellular milieu in PAECs is more conducive to cNMP generation. PMID:26386118

  5. Outbreak of pulmonary Pseudomonas aeruginosa and Stenotrophomonas maltophilia infections related to contaminated bronchoscope suction valves, Lyon, France, 2014.

    PubMed

    Guy, Marine; Vanhems, Philippe; Dananché, Cédric; Perraud, Michel; Regard, Anne; Hulin, Monique; Dauwalder, Olivier; Bertrand, Xavier; Crozon-Clauzel, Jullien; Floccard, Bernard; Argaud, Laurent; Cassier, Pierre; Bénet, Thomas

    2016-07-14

    In April 2014, pulmonary Pseudomonas aeruginosa and Stenotrophomonas maltophilia co-infections potentially related to bronchoscopic procedures were identified in the intensive care units of a university hospital in Lyon, France. A retrospective cohort of 157 patients exposed to bronchoscopes from 1 December 2013 to 17 June 2014 was analysed. Environmental samples of suspected endoscopes were cultured. Bronchoscope disinfection was reviewed. Ten cases of pulmonary P. aeruginosa/S. maltophilia co-infections were identified, including two patients with secondary pneumonia. Eight cases were linked to bronchoscope A1 and two to bronchoscope A2. Cultures deriving from suction valves were positive for P. aeruginosa/S. maltophilia. Exposure to bronchoscopes A1 and A2 was independently coupled with increased risk of co-infection (adjusted odds ratio (aOR) = 84.6; 95% confidence interval (CI): 9.3-771.6 and aOR = 11.8, 95% CI: 1.2-121.3). Isolates from suction valves and clinical samples presented identical pulsotypes. The audit detected deficiencies in endoscope disinfection. No further cases occurred after discontinuation of the implicated bronchoscopes and change in cleaning procedures. This outbreak of pulmonary P. aeruginosa/S. maltophilia co-infections was caused by suction valve contamination of two bronchoscopes of the same manufacturer. Our findings underscore the need to test suction valves, in addition to bronchoscope channels, for routine detection of bacteria. PMID:27458712

  6. Activation of pulmonary and lymph node dendritic cells during chronic Pseudomonas aeruginosa lung infection in mice.

    PubMed

    Damlund, Dina Silke Malling; Christophersen, Lars; Jensen, Peter Østrup; Alhede, Morten; Høiby, Niels; Moser, Claus

    2016-06-01

    The majority of cystic fibrosis (CF) patients acquire chronic Pseudomonas aeruginosa lung infection, resulting in increased mortality and morbidity. The chronic P. aeruginosa lung infection is characterized by bacteria growing in biofilm surrounded by polymorphonuclear neutrophils (PMNs). However, the infection is not eradicated and the inflammatory response leads to gradual degradation of the lung tissue. In CF patients, a Th2-dominated adaptive immune response with a pronounced antibody response is correlated with poorer outcome. Dendritic cells (DCs) are crucial in bridging the innate immune system with the adaptive immune response. Once activated, the DCs deliver a set of signals to uncommitted T cells that induce development, such as expansion of regulatory T cells and polarization of Th1, Th2 or Th17 subsets. In this study, we characterized DCs in lungs and regional lymph nodes in BALB/c mice infected using intratracheal installation of P. aeruginosa embedded in seaweed alginate in the lungs. A significantly elevated concentration of DCs was detected earlier in the lungs than in the regional lymph nodes. To evaluate whether the chronic P. aeruginosa lung infection leads to activation of DCs, costimulatory molecules CD80 and CD86 were analyzed. During infection, the DCs showed significant elevation of CD80 and CD86 expression in both the lungs and the regional lymph nodes. Interestingly, the percentage of CD86-positive cells was significantly higher than the percentage of CD80-positive cells in the lymph nodes. In addition, cytokine production from Lipopolysaccharides (LPS)-stimulated DCs was analyzed demonstrating elevated production of IL-6, IL-10 and IL-12. However, production of IL-12 was suppressed earlier than IL-6 and IL-10. These results support that DCs are involved in skewing of the Th1/Th2 balance in CF and may be a possible treatment target. PMID:27009697

  7. Pulmonary delivery of tobramycin-loaded nanostructured lipid carriers for Pseudomonas aeruginosa infections associated with cystic fibrosis.

    PubMed

    Moreno-Sastre, María; Pastor, Marta; Esquisabel, Amaia; Sans, Eulàlia; Viñas, Miguel; Fleischer, Aarne; Palomino, Esther; Bachiller, Daniel; Pedraz, José Luis

    2016-02-10

    Among the pathogens that affect cystic fibrosis (CF) patients, Pseudomonas aeruginosa is the most prevalent. As a way to fight against this infection, nanotechnology has emerged over the last decades as a promising alternative to overcome resistance to antibiotics in infectious diseases. The goal of this work was to elaborate and characterize lipid nanoparticles for pulmonary delivery of tobramycin. Tobramycin-loaded nanostructured lipid carriers (Tb-NLCs) were prepared by hot melt homogenization technique. In addition, nanoparticles labeled with infrared dye (IR-NLCs) were used to investigate their in vivo performance after pulmonary administration. Tb-NLCs displayed a mean diameter size around 250 nm, high drug encapsulation (93%) and sustained release profile. Tb-NLCs showed to be active against clinically isolated P. aeruginosa. Moreover, Tb-NLCs did not decrease cell viability and were able to overcome an artificial mucus barrier in the presence of mucolytics agents. During the in vivo assay, IR-NLCs were administered to several mice by the intratracheal route using a Penn Century device. Next, the biodistribution of the nanoparticles was analyzed at different time points showing a wide nanosystem distribution in the lungs. Altogether, tobramycin-loaded NLCs seem to us an encouraging alternative to the currently available CF therapies. PMID:26705155

  8. Production of elastase, exotoxin A, and alkaline protease in sputa during pulmonary exacerbation of cystic fibrosis in patients chronically infected by Pseudomonas aeruginosa.

    PubMed Central

    Jaffar-Bandjee, M C; Lazdunski, A; Bally, M; Carrère, J; Chazalette, J P; Galabert, C

    1995-01-01

    Secretion of Pseudomonas aeruginosa elastase, exotoxin A, and alkaline protease in sputum during bronchopulmonary exacerbations was examined in 18 cystic fibrosis patients chronically infected with this microorganism. The patients were studied during one or several exacerbation periods necessitating hospitalizations of 12 to 20 days. In all cases, P. aeruginosa was present in bronchial secretions at admission and was not eradicated after treatment. The P. aeruginosa density decreased significantly after antibiotic therapy but remained greater than 10(6) CFU/g of sputum in most cases. Significant amounts of P. aeruginosa exoproteins were measured in total homogenized bronchial secretions by immunoenzymatic assays. The detection of higher levels of exoproteins at admission, the significant decrease after treatment, and the absence of exoproteins during intercrisis phases constituted arguments for a renewal of virulence of P. aeruginosa during exacerbations. Nevertheless, the concomitant changes in bacteria load and the triggering of the inflammatory process and immune complex formation could also contribute to pulmonary exacerbations. PMID:7790462

  9. Efficacy of Liposomal Bismuth-Ethanedithiol-Loaded Tobramycin after Intratracheal Administration in Rats with Pulmonary Pseudomonas aeruginosa Infection

    PubMed Central

    Alhariri, Moayad

    2013-01-01

    We sought to investigate alterations in quorum-sensing signal molecule N-acyl homoserine lactone secretion and in the release of Pseudomonas aeruginosa virulence factors, as well as the in vivo antimicrobial activity of bismuth-ethanedithiol incorporated into a liposome-loaded tobramycin formulation (LipoBiEDT-TOB) administered to rats chronically infected with P. aeruginosa. The quorum-sensing signal molecule N-acyl homoserine lactone was monitored by using a biosensor organism. P. aeruginosa virulence factors were assessed spectrophotometrically. An agar beads model of chronic Pseudomonas lung infection in rats was used to evaluate the efficacy of the liposomal formulation in the reduction of bacterial count. The levels of active tobramycin in the lungs and the kidneys were evaluated by microbiological assay. LipoBiEDT-TOB was effective in disrupting both quorum-sensing signal molecules N-3-oxo-dodeccanoylhomoserine lactone and N-butanoylhomoserine lactone, as well as significantly (P < 0.05) reducing lipase, chitinase, and protease production. At 24 h after 3 treatments, the CFU counts in lungs of animals treated with LipoBiEDT-TOB were of 3 log10 CFU/lung, comparated to 7.4 and 4.7 log10 CFU/lung, respectively, in untreated lungs and in lungs treated with free antibiotic. The antibiotic concentration after the last dose of LipoBiEDT-TOB was 25.1 μg/lung, while no tobramycin was detected in the kidneys. As for the free antibiotic, we found 6.5 μg/kidney but could not detect any tobramycin in the lungs. Taken together, LipoBiEDT-TOB reduced the production of quorum-sensing molecules and virulence factors and could highly improve the management of chronic pulmonary infection in cystic fibrosis patients. PMID:23147741

  10. Vaccination against respiratory Pseudomonas aeruginosa infection

    PubMed Central

    Grimwood, Keith; Kyd, Jennelle M; Owen, Suzzanne J; Massa, Helen M; Cripps, Allan W

    2014-01-01

    Respiratory infections caused by Pseudomonas aeruginosa are a major clinical problem globally, particularly for patients with chronic pulmonary disorders, such as those with cystic fibrosis (CF), non-CF bronchiectasis (nCFB) and severe chronic obstructive pulmonary disease (COPD). In addition, critically ill and immunocompromised patients are also at significant risk of P. aeruginosa infection. For almost half a century, research efforts have focused toward development of a vaccine against infections caused by P. aeruginosa, but a licensed vaccine is not yet available. Significant advances in identifying potential vaccine antigens have been made. Immunisations via both the mucosal and systemic routes have been trialled in animal models and their effectiveness in clearing acute infections demonstrated. The challenge for translation of this research to human applications remains, since P. aeruginosa infections in the human respiratory tract can present both as an acute or chronic infection. In addition, immunisation prior to infection may not be possible for many patients with CF, nCFB or COPD. Therefore, development of a therapeutic vaccine provides an alternative approach for treatment of chronic infection. Preliminary animal and human studies suggest that mucosal immunisation may be effective as a therapeutic vaccine against P. aeruginosa respiratory infections. Nevertheless, more research is needed to improve our understanding of the basic biology of P. aeruginosa and the mechanisms needed to upregulate the induction of host immune pathways to prevent infection. Recognition of variability in the host immune responses for a range of patient health conditions at risk from P. aeruginosa infection is also required to support development of a successful vaccine delivery strategy and vaccine. Activation of mucosal immune responses may provide improved efficacy of vaccination for P. aeruginosa during both acute exacerbations and chronic infection. PMID:25483510

  11. Pulmonary retention of free and liposome-encapsulated tobramycin after intratracheal administration in uninfected rats and rats infected with Pseudomonas aeruginosa.

    PubMed Central

    Omri, A; Beaulac, C; Bouhajib, M; Montplaisir, S; Sharkawi, M; Lagacé, J

    1994-01-01

    The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(8) CFU of P. aeruginosa PA 508 prepared in agar beads. After 3 days, a single dose (300 micrograms) of free or liposome-encapsulated tobramycin was given intratracheally to both infected and uninfected rats. At various time intervals (0.25 to 16 h) after drug instillations, the remaining tobramycin was evaluated in blood, lungs, and kidneys by a microbiological assay. Intratracheal instillation of liposome-encapsulated tobramycin resulted in high and sustained levels of tobramycin in lungs of uninfected and infected rats over the 16-h period studied; however, the tobramycin levels were two times higher in uninfected rats. There was no tobramycin detected in the blood or kidneys from these animals. In contrast, the intratracheally instilled free tobramycin was cleared within 3 and 1 h from the lungs of uninfected and infected animals, respectively. These data suggest that the encapsulation of tobramycin in liposomes can result in a significant increase of its residence time within lungs. This study also shows that pulmonary infection was associated with a lowering of tobramycin levels in lungs. PMID:8067743

  12. Development of a dry, stable and inhalable acyl-homoserine-lactone-acylase powder formulation for the treatment of pulmonary Pseudomonas aeruginosa infections.

    PubMed

    Wahjudi, Mariana; Murugappan, Senthil; van Merkerk, Ronald; Eissens, Anko C; Visser, Marinella R; Hinrichs, Wouter L J; Quax, Wim J

    2013-03-12

    In the lungs of cystic fibrosis (CF) patients, Pseudomonas aeruginosa commonly causes chronic infections. It has been shown that the P. aeruginosa quorum sensing (QS) system controls the expression of virulence factors during invasion and infection to host cells. PvdQ is an acyl-homoserine lactone (AHL) acylase able to degrade the signal molecule of P. aeruginosa QS. The role of PvdQ in inhibiting the QS and its successive virulence determinants has been established in in vitro as well as in in vivo, the latter in a Caenorabdhitis elegans model. For the treatment of pulmonary P. aeruginosa infections, we propose that PvdQ can be best administered directly to the lungs of the patients as a dry powder because this is expected to give specific advantages in delivery as compared to nebulizing. Therefore in this study we investigated the production of a PvdQ powder by spray-freeze drying using mannitol, trehalose and inulin as excipient. The activity of PvdQ in the powder was determined immediately after production and after subsequent storage during 4 weeks at 20°C and 55°C. We found that the enzymatic activity of PvdQ is fully maintained during spray-freeze drying using mannitol, trehalose or inulin as excipient. However, mannitol was not able to stabilize the protein during storage, while PvdQ incorporated in trehalose or inulin was fully stabilized even during storage at 55°C for at least 4 weeks. The poor stabilizing capacities of mannitol during storage could be related to its crystalline nature while the excellent stabilizing capacities of trehalose and inulin during storage could be related to their amorphous nature. The trehalose and inulin-based particles consisted of porous spheres with a volume average aerodynamical diameter of ∼1.8 μm implying that they are suitable for pulmonary delivery. This is the first study in which an AHL-degrading enzyme is processed into spray-freeze-dried powder suitable for inhalation. PMID:23277289

  13. Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa

    PubMed Central

    Pewzner-Jung, Yael; Tavakoli Tabazavareh, Shaghayegh; Grassmé, Heike; Becker, Katrin Anne; Japtok, Lukasz; Steinmann, Jörg; Joseph, Tammar; Lang, Stephan; Tuemmler, Burkhard; Schuchman, Edward H; Lentsch, Alex B; Kleuser, Burkhard; Edwards, Michael J; Futerman, Anthony H; Gulbins, Erich

    2014-01-01

    Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection. PMID:25085879

  14. Long Term Chronic Pseudomonas aeruginosa Airway Infection in Mice

    PubMed Central

    Facchini, Marcella; De Fino, Ida; Riva, Camilla; Bragonzi, Alessandra

    2014-01-01

    A mouse model of chronic airway infection is a key asset in cystic fibrosis (CF) research, although there are a number of concerns regarding the model itself. Early phases of inflammation and infection have been widely studied by using the Pseudomonas aeruginosa agar-beads mouse model, while only few reports have focused on the long-term chronic infection in vivo. The main challenge for long term chronic infection remains the low bacterial burden by P. aeruginosa and the low percentage of infected mice weeks after challenge, indicating that bacterial cells are progressively cleared by the host. This paper presents a method for obtaining efficient long-term chronic infection in mice. This method is based on the embedding of the P. aeruginosa clinical strains in the agar-beads in vitro, followed by intratracheal instillation in C57Bl/6NCrl mice. Bilateral lung infection is associated with several measurable read-outs including weight loss, mortality, chronic infection, and inflammatory response. The P. aeruginosa RP73 clinical strain was preferred over the PAO1 reference laboratory strain since it resulted in a comparatively lower mortality, more severe lesions, and higher chronic infection. P. aeruginosa colonization may persist in the lung for over three months. Murine lung pathology resembles that of CF patients with advanced chronic pulmonary disease. This murine model most closely mimics the course of the human disease and can be used both for studies on the pathogenesis and for the evaluation of novel therapies. PMID:24686327

  15. Targeting iron uptake to control Pseudomonas aeruginosa infections in cystic fibrosis.

    PubMed

    Smith, Daniel J; Lamont, Iain L; Anderson, Greg J; Reid, David W

    2013-12-01

    The aerobic Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen responsible for life-threatening acute and chronic infections in humans. As part of chronic infection P. aeruginosa forms biofilms, which shield the encased bacteria from host immune clearance and provide an impermeable and protective barrier against currently available antimicrobial agents. P. aeruginosa has an absolute requirement for iron for infection success. By influencing cell-cell communication (quorum sensing) and virulence factor expression, iron is a powerful regulator of P. aeruginosa behaviour. Consequently, the imposed perturbation of iron acquisition systems has been proposed as a novel therapeutic approach to the treatment of P. aeruginosa biofilm infection. In this review, we explore the influence of iron availability on P. aeruginosa infection in the lungs of the people with the autosomal recessive condition cystic fibrosis as an archetypal model of chronic P. aeruginosa biofilm infection. Novel therapeutics aimed at disrupting P. aeruginosa are discussed, with an emphasis placed on identifying the barriers that need to be overcome in order to translate these promising in vitro agents into effective therapies in human pulmonary infections. PMID:23143541

  16. Nontuberculous mycobacterial pulmonary infections

    PubMed Central

    Odell, John A.

    2014-01-01

    Pulmonary infections due to nontuberculous mycobacteria (NTM) are increasingly recognized worldwide. Although over 150 different species of NTM have been described, pulmonary infections are most commonly due to Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus. The identification of these organisms in pulmonary specimens does not always equate with active infection; supportive radiographic and clinical findings are needed to establish the diagnosis. It is difficult to eradicate NTM infections. A prolonged course of therapy with a combination of drugs is required. Unfortunately, recurrent infection with new strains of mycobacteria or a relapse of infection caused by the original organism is not uncommon. Surgical resection is appropriate in selected cases of localized disease or in cases in which the infecting organism is resistant to medical therapy. Additionally, surgery may be required for infections complicated by hemoptysis or abscess formation. This review will summarize the practical aspects of the diagnosis and management of NTM thoracic infections, with emphasis on the indications for surgery and the results of surgical intervention. The management of NTM disease in patients with human immunodeficiency virus (HIV) infections is beyond the scope of this article and, unless otherwise noted, comments apply to hosts without HIV infection PMID:24624285

  17. Bioengineered lysozyme in combination therapies for Pseudomonas aeruginosa lung infections.

    PubMed

    Griswold, Karl E; Bement, Jenna L; Teneback, Charlotte C; Scanlon, Thomas C; Wargo, Matthew J; Leclair, Laurie W

    2014-01-01

    There is increasing urgency in the battle against drug-resistant bacterial pathogens, and this public health crisis has created a desperate need for novel antimicrobial agents. Recombinant human lysozyme represents one interesting candidate for treating pulmonary infections, but the wild type enzyme is subject to electrostatic mediated inhibition by anionic biopolymers that accumulate in the infected lung. We have redesigned lysozyme's electrostatic potential field, creating a genetically engineered variant that is less susceptible to polyanion inhibition, yet retains potent bactericidal activity. A recent publication demonstrated that the engineered enzyme outperforms wild type lysozyme in a murine model of Pseudomonas aeruginosa lung infection. Here, we expand upon our initial studies and consider dual therapies that combine lysozymes with an antimicrobial peptide. Consistent with our earlier results, the charge modified lysozyme combination outperformed its wild type counterpart, yielding more than an order-of-magnitude reduction in bacterial burden following treatment with a single dose. PMID:24637705

  18. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: characterization and risk factors

    PubMed Central

    2014-01-01

    Background Patients with severe chronic obstructive pulmonary disease (COPD) are at increased risk of infection by P. aeruginosa. The specific role of bronchiectasis in both infection and chronic colonization by this microorganism in COPD, however, remains ill defined. To evaluate the prevalence and risk factors for P. aeruginosa recovery from sputum in outpatients with severe COPD, characterizing P. aeruginosa isolates by pulsed-field gel electrophoresis (PFGE) and focusing on the influence of bronchiectasis on chronic colonization in these patients. Methods A case-cohort study of 118 patients with severe COPD attended at a Respiratory Day Unit for an acute infectious exacerbation and followed up over one year. High-resolution CT scans were performed during stability for bronchiectasis assessment and sputum cultures were obtained during exacerbation and stability in all patients. P. aeruginosa isolates were genotyped by PFGE. Determinants of the recovery of P. aeruginosa in sputum and chronic colonization by this microorganism were assessed by multivariate analysis. Results P. aeruginosa was isolated from 41 of the 118 patients studied (34.7%). Five of these 41 patients (12.2%) with P. aeruginosa recovery fulfilled criteria for chronic colonization. In the multivariate analysis, the extent of bronchiectasis (OR 9.8, 95% CI: 1.7 to 54.8) and the number of antibiotic courses (OR 1.7, 95% CI: 1.1 to 2.5) were independently associated with an increased risk of P. aeruginosa isolation. Chronic colonization was unrelated to the presence of bronchiectasis (p=0.75). In patients with chronic colonization the isolates of P. aeruginosa retrieved corresponded to the same clones during the follow-up, and most of the multidrug resistant isolates (19/21) were harbored by these patients. Conclusions The main risk factors for P. aeruginosa isolation in severe COPD were the extent of bronchiectasis and exposure to antibiotics. Over 10% of these patients fulfilled criteria for

  19. [Immunodepression and pulmonary infections].

    PubMed

    Yao, N A; Ngoran, N; de Jaureguiberry, J P; Bérard, H; Jaubert, D

    2002-11-01

    The acquired immunosuppressed states are increasingly numerous. Pneumopathies are a frequent, serious complication and etiologic diagnosis is often difficult. The nature of the micro-organism in question is a function of the immunizing type of deficiency. In neutropenias, the infections are primarily bacterial, their potential gravity being correlated with the depth of the deficiency into polynuclear, or fungic, especially in prolonged neutropenias. The aspleened states are responsible for a deficit of the macrophage system and contribute to the infections with encapsulated germs (pneumococci, klebsiellas...). The organic grafts imply an attack of cell-mediated immunity, in the particular case of the auxiliary T lymphocytes (CD4)), with a special predisposition for viral and fungic infections. During VIH infection, the immunizing deficit of CD4 lymphocytes worsens with time. At the early stage, the infections are especially bacterial. At the more advanced stages, the pulmonary pneumocystosis and tuberculosis dominate. At the late stage, finally, deep immunosuppression allows emerging of the atypical mycobacteries. In the deficiencies of humoral immunity (congenital hypogammaglobulinemias, lymphoid hemopathies B), the germs to be mentioned are the pneumococcus, Haemophilus influenzae, the salmonellas and the legionellas. Immunosuppressed pneumopathies are characterized by radio-clinical pictures of very variable gravity, ranging from focused acute pneumopathy to bilateral diffuse pneumopathy with acute respiratory distress syndrome, with phases of atypical tables with respiratory symptomatology larval or absent. The highlighting of the micro-organisms in question requires urgent complementary investigations: hemocultures, bronchiolo-alveolar washing. In certain cases, it will be possible to resort to the transtracheal puncture or transthoracic puncture guided by tomodensitometry, and if necessary to pulmonary biopsy under videothoracoscopy. Emergency of the anti

  20. Pulmonary fungal infections.

    PubMed

    Smith, Jeannina A; Kauffman, Carol A

    2012-08-01

    This review details some of the advances that have been made in the recent decade in the diagnosis, treatment and epidemiology of pulmonary fungal infections. These advances have occurred because of increasing knowledge regarding the fungal genome, better understanding of the structures of the fungal cell wall and cell membrane and the use of molecular epidemiological techniques. The clinical implications of these advances are more rapid diagnosis and more effective and less toxic antifungal agents. For example, the diagnosis of invasive pulmonary aspergillosis, as well as histoplasmosis and blastomycosis, has improved with the use of easily performed antigen detection systems in serum and bronchoalveolar lavage fluid. Treatment of angioinvasive moulds has improved with the introduction of the new azoles, voriconazole and posaconazole that have broad antifungal activity. Amphotericin B is less frequently used, and when used is often given as lipid formulation to decrease toxicity. The newest agents, the echinocandins, are especially safe as they interfere with the metabolism of the fungal cell wall, a structure not shared with humans cells. Epidemiological advances include the description of the emergence of Cryptococcus gattii in North America and the increase in pulmonary mucormycosis and pneumonia due to Fusarium and Scedosporium species in transplant recipients and patients with haematological malignancies. The emergence of azole resistance among Aspergillus species is especially worrisome and is likely related to increased azole use for treatment of patients, but also to agricultural use of azoles as fungicides in certain countries. PMID:22335254

  1. Respiratory infections: pulmonary tuberculosis.

    PubMed

    Choby, Beth A; Hunter, Paul

    2015-02-01

    Family physicians can prevent mortality and disability due to pulmonary tuberculosis (TB) by identifying high-risk patients. Recognition of symptoms (eg, cough for 3 weeks or longer) helps prevent overlooked diagnoses because results of tuberculin skin tests and interferon-gamma release assays are negative in up to 25% and 21%, respectively, of severe acute cases. The typical x-ray findings of cavities, infiltrates, and lymphadenopathy are minimal among immunosuppressed patients. Cases of active TB must be reported to local or state health departments within 24 hours of diagnosis. Sputum acid-fast bacillus tests provide results within hours and help quantify bacterial load but are not highly sensitive, and infection with nontuberculous mycobacteria can cause positive test results. Sputum cultures are adequately sensitive, identify mycobacterial species, and provide organisms for antibiotic susceptibility testing but require weeks for results. Molecular detection of Mycobacterium tuberculosis and of antibiotic-resistant mutations can expedite diagnosis and management of drug-resistant TB. Management of active TB should include directly observed therapy. Standard 6-month therapy with rifampin, isoniazid, pyrazinamide, and ethambutol resolves infection in nearly all immunocompetent adults with pansensitive TB. Multidrug-resistant TB requires second-line antibiotics (eg, fluoroquinolones, linezolid) in individualized regimens lasting 2 years. Management of latent TB infection prevents progression to active TB disease, particularly if management is completed within 2 years of infection. PMID:25685923

  2. Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes.

    PubMed

    Limoli, D H; Yang, J; Khansaheb, M K; Helfman, B; Peng, L; Stecenko, A A; Goldberg, J B

    2016-06-01

    Cystic fibrosis-related diabetes (CFRD) patients suffer from accelerated rates of pulmonary decline compared to cystic fibrosis (CF) patients with normal glucose tolerance (NGT). However, the mechanisms underlying this difference are unknown. While CFRD is associated with increased respiratory infections, a link between infection and enhanced pulmonary dysfunction remains unclear. The development of glucose intolerance is spectral, resulting in impaired glucose tolerance (IGT) prior to the diagnosis of CFRD. Inclusion of IGT patients within the NGT group may diminish the ability to identify correlations with CFRD. With this in mind, this study aimed to determine if the association between CFRD and respiratory infections is correlated with pulmonary decline. Respiratory cultures from 234 CF patients with confirmed diagnosis of NGT or CFRD were analyzed to measure rates of infection, focusing on the two most prevalent bacteria in CF, Staphylococcus aureus and Pseudomonas aeruginosa. Infection status was correlated with pulmonary function and confounding clinical variables including age, gender, blood glucose levels, and CF transmembrane conductance regulator (CFTR) phenotype were considered in multivariate analyses. CFRD patients, particularly those with extremely high blood glucose levels, were more likely than NGT patients to be co-infected with S. aureus and P. aeruginosa, compared to infection with only one pathogen. Co-infection was associated with decreased lung function and increased frequency of pulmonary exacerbations, even after adjustment for confounding variables. Alterations in the microbial community composition, as opposed to the presence of a single pathogen, may account for greater pulmonary decline in CFRD patients. PMID:26993289

  3. Cell-to-cell signaling and Pseudomonas aeruginosa infections.

    PubMed Central

    Van Delden, C.; Iglewski, B. H.

    1998-01-01

    Pseudomonas aeruginosa is a bacterium responsible for severe nosocomial infections, life-threatening infections in immunocompromised persons, and chronic infections in cystic fibrosis patients. The bacterium's virulence depends on a large number of cell-associated and extracellular factors. Cell-to-cell signaling systems control the expression and allow a coordinated, cell-density-dependent production of many extracellular virulence factors. We discuss the possible role of cell-to-cell signaling in the pathogenesis of P. aeruginosa infections and present a rationale for targeting cell-to-cell signaling systems in the development of new therapeutic approaches. PMID:9866731

  4. Bacteriophage-based therapy in cystic fibrosis-associated Pseudomonas aeruginosa infections: rationale and current status

    PubMed Central

    Hraiech, Sami; Brégeon, Fabienne; Rolain, Jean-Marc

    2015-01-01

    Pulmonary infections involving Pseudomonas aeruginosa are among the leading causes of the deterioration of the respiratory status of cystic fibrosis (CF) patients. The emergence of multidrug-resistant strains in such populations, favored by iterative antibiotic cures, has led to the urgent need for new therapies. Among them, bacteriophage-based therapies deserve a focus. One century of empiric use in the ex-USSR countries suggests that bacteriophages may have beneficial effects against a large range of bacterial infections. Interest in bacteriophages has recently renewed in Western countries, and the in vitro data available suggest that bacteriophage-based therapy may be of significant interest for the treatment of pulmonary infections in CF patients. Although the clinical data concerning this specific population are relatively scarce, the beginning of the first large randomized study evaluating bacteriophage-based therapy in burn infections suggests that the time has come to assess the effectiveness of this new therapy in CF P. aeruginosa pneumonia. Consequently, the aim of this review is, after a brief history, to summarize the evidence concerning bacteriophage efficacy against P. aeruginosa and, more specifically, the in vitro studies, animal models, and clinical trials targeting CF. PMID:26213462

  5. Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections

    PubMed Central

    Cigana, Cristina; Lorè, Nicola Ivan; Riva, Camilla; De Fino, Ida; Spagnuolo, Lorenza; Sipione, Barbara; Rossi, Giacomo; Nonis, Alessandro; Cabrini, Giulio; Bragonzi, Alessandra

    2016-01-01

    Repeated cycles of infections, caused mainly by Pseudomonas aeruginosa, combined with a robust host immune response and tissue injury, determine the course and outcome of cystic fibrosis (CF) lung disease. As the disease progresses, P. aeruginosa adapts to the host modifying dramatically its phenotype; however, it remains unclear whether and how bacterial adaptive variants and their persistence influence the pathogenesis and disease development. Using in vitro and murine models of infection, we showed that P. aeruginosa CF-adaptive variants shaped the innate immune response favoring their persistence. Next, we refined a murine model of chronic pneumonia extending P. aeruginosa infection up to three months. In this model, including CFTR-deficient mice, we unveil that the P. aeruginosa persistence lead to CF hallmarks of airway remodelling and fibrosis, including epithelial hyperplasia and structure degeneration, goblet cell metaplasia, collagen deposition, elastin degradation and several additional markers of tissue damage. This murine model of P. aeruginosa chronic infection, reproducing CF lung pathology, will be instrumental to identify novel molecular targets and test newly tailored molecules inhibiting chronic inflammation and tissue damage processes in pre-clinical studies. PMID:26883959

  6. Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections.

    PubMed

    Cigana, Cristina; Lorè, Nicola Ivan; Riva, Camilla; De Fino, Ida; Spagnuolo, Lorenza; Sipione, Barbara; Rossi, Giacomo; Nonis, Alessandro; Cabrini, Giulio; Bragonzi, Alessandra

    2016-01-01

    Repeated cycles of infections, caused mainly by Pseudomonas aeruginosa, combined with a robust host immune response and tissue injury, determine the course and outcome of cystic fibrosis (CF) lung disease. As the disease progresses, P. aeruginosa adapts to the host modifying dramatically its phenotype; however, it remains unclear whether and how bacterial adaptive variants and their persistence influence the pathogenesis and disease development. Using in vitro and murine models of infection, we showed that P. aeruginosa CF-adaptive variants shaped the innate immune response favoring their persistence. Next, we refined a murine model of chronic pneumonia extending P. aeruginosa infection up to three months. In this model, including CFTR-deficient mice, we unveil that the P. aeruginosa persistence lead to CF hallmarks of airway remodelling and fibrosis, including epithelial hyperplasia and structure degeneration, goblet cell metaplasia, collagen deposition, elastin degradation and several additional markers of tissue damage. This murine model of P. aeruginosa chronic infection, reproducing CF lung pathology, will be instrumental to identify novel molecular targets and test newly tailored molecules inhibiting chronic inflammation and tissue damage processes in pre-clinical studies. PMID:26883959

  7. Nitrite reductase is critical for Pseudomonas aeruginosa survival during co-infection with the oral commensal Streptococcus parasanguinis.

    PubMed

    Scoffield, Jessica A; Wu, Hui

    2016-02-01

    Pseudomonas aeruginosa is the major aetiological agent of chronic pulmonary infections in cystic fibrosis (CF) patients. However, recent evidence suggests that the polymicrobial community of the CF lung may also harbour oral streptococci, and colonization by these micro-organisms may have a negative impact on P. aeruginosa within the CF lung. Our previous studies demonstrated that nitrite abundance plays an important role in P. aeruginosa survival during co-infection with oral streptococci. Nitrite reductase is a key enzyme involved in nitrite metabolism. Therefore, the objective of this study was to examine the role nitrite reductase (gene nirS) plays in P. aeruginosa survival during co-infection with an oral streptococcus, Streptococcus parasanguinis. Inactivation of nirS in both the chronic CF isolate FRD1 and acute wound isolate PAO1 reduced the survival rate of P. aeruginosa when co-cultured with S. parasanguinis. Growth of both mutants was restored when co-cultured with S. parasanguinis that was defective for H2O2 production. Furthermore, the nitrite reductase mutant was unable to kill Drosophila melanogaster during co-infection with S. parasanguinis. Taken together, these results suggest that nitrite reductase plays an important role for survival of P. aeruginosa during co-infection with S. parasanguinis. PMID:26673783

  8. Why Does the Healthy Cornea Resist Pseudomonas aeruginosa Infection?

    PubMed Central

    Evans, David J.; Fleiszig, Suzanne M. J.

    2013-01-01

    Purpose To provide our perspective on why the cornea is resistant to infection based on our research results with Pseudomonas aeruginosa. Perspective We focus on our current understanding of the interplay between bacteria, tear fluid and the corneal epithelium that determine health as the usual outcome, and propose a theoretical model for how contact lens wear might change those interactions to enable susceptibility to P. aeruginosa infection. Methods Use of “null-infection” in vivo models, cultured human corneal epithelial cells, contact lens-wearing animal models, and bacterial genetics help to elucidate mechanisms by which P. aeruginosa survive at the ocular surface, adheres, and traverses multilayered corneal epithelia. These models also help elucidate the molecular mechanisms of corneal epithelial innate defense. Results and Discussion Tear fluid and the corneal epithelium combine to make a formidable defense against P. aeruginosa infection of the cornea. Part of that defense involves the expression of antimicrobials such as β-defensins, the cathelicidin LL-37, cytokeratin-derived antimicrobial peptides, and RNase7. Immunomodulators such as SP-D and ST2 also contribute. Innate defenses of the cornea depend in part on MyD88, a key adaptor protein of TLR and IL-1R signaling, but the basal lamina represents the final barrier to bacterial penetration. Overcoming these defenses involves P. aeruginosa adaptation, expression of the type three secretion system, proteases, and P. aeruginosa biofilm formation on contact lenses. Conclusion After more than two decades of research focused on understanding how contact lens wear predisposes to P. aeruginosa infection, our working hypothesis places blame for microbial keratitis on bacterial adaptation to ocular surface defenses, combined with changes to the biochemistry of the corneal surface caused by trapping bacteria and tear fluid against the cornea under the lens. PMID:23601656

  9. Reduced Mucosal Associated Invariant T-Cells Are Associated with Increased Disease Severity and Pseudomonas aeruginosa Infection in Cystic Fibrosis

    PubMed Central

    Smith, Daniel J.; Hill, Geoffrey R.; Bell, Scott C.; Reid, David W.

    2014-01-01

    Background Primary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF) to effectively clear pulmonary infections. Innate T-lymphocytes provide rapid pathogen-specific responses prior to the development of classical MHC class I and II restricted T-cell responses and are essential to the initial control of pulmonary infection. We aimed to examine the relationship between peripheral blood lymphocyte phenotype and clinical outcomes in adults with CF. Methods We studied 41 subjects with CF and 22, age matched, non-smoking healthy control subjects. Lymphocytes were extracted from peripheral blood samples and phenotyped by flow-cytometry. Lymphocyte phenotype was correlated with sputum microbiology and clinical parameters. Results In comparison to healthy control subjects, mucosal associated invariant T (MAIT)-lymphocytes were significantly reduced in the peripheral blood of subjects with CF (1.1% versus 2.0% of T-lymphocytes, P = 0.002). MAIT cell concentration was lowest in CF subjects infected with P. aeruginosa and in subjects receiving treatment for a pulmonary exacerbation. Furthermore a reduced MAIT cell concentration correlated with severity of lung disease. Conclusion Reduced numbers of MAIT cells in subjects with CF were associated with P. aeruginosa pulmonary infection, pulmonary exacerbations and more severe lung disease. These findings provide the impetus for future studies examining the utility of MAIT cells in immunotherapies and vaccine development. Longitudinal studies of MAIT cells as biomarkers of CF pulmonary infection are awaited. PMID:25296025

  10. Phage therapy of pulmonary infections

    PubMed Central

    Abedon, Stephen T

    2015-01-01

    It is generally agreed that a bacteriophage-associated phenomenon was first unambiguously observed one-hundred years ago with the findings of Twort in 1915. This was independently followed by complementary observations by d'Hérelle in 1917. D'Hérelle's appreciation of the bacteriophage phenomenon appears to have directly led to the development of phages as antibacterial agents within a variety of contexts, including medical and agricultural. Phage use to combat nuisance bacteria appears to be especially useful where targets are sufficiently problematic, suitably bactericidal phages exist, and alternative approaches are lacking in effectiveness, availability, safety, or cost effectiveness, etc. Phage development as antibacterial agents has been strongest particularly when antibiotics have been less available or useful, e.g., such as in the treatment of chronic infections by antibiotic-resistant bacteria. One relatively under-explored or at least not highly reported use of phages as therapeutic agents has been to combat bacterial infections of the lungs and associated tissues. These infections are diverse in terms of their etiologies, manifestations, and also in terms of potential strategies of phage delivery. Here I review the literature considering the phage therapy of pulmonary and pulmonary-related infections, with emphasis on reports of clinical treatment along with experimental treatment of pulmonary infections using animal models. PMID:26442188

  11. Phenotypic diversity within a Pseudomonas aeruginosa population infecting an adult with cystic fibrosis.

    PubMed

    Clark, Shawn T; Diaz Caballero, Julio; Cheang, Mary; Coburn, Bryan; Wang, Pauline W; Donaldson, Sylva L; Zhang, Yu; Liu, Mingyao; Keshavjee, Shaf; Yau, Yvonne C W; Waters, Valerie J; Elizabeth Tullis, D; Guttman, David S; Hwang, David M

    2015-01-01

    Chronic airway infections caused by Pseudomonas aeruginosa contribute to the progression of pulmonary disease in individuals with cystic fibrosis (CF). In the setting of CF, within-patient adaptation of a P. aeruginosa strain generates phenotypic diversity that can complicate microbiological analysis of patient samples. We investigated within- and between- sample diversity of 34 phenotypes among 235 P. aeruginosa isolates cultured from sputum samples collected from a single CF patient over the span of one year, and assessed colony morphology as a screening tool for predicting phenotypes, including antimicrobial susceptibilities. We identified 15 distinct colony morphotypes that varied significantly in abundance both within and between sputum samples. Substantial within sample phenotypic heterogeneity was also noted in other phenotypes, with morphotypes being unreliable predictors of antimicrobial susceptibility and other phenotypes. Emergence of isolates with reduced susceptibility to β-lactams was observed during periods of clinical therapy with aztreonam. Our findings confirm that the P. aeruginosa population in chronic CF lung infections is highly dynamic, and that intra-sample phenotypic diversity is underestimated if only one or few colonies are analyzed per sample. PMID:26047320

  12. Phenotypic diversity within a Pseudomonas aeruginosa population infecting an adult with cystic fibrosis

    PubMed Central

    Clark, Shawn T.; Diaz Caballero, Julio; Cheang, Mary; Coburn, Bryan; Wang, Pauline W.; Donaldson, Sylva L.; Zhang, Yu; Liu, Mingyao; Keshavjee, Shaf; Yau, Yvonne C.W.; Waters, Valerie J.; Elizabeth Tullis, D.; Guttman, David S.; Hwang, David M.

    2015-01-01

    Chronic airway infections caused by Pseudomonas aeruginosa contribute to the progression of pulmonary disease in individuals with cystic fibrosis (CF). In the setting of CF, within-patient adaptation of a P. aeruginosa strain generates phenotypic diversity that can complicate microbiological analysis of patient samples. We investigated within- and between- sample diversity of 34 phenotypes among 235 P. aeruginosa isolates cultured from sputum samples collected from a single CF patient over the span of one year, and assessed colony morphology as a screening tool for predicting phenotypes, including antimicrobial susceptibilities. We identified 15 distinct colony morphotypes that varied significantly in abundance both within and between sputum samples. Substantial within sample phenotypic heterogeneity was also noted in other phenotypes, with morphotypes being unreliable predictors of antimicrobial susceptibility and other phenotypes. Emergence of isolates with reduced susceptibility to β-lactams was observed during periods of clinical therapy with aztreonam. Our findings confirm that the P. aeruginosa population in chronic CF lung infections is highly dynamic, and that intra-sample phenotypic diversity is underestimated if only one or few colonies are analyzed per sample. PMID:26047320

  13. DIAGNOSIS OF PULMONARY COCCIDIOIDAL INFECTIONS

    PubMed Central

    Smith, Charles E.

    1951-01-01

    A wide variety of pulmonary lesions may be caused by coccidioidomycosis. Suspicion of coccidioidomycosis may be substantiated by careful clinical-epidemiological histories. The first laboratory procedure should be a coccidioidin skin test. If the reaction to the test is positive, serological tests are next. Also, if there is no reaction to coccidioidin, serological tests are still indicated if dissemination is suspected. The more severe the infection, the greater the probability of establishing a diagnosis serologically. In only three-fifths of patients with coccidioidal cavities can the diagnosis be fixed serologically. In such patients if differential skin tests are not conclusive, attempt should be made to recover the fungus. However, this is accompanied by great risk of laboratory infection. Eosinophilia and accelerated erythrocyte sedimentation are only circumstantial items of evidence, as is the appearance of the pulmonary roentgenogram. ImagesFigure 1. PMID:14886741

  14. Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients

    PubMed Central

    Al-Aloul, M; Crawley, J; Winstanley, C; Hart, C; Ledson, M; Walshaw, M

    2004-01-01

    Background: Chronic pulmonary infection with transmissible Pseudomonas aeruginosa strains in individuals with cystic fibrosis (CF) has been reported, raising issues of cross infection and patient segregation. The first such strain to be described (the Liverpool epidemic strain, LES) is now widespread in many UK CF centres. However, whether such infection carries a worse prognosis is unknown. To address this, the clinical course of a group of CF patients chronically infected by LES was compared with that in patients harbouring unique strains. Methods: Using P aeruginosa strain genotyping, two cohorts of CF patients attending the Liverpool CF service were identified who were LES positive or negative in 1998 and remained so until 2002. From these, two groups of 12 patients were matched in 1998 for age, spirometric parameters, and nutritional state and their clinical course was followed for 5 years. Patients chronically infected with Burkholderia cepacia were excluded. Results: Patients chronically infected with LES had a greater annual loss of lung function than those not chronically infected by LES (mean difference between groups -4.4% (95% CI -8.1 to -0.9; p<0.02)), and by 2002 their percentage predicted forced expiratory volume in 1 second (FEV1) was worse (mean 65.0% v 82.6%, p<0.03). Their nutritional state also deteriorated over the study period (mean difference between groups in body mass index -0.7 (95% CI -1.2 to -0.2; p<0.01)), such that by 2002 they were malnourished compared with LES negative patients (mean BMI 19.4 v 22.7, p<0.02). Conclusions: Chronic infection with the Liverpool epidemic P aeruginosa strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods. PMID:15047956

  15. Novel Strategies for the Treatment of Pseudomonas aeruginosa Infections.

    PubMed

    Wagner, Stefanie; Sommer, Roman; Hinsberger, Stefan; Lu, Cenbin; Hartmann, Rolf W; Empting, Martin; Titz, Alexander

    2016-07-14

    Infections with Pseudomonas aeruginosa have become a concerning threat in hospital-acquired infections and for cystic fibrosis patients. The major problem leading to high mortality lies in the appearance of drug-resistant strains. Therefore, a vast number of approaches to develop novel anti-infectives is currently pursued. These diverse strategies span from killing (new antibiotics) to disarming (antivirulence) the pathogen. Particular emphasis lies on the development of compounds that inhibit biofilms formed in chronic infections to restore susceptibility toward antibiotics. Numerous promising results are summarized in this perspective. Antibiotics with a novel mode of action will be needed to avoid cross resistance against currently used therapeutic agents. Importantly, antivirulence drugs are expected to yield a significantly reduced rate of resistance development. Most developments are still far from the application. It can however be expected that combination therapies, also containing antivirulence agents, will pave the way toward novel treatment options against P. aeruginosa. PMID:26804741

  16. More than 10 years' continuous oral treatment with specific immunoglobulin Y for the prevention of Pseudomonas aeruginosa infections: a case report.

    PubMed

    Nilsson, Elin; Kollberg, Hans; Johannesson, Marie; Wejåker, Per-Erik; Carlander, David; Larsson, Anders

    2007-06-01

    Immunotherapy with specific antibodies is an alternative to antibiotics for the prevention of infections in humans and animals. We have used orally administered immunoglobulin Y (IgY) preparations, purified from eggs of hens immunized with Pseudomonas aeruginosa bacteria, to prevent pulmonary P. aeruginosa infections in a group of patients with cystic fibrosis (CF). Respiratory infections are major problems for CF patients because of the thick mucus in the airways, and chronic P. aeruginosa lung infections occur in virtually all CF patients and cause morbidity and mortality. The IgY-treated group had only 2.5 P. aeruginosa-positive sputum cultures per 100 months, and none of the IgY-treated patients became chronically colonized with P. aeruginosa. In the control group, 13.7 of the cultures per 100 months were positive for P. aeruginosa, and 24% of patients became chronically colonized with P. aeruginosa. The first enrolled patient in this study has now been treated continuously for more than 10 years. During the first 8 years she only had four P. aeruginosa-positive cultures. After 8 years she became chronically infected, but still after 10 years the bacteria have not turned mucoid. No negative side effects of IgY treatment have been noted during these 10 years. To our knowledge this is the longest treatment with specific yolk antibodies for therapeutic purposes. PMID:17651078

  17. Pseudomonas aeruginosa infection mimicking erythema annulare centrifugum.

    PubMed

    Czechowicz, R T; Warren, L J; Moore, L; Saxon, B

    2001-02-01

    A 3-year-old girl receiving chemotherapy for acute lymphocytic leukaemia developed a rapidly expanding red annular plaque on her thigh, initially without signs of systemic toxicity or local pain. Subsequently she developed Pseudomonas aeruginosa sepsis and purpura at the leading edge of the plaque. Skin biopsy showed an extensive necrotizing vasculitis with numerous Gram-negative bacilli in the blood vessel walls. In immunocompromised individuals, skin biopsy and culture of cutaneous lesions for bacteria and fungi should be considered even in the absence of signs of systemic toxicity or multiple lesions. PMID:11233725

  18. Pulmonary Strongyloides stercoralis infection

    PubMed Central

    Dogan, Canan; Gayaf, Mine; Ozsoz, Ayse; Sahin, Birsen; Aksel, Nimet; Karasu, Isil; Aydogdu, Zekiye; Turgay, Nevin

    2014-01-01

    The 17-year-old male patient presented with fever, weakness, dyspnea and weight loss. His chest radiography demonstrated diffuse reticulonodular density, and high-resolution lung tomography indicated diffuse micronodules and prevalent ground-glass pattern. The findings were consistent with miliary involvement. The patient underwent examinations for rheumatology, immunology, cytology and infectious conditions. His immune system was normal and had no comorbidities or any history of immunosuppressive treatment. Strongyloides stercoralis larvae were noted upon direct inspection of the feces. Clinical and radiological improvement was achieved with albendazole 400 mg/day. This case is being presented since miliary involvement in the lungs caused by S. stercoralis infection in an individual with intact immune system is rare and difficult to diagnosis. PMID:26029521

  19. Impaired Pulmonary Defense Against Pseudomonas aeruginosa in VEGF Gene Inactivated Mouse Lung

    PubMed Central

    Breen, Ellen C.; Malloy, Jaret L.; Tang, Kechun; Xia, Feng; Fu, Zhenxing; Hancock, Robert E. W.; Overhage, Joerg; Wagner, Peter D.; Spragg, Roger G.

    2012-01-01

    Repeated bacterial and viral infections are known to contribute to worsening lung function in several respiratory diseases, including asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD). Previous studies have reported alveolar wall cell apoptosis and parenchymal damage in adult pulmonary VEGF gene ablated mice. We hypothesized that VEGF expressed by type II cells is also necessary to provide an effective host defense against bacteria in part by maintaining surfactant homeostasis. Therefore, Pseudomonas aeruginosa (PAO1) levels were evaluated in mice following lung-targeted VEGF gene inactivation, and alterations in VEGF-dependent type II cell function were evaluated by measuring surfactant homeostasis in mouse lungs and isolated type II cells. In VEGF-deficient lungs increased PAO1 levels and pro-inflammatory cytokines, TNFα and IL-6, were detected 24 hours after bacterial instillation compared to control lungs. In vivo lung-targeted VEGF gene deletion (57% decrease in total pulmonary VEGF) did not alter alveolar surfactant or tissue disaturated phosphatidylcholine (DSPC) levels. However, sphingomyelin content, choline phosphate cytidylyltransferase (CCT) mRNA and SP-D expression were decreased. In isolated type II cells an 80% reduction of VEGF protein resulted in decreases in total phospholipids (PL), DSPC, DSPC synthesis, surfactant associated proteins (SP)-B and -D, and the lipid transporters, ABCA1 and Rab3D. TPA-induced DSPC secretion and apoptosis were elevated in VEGF-deficient type II cells. These results suggest a potential protective role for type II cell-expressed VEGF against bacterial initiated infection. PMID:22718316

  20. Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection

    PubMed Central

    Zou, Cheng-Gang; Ma, Yi-Cheng; Dai, Li-Li; Zhang, Ke-Qin

    2014-01-01

    Autophagy, a conserved pathway that delivers intracellular materials into lysosomes for degradation, is involved in development, aging, and a variety of diseases. Accumulating evidence demonstrates that autophagy plays a protective role against infectious diseases by diminishing intracellular pathogens, including bacteria, viruses, and parasites. However, the mechanism by which autophagy regulates innate immunity remains largely unknown. Here, we show that autophagy is involved in host defense against a pathogenic bacterium Pseudomonas aeruginosa in the metazoan Caenorhabditis elegans. P. aeruginosa infection induces autophagy via a conserved extracellular signal-regulated kinase (ERK). Intriguingly, impairment of autophagy does not influence the intestinal accumulation of P. aeruginosa, but instead induces intestinal necrosis. Inhibition of necrosis results in the survival of autophagy-deficient worms after P. aeruginosa infection. These findings reveal a previously unidentified role for autophagy in protection against necrosis triggered by pathogenic bacteria in C. elegans and implicate that such a function of autophagy may be conserved through the inflammatory response in diverse organisms. PMID:25114220

  1. Genotypic analysis of Pseudomonas aeruginosa isolated from ocular infection.

    PubMed

    Yamaguchi, Satoshi; Suzuki, Takashi; Kobayashi, Takeshi; Oka, Naoko; Ishikawa, Eri; Shinomiya, Hiroto; Ohashi, Yuichi

    2014-07-01

    Pseudomonas aeruginosa is the causative pathogen of keratitis, conjunctivitis, and dacryocystitis. However little is known about their clinical epidemiology in Japan. In this study we investigated the genotypic characterization and serotype of P. aeruginosa isolates from ocular infections. Thirty-four clinical P. aeruginosa isolates were characterized according to infection type, the type III secretion system (TTSS), serotype, and multilocus sequence typing (MLST). We divided the isolates into four clinical infection types as follows: Contact lens (CL)-related keratitis (CL-keratitis; 15 isolates), non CL-related keratitis (non CL-keratitis; 8 isolates), conjunctivitis (7 isolates), and dacryocystitis (4 isolates). Regarding the TTSS classification and serotyping classification, no significant differences were found among the infection types. Two clusters (I, II) and three subclusters (A, B, C) were classified according to MLST. CL-keratitis isolates with exoU positivity were clustered in II-B, and conjunctivitis was clustered in cluster I. Some linkage was found between the genetic background and CL-keratitis or conjunctivitis. PMID:24746897

  2. Protection against Pseudomonas aeruginosa Chronic Lung Infection in Mice by Genetic Immunization against Outer Membrane Protein F (OprF) of P. aeruginosa

    PubMed Central

    Price, Brian M.; Galloway, Darrell R.; Baker, Neil R.; Gilleland, Linda B.; Staczek, John; Gilleland, Harry E.

    2001-01-01

    The Pseudomonas aeruginosa major constitutive outer membrane porin protein OprF, which has previously been shown to be a protective antigen, was targeted as a DNA vaccine candidate. The oprF gene was cloned into plasmid vector pVR1020, and the plasmid vaccines were delivered to mice by biolistic (gene gun) intradermal inoculation. Antibody titers in antisera from immunized mice were determined by enzyme-linked immunosorbent assay, and the elicited antibodies were shown to be specifically reactive to OprF by immunoblotting. The immunoglobulin G (IgG) immune response was predominantly of the IgG1 isotype. Sera from DNA vaccine-immunized mice had significantly greater opsonic activity in opsonophagocytic assays than did sera from control mice. Following the initial immunization and two consecutive boosts, each at 2-week intervals, protection was demonstrated in a mouse model of chronic pulmonary infection by P. aeruginosa. Eight days postchallenge, both lungs were removed and examined. A significant reduction in the presence of severe macroscopic lesions, as well as in the number of bacteria present in the lungs, was seen. Based on these findings, genetic immunization with oprF has potential for development as a vaccine to protect humans against infection by P. aeruginosa. PMID:11292786

  3. Pseudomonas aeruginosa forms Biofilms in Acute InfectionIndependent of Cell-to-Cell Signaling

    SciTech Connect

    Schaber, J. Andy; Triffo, W.J.; Suh, Sang J.; Oliver, Jeffrey W.; Hastert, Mary C.; Griswold, John A.; Auer, Manfred; Hamood, Abdul N.; Rumbaugh, Kendra P.

    2006-09-20

    Biofilms are bacterial communities residing within a polysaccharide matrix that are associated with persistence and antibiotic resistance in chronic infections. We show that the opportunistic pathogen Pseudomonas aeruginosa forms biofilms within 8 hours of infection in thermally-injured mice, demonstrating that biofilms contribute to bacterial colonization in acute infections. P. aeruginosa biofilms were visualized within burned tissue surrounding blood vessels and adipose cells. Although quorum sensing (QS), a bacterial signaling mechanism, coordinates differentiation of biofilms in vitro, wild type and QS-deficient P. aeruginosa formed similar biofilms in vivo. Our findings demonstrate that P. aeruginosa forms biofilms on specific host tissues independent of QS.

  4. Lung Microbiota Changes Associated with Chronic Pseudomonas aeruginosa Lung Infection and the Impact of Intravenous Colistimethate Sodium

    PubMed Central

    Collie, David; Glendinning, Laura; Govan, John; Wright, Steven; Thornton, Elisabeth; Tennant, Peter; Doherty, Catherine; McLachlan, Gerry

    2015-01-01

    Background Exacerbations associated with chronic lung infection with Pseudomonas aeruginosa are a major contributor to morbidity, mortality and premature death in cystic fibrosis. Such exacerbations are treated with antibiotics, which generally lead to an improvement in lung function and reduced sputum P. aeruginosa density. This potentially suggests a role for the latter in the pathogenesis of exacerbations. However, other data suggesting that changes in P. aeruginosa sputum culture status may not reliably predict an improvement in clinical status, and data indicating no significant changes in either total bacterial counts or in P. aeruginosa numbers in sputum samples collected prior to pulmonary exacerbation sheds doubt on this assumption. We used our recently developed lung segmental model of chronic Pseudomonas infection in sheep to investigate the lung microbiota changes associated with chronic P. aeruginosa lung infection and the impact of systemic therapy with colistimethate sodium (CMS). Methodology/Principal Findings We collected protected specimen brush (PSB) samples from sheep (n = 8) both prior to and 14 days after establishment of chronic local lung infection with P aeruginosa. Samples were taken from both directly infected lung segments (direct) and segments spatially remote to such sites (remote). Four sheep were treated with daily intravenous injections of CMS between days 7 and 14, and four were treated with a placebo. Necropsy examination at d14 confirmed the presence of chronic local lung infection and lung pathology in every direct lung segment. The predominant orders in lung microbiota communities before infection were Bacillales, Actinomycetales and Clostridiales. While lung microbiota samples were more likely to share similarities with other samples derived from the same lung, considerable within- and between-animal heterogeneity could be appreciated. Pseudomonadales joined the aforementioned list of predominant orders in lung microbiota

  5. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

    PubMed Central

    Chai, S.D.; Liu, T.; Dong, M.F.; Li, Z.K.; Tang, P.Z.; Wang, J.T.; Ma, S.J.

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  6. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling.

    PubMed

    Chai, S D; Liu, T; Dong, M F; Li, Z K; Tang, P Z; Wang, J T; Ma, S J

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  7. Cystic fibrosis-niche adaptation of Pseudomonas aeruginosa reduces virulence in multiple infection hosts.

    PubMed

    Lorè, Nicola Ivan; Cigana, Cristina; De Fino, Ida; Riva, Camilla; Juhas, Mario; Schwager, Stephan; Eberl, Leo; Bragonzi, Alessandra

    2012-01-01

    The opportunistic pathogen Pseudomonas aeruginosa is able to thrive in diverse ecological niches and to cause serious human infection. P. aeruginosa environmental strains are producing various virulence factors that are required for establishing acute infections in several host organisms; however, the P. aeruginosa phenotypic variants favour long-term persistence in the cystic fibrosis (CF) airways. Whether P. aeruginosa strains, which have adapted to the CF-niche, have lost their competitive fitness in the other environment remains to be investigated. In this paper, three P. aeruginosa clonal lineages, including early strains isolated at the onset of infection, and late strains, isolated after several years of chronic lung infection from patients with CF, were analysed in multi-host model systems of acute infection. P. aeruginosa early isolates caused lethality in the three non-mammalian hosts, namely Caenorhabditis elegans, Galleria mellonella, and Drosophila melanogaster, while late adapted clonal isolates were attenuated in acute virulence. When two different mouse genetic background strains, namely C57Bl/6NCrl and Balb/cAnNCrl, were used as acute infection models, early P. aeruginosa CF isolates were lethal, while late isolates exhibited reduced or abolished acute virulence. Severe histopathological lesions, including high leukocytes recruitment and bacterial load, were detected in the lungs of mice infected with P. aeruginosa CF early isolates, while late isolates were progressively cleared. In addition, systemic bacterial spread and invasion of epithelial cells, which were detected for P. aeruginosa CF early strains, were not observed with late strains. Our findings indicate that niche-specific selection in P. aeruginosa reduced its ability to cause acute infections across a broad range of hosts while maintaining the capacity for chronic infection in the CF host. PMID:22558188

  8. Cystic Fibrosis-Niche Adaptation of Pseudomonas aeruginosa Reduces Virulence in Multiple Infection Hosts

    PubMed Central

    De Fino, Ida; Riva, Camilla; Juhas, Mario; Schwager, Stephan; Eberl, Leo; Bragonzi, Alessandra

    2012-01-01

    The opportunistic pathogen Pseudomonas aeruginosa is able to thrive in diverse ecological niches and to cause serious human infection. P. aeruginosa environmental strains are producing various virulence factors that are required for establishing acute infections in several host organisms; however, the P. aeruginosa phenotypic variants favour long-term persistence in the cystic fibrosis (CF) airways. Whether P. aeruginosa strains, which have adapted to the CF-niche, have lost their competitive fitness in the other environment remains to be investigated. In this paper, three P. aeruginosa clonal lineages, including early strains isolated at the onset of infection, and late strains, isolated after several years of chronic lung infection from patients with CF, were analysed in multi-host model systems of acute infection. P. aeruginosa early isolates caused lethality in the three non-mammalian hosts, namely Caenorhabditis elegans, Galleria mellonella, and Drosophila melanogaster, while late adapted clonal isolates were attenuated in acute virulence. When two different mouse genetic background strains, namely C57Bl/6NCrl and Balb/cAnNCrl, were used as acute infection models, early P. aeruginosa CF isolates were lethal, while late isolates exhibited reduced or abolished acute virulence. Severe histopathological lesions, including high leukocytes recruitment and bacterial load, were detected in the lungs of mice infected with P. aeruginosa CF early isolates, while late isolates were progressively cleared. In addition, systemic bacterial spread and invasion of epithelial cells, which were detected for P. aeruginosa CF early strains, were not observed with late strains. Our findings indicate that niche-specific selection in P. aeruginosa reduced its ability to cause acute infections across a broad range of hosts while maintaining the capacity for chronic infection in the CF host. PMID:22558188

  9. Pulmonary Fungal Infection Caused by Neoscytalidium dimidiatum

    PubMed Central

    Neff, Luke; Lee, Samuel A.; Sutton, Deanna A.; Wiederhold, Nathan P.; Lindner, Jonathan; Fan, Hongxin

    2015-01-01

    Neoscytalidium dimidiatum is a mold known to cause onychomycosis and dermatomycosis; however, it is an extremely rare cause of systemic infection. We report a case of pulmonary infection with Neoscytalidium dimidiatum in an immunocompromised patient and discuss in vitro susceptibility data from this case and previous literature. PMID:25948605

  10. Pulmonary Fungal Infection Caused by Neoscytalidium dimidiatum.

    PubMed

    Dionne, Brandon; Neff, Luke; Lee, Samuel A; Sutton, Deanna A; Wiederhold, Nathan P; Lindner, Jonathan; Fan, Hongxin; Jakeman, Bernadette

    2015-07-01

    Neoscytalidium dimidiatum is a mold known to cause onychomycosis and dermatomycosis; however, it is an extremely rare cause of systemic infection. We report a case of pulmonary infection with Neoscytalidium dimidiatum in an immunocompromised patient and discuss in vitro susceptibility data from this case and previous literature. PMID:25948605

  11. Pseudomonas aeruginosa Dose-Response and Bathing Water Infection

    EPA Science Inventory

    Pseudomonas aeruginosa is the most commonly identified opportunistic pathogen associated with pool acquired bather disease. To better understand why this microorganism poses this protracted problem we recently appraised P. aeruginosa pool risk management. Much is known about the ...

  12. Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections.

    PubMed

    Cornelis, Pierre; Dingemans, Jozef

    2013-01-01

    Pseudomonas aeruginosa is a Gram-negative γ-Proteobacterium which is known for its capacity to colonize various niches, including some invertebrate and vertebrate hosts, making it one of the most frequent bacteria causing opportunistic infections. P. aeruginosa is able to cause acute as well as chronic infections and it uses different colonization and virulence factors to do so. Infections range from septicemia, urinary infections, burn wound colonization, and chronic colonization of the lungs of cystic fibrosis patients. Like the vast majority of organisms, P. aeruginosa needs iron to sustain growth. P. aeruginosa utilizes different strategies to take up iron, depending on the type of infection it causes. Two siderophores are produced by this bacterium, pyoverdine and pyochelin, characterized by high and low affinities for iron respectively. P. aeruginosa is also able to utilize different siderophores from other microorganisms (siderophore piracy). It can also take up heme from hemoproteins via two different systems. Under microaerobic or anaerobic conditions, P. aeruginosa is also able to take up ferrous iron via its Feo system using redox-cycling phenazines. Depending on the type of infection, P. aeruginosa can therefore adapt by switching from one iron uptake system to another as we will describe in this short review. PMID:24294593

  13. Pseudomonas aeruginosa infection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches.

    PubMed

    Lund-Palau, Helena; Turnbull, Andrew R; Bush, Andrew; Bardin, Emmanuelle; Cameron, Loren; Soren, Odel; Wierre-Gore, Natasha; Alton, Eric W F W; Bundy, Jacob G; Connett, Gary; Faust, Saul N; Filloux, Alain; Freemont, Paul; Jones, Andy; Khoo, Valerie; Morales, Sandra; Murphy, Ronan; Pabary, Rishi; Simbo, Ameze; Schelenz, Silke; Takats, Zoltan; Webb, Jeremy; Williams, Huw D; Davies, Jane C

    2016-06-01

    Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development. PMID:27175979

  14. Pulmonary embolism and acute cytomegalovirus infection in an immunocompetent patient.

    PubMed

    Del Borgo, Cosmo; Gianfreda, Romina; Belvisi, Valeria; Citton, Rita; Soscia, Fabrizio; Notarianni, Ermanno; Tieghi, Tiziana; Mastroianni, Claudio Maria

    2010-12-01

    A case of an immunocompetent man with acute CMV infection associated with a pulmonary embolism is described. Acute CMV infection could be a risk factor for developing thromboembolism. Pulmonary embolism should be included in differential diagnosis in patients with acute CMV infections and pulmonary opacities. PMID:21196823

  15. [Pulmonary non invasive infection by Scedosporium apiospermum].

    PubMed

    Cruz, Rodrigo; Barros, Manuel; Reyes, Mirtha

    2015-08-01

    We reported a case of non-invasive pulmonary infection by Scedosporium apiospermum in 67 years old female with bronchiectasis and caverns secondary to tuberculosis. Diagnosis was made with lung CT and bronchial lavage cultures. The patient was initially treated with itraconazole for six weeks without success and then voriconazole for 16 weeks, with good clinical response. PMID:26436797

  16. Distinct Pathogenesis and Host Responses during Infection of C. elegans by P. aeruginosa and S. aureus

    PubMed Central

    Irazoqui, Javier E.; Troemel, Emily R.; Feinbaum, Rhonda L.; Luhachack, Lyly G.; Cezairliyan, Brent O.; Ausubel, Frederick M.

    2010-01-01

    The genetically tractable model host Caenorhabditis elegans provides a valuable tool to dissect host-microbe interactions in vivo. Pseudomonas aeruginosa and Staphylococcus aureus utilize virulence factors involved in human disease to infect and kill C. elegans. Despite much progress, virtually nothing is known regarding the cytopathology of infection and the proximate causes of nematode death. Using light and electron microscopy, we found that P. aeruginosa infection entails intestinal distention, accumulation of an unidentified extracellular matrix and P. aeruginosa-synthesized outer membrane vesicles in the gut lumen and on the apical surface of intestinal cells, the appearance of abnormal autophagosomes inside intestinal cells, and P. aeruginosa intracellular invasion of C. elegans. Importantly, heat-killed P. aeruginosa fails to elicit a significant host response, suggesting that the C. elegans response to P. aeruginosa is activated either by heat-labile signals or pathogen-induced damage. In contrast, S. aureus infection causes enterocyte effacement, intestinal epithelium destruction, and complete degradation of internal organs. S. aureus activates a strong transcriptional response in C. elegans intestinal epithelial cells, which aids host survival during infection and shares elements with human innate responses. The C. elegans genes induced in response to S. aureus are mostly distinct from those induced by P. aeruginosa. In contrast to P. aeruginosa, heat-killed S. aureus activates a similar response as live S. aureus, which appears to be independent of the single C. elegans Toll-Like Receptor (TLR) protein. These data suggest that the host response to S. aureus is possibly mediated by pathogen-associated molecular patterns (PAMPs). Because our data suggest that neither the P. aeruginosa nor the S. aureus–triggered response requires canonical TLR signaling, they imply the existence of unidentified mechanisms for pathogen detection in C. elegans, with

  17. [Septic pulmonary emboli caused by parenteral nutrition catheter infection].

    PubMed

    Kuwabara, M; Itoi, K; Ariyasu, T; Yanagihara, K; Nasu, T

    1990-09-01

    A case of septic pulmonary emboli due to parenteral nutrition catheter infection was reported. Characteristic radiologic features were recognized. A 50-year-old man, who was receiving parenteral nutrition after total gastrectomy, consulted our department with complaints of fever and general malaise. A chest radiograph showed scattered ill-defined small peripheral nodules, which were not present before parenteral nutrition, and these nodules were quickly formed cavities + in 2nd day. He was suffering from high fever, hemo-sputum and dyspnea after removal of the parenteral nutrition catheter. Pseudomonas aeruginosa was isolated from the tip of parenteral nutrition catheter and sputum cultures. Septic pulmonary emboli were diagnosed and antibiotic therapy was performed. Bacterial endocarditis and septic thrombophlebitis were ruled out. The multiple cavity nodules extended to involve the peripheral areas of the lung and invasive shadows appeared on the chest radiograph in 8th day. Then, the invasive shadows disappeared and the walls of the cavitary lesions became thinner. After 2 months, all cavitary lesions disappeared with only linear shadows remaining. PMID:2125088

  18. Pseudomonas aeruginosa uses multiple pathways to acquire iron during chronic infection in cystic fibrosis lungs.

    PubMed

    Konings, Anna F; Martin, Lois W; Sharples, Katrina J; Roddam, Louise F; Latham, Roger; Reid, David W; Lamont, Iain L

    2013-08-01

    Pseudomonas aeruginosa chronically infects the lungs of more than 80% of adult patients with cystic fibrosis (CF) and is a major contributor to the progression of disease pathology. P. aeruginosa requires iron for growth and has multiple iron uptake systems that have been studied in bacteria grown in laboratory culture. The purpose of this research was to determine which of these are active during infection in CF. RNA was extracted from 149 sputum samples obtained from 23 CF patients. Reverse transcription-quantitative real-time PCR (RT-qPCR) was used to measure the expression of P. aeruginosa genes encoding transport systems for the siderophores pyoverdine and pyochelin, for heme, and for ferrous ions. Expression of P. aeruginosa genes could be quantified in 89% of the sputum samples. Expression of genes associated with siderophore-mediated iron uptake was detected in most samples but was at low levels in some samples, indicating that other iron uptake mechanisms are active. Expression of genes encoding heme transport systems was also detected in most samples, indicating that heme uptake occurs during infection in CF. feoB expression was detected in all sputum samples, implying an important role for ferrous ion uptake by P. aeruginosa in CF. Our data show that multiple P. aeruginosa iron uptake mechanisms are active in chronic CF infection and that RT-qPCR of RNA extracted from sputum provides a powerful tool for investigating bacterial physiology during infection in CF. PMID:23690396

  19. PcrV antibody-antibiotic combination improves survival in Pseudomonas aeruginosa-infected mice.

    PubMed

    Song, Y; Baer, M; Srinivasan, R; Lima, J; Yarranton, G; Bebbington, C; Lynch, S V

    2012-08-01

    The type III secretion system (TTSS) of Pseudomonas aeruginosa, associated with acute infection, facilitates the direct injection of cytotoxins into the host cell cytoplasm. Mab166, a murine monoclonal antibody against PcrV, a protein located at the tip of the injectisome, has demonstrated efficacy against P. aeruginosa infection, resulting in reduced lung injury and increased survival in murine models of infection. We hypothesised that the administration of Mab166 in combination with an antibiotic would further improve the survival of P. aeruginosa-infected mice. A murine model of P. aeruginosa acute infection, three clinically relevant antibiotics (ciprofloxacin, tobramycin and ceftazidime) and the Mab166 antibody were used for this study. Consistently, compared to other treatment groups (antibiotic or antibody administered in isolation), the combination of Mab166 and antibiotic significantly improved the survival of mice infected with three times the lethal dose (LD(90)) of the highly cytotoxic ExoU-secreting strain, PA103. This synergistic effect was primarily due to enhanced bactericidal effect and protection against lung injury, which prevented bacterial dissemination to other organs. Hence, the combination of Mab166 with antibiotic administration provides a new, more effective strategy against P. aeruginosa airway infection, especially when large numbers of highly virulent strains are present. PMID:22187351

  20. IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa.

    PubMed

    Lorè, Nicola Ivan; Cigana, Cristina; Riva, Camilla; De Fino, Ida; Nonis, Alessandro; Spagnuolo, Lorenza; Sipione, Barbara; Cariani, Lisa; Girelli, Daniela; Rossi, Giacomo; Basso, Veronica; Colombo, Carla; Mondino, Anna; Bragonzi, Alessandra

    2016-01-01

    Resistance and tolerance mechanisms participate to the interplay between host and pathogens. IL-17-mediated response has been shown to be crucial for host resistance to respiratory infections, whereas its role in host tolerance during chronic airway colonization is still unclear. Here, we investigated whether IL-17-mediated response modulates mechanisms of host tolerance during airways chronic infection by P. aeruginosa. First, we found that IL-17A levels were sustained in mice at both early and advanced stages of P. aeruginosa chronic infection and confirmed these observations in human respiratory samples from cystic fibrosis patients infected by P. aeruginosa. Using IL-17a(-/-) or IL-17ra(-/-) mice, we found that the deficiency of IL-17A/IL-17RA axis was associated with: i) increased incidence of chronic infection and bacterial burden, indicating its role in the host resistance to P. aeruginosa; ii) reduced cytokine levels (KC), tissue innate immune cells and markers of tissue damage (pro-MMP-9, elastin degradation, TGF-β1), proving alteration of host tolerance. Blockade of IL-17A activity by a monoclonal antibody, started when chronic infection is established, did not alter host resistance but increased tolerance. In conclusion, this study identifies IL-17-mediated response as a negative regulator of host tolerance during P. aeruginosa chronic airway infection. PMID:27189736

  1. IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa

    PubMed Central

    Lorè, Nicola Ivan; Cigana, Cristina; Riva, Camilla; De Fino, Ida; Nonis, Alessandro; Spagnuolo, Lorenza; Sipione, Barbara; Cariani, Lisa; Girelli, Daniela; Rossi, Giacomo; Basso, Veronica; Colombo, Carla; Mondino, Anna; Bragonzi, Alessandra

    2016-01-01

    Resistance and tolerance mechanisms participate to the interplay between host and pathogens. IL-17-mediated response has been shown to be crucial for host resistance to respiratory infections, whereas its role in host tolerance during chronic airway colonization is still unclear. Here, we investigated whether IL-17-mediated response modulates mechanisms of host tolerance during airways chronic infection by P. aeruginosa. First, we found that IL-17A levels were sustained in mice at both early and advanced stages of P. aeruginosa chronic infection and confirmed these observations in human respiratory samples from cystic fibrosis patients infected by P. aeruginosa. Using IL-17a−/− or IL-17ra−/− mice, we found that the deficiency of IL-17A/IL-17RA axis was associated with: i) increased incidence of chronic infection and bacterial burden, indicating its role in the host resistance to P. aeruginosa; ii) reduced cytokine levels (KC), tissue innate immune cells and markers of tissue damage (pro-MMP-9, elastin degradation, TGF-β1), proving alteration of host tolerance. Blockade of IL-17A activity by a monoclonal antibody, started when chronic infection is established, did not alter host resistance but increased tolerance. In conclusion, this study identifies IL-17-mediated response as a negative regulator of host tolerance during P. aeruginosa chronic airway infection. PMID:27189736

  2. Treatment of Pseudomonas aeruginosa-infected orthopedic prostheses with ceftazidime-ciprofloxacin antibiotic combination.

    PubMed

    Brouqui, P; Rousseau, M C; Stein, A; Drancourt, M; Raoult, D

    1995-11-01

    Indwelling device infections are associated with considerable morbidity and extremely high cost. Pseudomonas aeruginosa is the most frequent gram-negative etiologic agent associated with infections of indwelling catheters and foreign body implants. It is generally agreed that eradication of infection in the presence of a foreign body requires removal of the foreign body. Using a combination of ceftazidime and ciprofloxacin, we cured nine of nine patients with P. aeruginosa-infected osteosynthetic material and four of five patients with hip and knee prostheses without removing the foreign material. Follow-up was for a mean of 21 months (range, 6 to 60 months). Some patients experienced minor side effects (arthralgia in one patient and rash in another patient). We conclude that this combination is effective and safe and should be useful in the treatment of P. aeruginosa-infected orthopedic implants. PMID:8585720

  3. Affecting Pseudomonas aeruginosa Phenotypic Plasticity by Quorum Sensing Dysregulation Hampers Pathogenicity in Murine Chronic Lung Infection

    PubMed Central

    Bondí, Roslen; Messina, Marco; De Fino, Ida; Bragonzi, Alessandra; Rampioni, Giordano; Leoni, Livia

    2014-01-01

    In Pseudomonas aeruginosa quorum sensing (QS) activates the production of virulence factors, playing a critical role in pathogenesis. Multiple negative regulators modulate the timing and the extent of the QS response either in the pre-quorum or post-quorum phases of growth. This regulation likely increases P. aeruginosa phenotypic plasticity and population fitness, facilitating colonization of challenging environments such as higher organisms. Accordingly, in addition to the factors required for QS signals synthesis and response, also QS regulators have been proposed as targets for anti-virulence therapies. However, while it is known that P. aeruginosa mutants impaired in QS are attenuated in their pathogenic potential, the effect of mutations causing a dysregulated timing and/or magnitude of the QS response has been poorly investigated so far in animal models of infection. In order to investigate the impact of QS dysregulation on P. aeruginosa pathogenesis in a murine model of lung infection, the QteE and RsaL proteins have been selected as representatives of negative regulators controlling P. aeruginosa QS in the pre- and post-quorum periods, respectively. Results showed that the qteE mutation does not affect P. aeruginosa lethality and ability to establish chronic infection in mice, despite causing a premature QS response and enhanced virulence factors production in test tube cultures compared to the wild type. Conversely, the post-quorum dysregulation caused by the rsaL mutation hampers the establishment of P. aeruginosa chronic lung infection in mice without affecting the mortality rate. On the whole, this study contributes to a better understanding of the impact of QS regulation on P. aeruginosa phenotypic plasticity during the infection process. Possible fallouts of these findings in the anti-virulence therapy field are also discussed. PMID:25420086

  4. Influence of carbapenem resistance on mortality of patients with Pseudomonas aeruginosa infection: a meta-analysis

    PubMed Central

    Liu, Qianqian; Li, Xiaoqing; Li, Wenzhang; Du, Xinmiao; He, Jian-Qing; Tao, Chuanmin; Feng, Yulin

    2015-01-01

    Treatment of infectious diseases caused by the carbapenem-resistant Pseudomonas aeruginosa (CRPA) is becoming more challenging with each passing year. We conducted a meta-analysis to assess the impact of carbapenem resistance on mortality of patients with P. aeruginosa infection. We searched PUBMED, Web of science, EMBASE, Google Scholar and the Cochrane Library up to December 25, 2014, to identify published cohort or case-control studies. 17 studies, including 6660 patients carrying P. aeruginosa, were identified. The pooling analysis indicated that patients infected with CRPA had significantly higher mortality than those infected with carbapenem-susceptible P. aeruginosa (CSPA) (crude OR = 1.64; 95%CI = 1.40, 1.93; adjusted OR = 2.38; 95%CI = 1.53, 3.69). The elevated risk of mortality in patients with CRPA infection was not lessened when stratified by study design, sites of infection, or type of carbapenem, except that the estimate effect vanished in CRPA high-incidence region, South America (crude OR = 1.12; 95%CI = 0.64, 1.99). Begg’s (z = 0.95, p = 0.34) and Egger’s test (t = 1.23, p = 0.24) showed no evidence of publication bias. Our results suggest that carbapenem resistance may increase the mortality of patients with P. aeruginosa infection, whether under univariate or multivariate analysis. PMID:26108476

  5. Tobramycin Inhalation Powder (TIP): An Efficient Treatment Strategy for the Management of Chronic Pseudomonas Aeruginosa Infection in Cystic Fibrosis

    PubMed Central

    Lam, John; Vaughan, Steven; Parkins, Michael D.

    2013-01-01

    Repeated bouts of acute and chronic lung infections are responsible for progressive pulmonary function decline in individuals with cystic fibrosis (CF), ultimately leading to respiratory failure and death. Pseudomonas aeruginosa is the archetypical CF pathogen, causes chronic infection in 70% of individuals, and is associated with an accelerated clinical decline. The management of P. aeruginosa in CF has been revolutionized with the development and widespread use of inhaled antibiotics. Aerosol delivery of antimicrobial compounds in CF enables extremely high concentrations of antibiotics to be reached directly at the site of infection potentially overcoming adaptive resistance and avoiding the potential for cumulative systemic toxicities. Tobramycin inhalation powder (TIP) represents the first dry powder inhaled (DPI) antibiotic available for use in CF. DPIs are notable for a markedly reduced time for administration, ease of portability, and increased compliance. TIP has been developed as a therapeutic alternative to tobramycin inhalation solution (TIS), the standard of care for the past 20 years within CF. Relative to TIS 300 mg nebulized twice daily in on-and-off cycles of 28 days duration, TIP 112 mg twice daily via the T-326 inhaler administered on the same schedule is associated with marked time savings, increased patient satisfaction, and comparable clinical end points. TIP represents an innovative treatment strategy for those individuals with CF and holds the promise of increased patient compliance and thus the potential for improved clinical outcomes. PMID:24324354

  6. [Pulmonary fungal infection in patients with AIDS].

    PubMed

    Denis, B; Lortholary, O

    2013-10-01

    Fungal infections are the most common opportunistic infections (OI) occurring during the course of HIV infection, though their incidence has decreased dramatically with the introduction of highly active antiretroviral therapy (cART). Most cases occur in untreated patients, noncompliant patients or patients whose multiple antiretroviral regimens have failed and they are a good marker of the severity of cellular immunodepression. Pneumocystis jiroveci pneumonia is the second most frequent OI in France and cryptococcosis remains a major problem in the Southern Hemisphere. With the increase in travel, imported endemic fungal infection can occur and may mimic other infections, notably tuberculosis. Fungal infections often have a pulmonary presentation but an exhaustive search for dissemination should be made in patients infected with HIV, at least those at an advanced stage of immune deficiency. Introduction of cART in combination with anti-fungal treatment depends on the risk of AIDS progression and on the risk of cumulative toxicity and the immune reconstitution inflammatory syndrome (IRIS) if introduced too early. Fungal infections in HIV infected patients remain a problem in the cART era. IRIS can complicate the management and requires an optimised treatment regime. PMID:24182654

  7. [The protective activity of 2 normal immunoglobulin preparations for intravenous administration in experimental Pseudomonas aeruginosa infection].

    PubMed

    Vasilev, Ch L; Veleva, K V; Tekelieva, R Kh; Pencheva, P I

    1991-02-01

    The antibody levels in 18 batches of the preparations of human immunoglobulin, Immunovenin and Immunovenin-Intact, for intravenous injection were determined in the enzyme immunoassay with the use of the mixture of P. aeruginosa lipopolysaccharide antigens of seven immunotypes. The average antibody titers in these preparations were identical. The preparations were found to have protective action against P. aeruginosa experimental infection in mice. PMID:1907793

  8. Phage Therapy: a Step Forward in the Treatment of Pseudomonas aeruginosa Infections

    PubMed Central

    Pires, Diana P.; Vilas Boas, Diana; Sillankorva, Sanna

    2015-01-01

    Antimicrobial resistance constitutes one of the major worldwide public health concerns. Bacteria are becoming resistant to the vast majority of antibiotics, and nowadays, a common infection can be fatal. To address this situation, the use of phages for the treatment of bacterial infections has been extensively studied as an alternative therapeutic strategy. Since Pseudomonas aeruginosa is one of the most common causes of health care-associated infections, many studies have reported the in vitro and in vivo antibacterial efficacy of phage therapy against this bacterium. This review collects data of all the P. aeruginosa phages sequenced to date, providing a better understanding about their biodiversity. This review further addresses the in vitro and in vivo results obtained by using phages to treat or prevent P. aeruginosa infections as well as the major hurdles associated with this therapy. PMID:25972556

  9. Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection.

    PubMed

    Minandri, Fabrizia; Imperi, Francesco; Frangipani, Emanuela; Bonchi, Carlo; Visaggio, Daniela; Facchini, Marcella; Pasquali, Paolo; Bragonzi, Alessandra; Visca, Paolo

    2016-08-01

    Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and chronic lung infections in cystic fibrosis patients. Iron is essential for bacterial growth, and P. aeruginosa expresses multiple iron uptake systems, whose role in lung infection deserves further investigation. P. aeruginosa Fe(3+) uptake systems include the pyoverdine and pyochelin siderophores and two systems for heme uptake, all of which are dependent on the TonB energy transducer. P. aeruginosa also has the FeoB transporter for Fe(2+) acquisition. To assess the roles of individual iron uptake systems in P. aeruginosa lung infection, single and double deletion mutants were generated in P. aeruginosa PAO1 and characterized in vitro, using iron-poor media and human serum, and in vivo, using a mouse model of lung infection. The iron uptake-null mutant (tonB1 feoB) and the Fe(3+) transport mutant (tonB1) did not grow aerobically under low-iron conditions and were avirulent in the mouse model. Conversely, the wild type and the feoB, hasR phuR (heme uptake), and pchD (pyochelin) mutants grew in vitro and caused 60 to 90% mortality in mice. The pyoverdine mutant (pvdA) and the siderophore-null mutant (pvdA pchD) grew aerobically in iron-poor media but not in human serum, and they caused low mortality in mice (10 to 20%). To differentiate the roles of pyoverdine in iron uptake and virulence regulation, a pvdA fpvR double mutant defective in pyoverdine production but expressing wild-type levels of pyoverdine-regulated virulence factors was generated. Deletion of fpvR in the pvdA background partially restored the lethal phenotype, indicating that pyoverdine contributes to the pathogenesis of P. aeruginosa lung infection by combining iron transport and virulence-inducing capabilities. PMID:27271740

  10. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa-infected wounds.

    PubMed

    Chouake, Jason; Schairer, David; Kutner, Allison; Sanchez, David A; Makdisi, Joy; Blecher-Paz, Karin; Nacharaju, Parimala; Tuckman-Vernon, Chaim; Gialanella, Phil; Friedman, Joel M; Nosanchuk, Joshua D; Friedman, Adam J

    2012-12-01

    Pseudomonas aeruginosa is a community-acquired, nosocomial pathogen that is an important cause of human morbidity and mortality; it is intrinsically resistant to several antibiotics and is capable of developing resistance to newly developed drugs via a variety of mechanisms. P aeruginosa's ubiquity and multidrug resistance (MDR) warrants the development of innovative methods that overcome its ability to develop resistance. We have previously described a nitric oxide-releasing nanoparticle (NO-np) platform that effectively kills gram-positive and gram-negative organisms in vitro and accelerates clinical recovery in vivo in murine wound and abscess infection models. We have also demonstrated that when glutathione (GSH) is added to NO-np, the nitroso intermediate S-nitrosoglutathione (GSNO) is formed, which has greater activity against P aeruginosa and other gram-negative organisms compared with NO-np alone. In the current study, we evaluate the potential of NO-np to generate GSNO both in vitro and in vivo in a murine excisional wound model infected with an MDR clinical isolate of P aeruginosa. Whereas NO-np alone inhibited P aeruginosa growth in vitro for up to 8 hours, NO-np+GSH completely inhibited P aeruginosa growth for 24 hours. Percent survival in the NO-np+GSH-treated isolates was significantly lower than in the NO-np (36.1% vs 8.3%; P=.004). In addition, NO-np+GSH accelerated wound closure in P aeruginosa-infected wounds, and NO-np+GSH-treated wounds had significantly lower bacterial burden when compared to NO-np-treated wounds (P<.001). We conclude that GSNO is easily generated from our NO-np platform and has the potential to be used as an antimicrobial agent against MDR organisms such as P aeruginosa. PMID:23377518

  11. Pseudomonas aeruginosa wound infection involves activation of its iron acquisition system in response to fascial contact

    PubMed Central

    Kim, M.; Christley, S.; Khodarev, N. N.; Fleming, I.; Huang, Y.; Chang, E.; Zaborina, O.; Alverdy, J.

    2015-01-01

    Background Wound infections are traditionally thought to occur when microbial burden exceeds the innate clearance capacity of host immune system. Here we introduce the idea that the wound environment itself plays a significant contributory role to wound infection. Methods We developed a clinically relevant murine model of soft tissue infection to explore the role of activation of microbial virulence in response to tissue factors as a mechanism by which pathogenic bacteria cause wound infections. Mice underwent abdominal skin incision and light muscle injury with a crushing forceps versus skin incision alone followed by topical inoculation of P. aeruginosa. Mice were sacrificed on postoperative day 6 and abdominal tissues analyzed for clinical signs of wound infection. To determine if specific wound tissues components induce bacterial virulence, P. aeruginosa was exposed to skin, fascia, and muscle. Results Gross wound infection due to P. aeruginosa was observed to be significantly increased in injured tissues vs non-injured (80% vs 10%) tissues (n=20/group, p<0.0001). Exposure of P. aeruginosa to individual tissue components demonstrated that fascia significantly induced bacterial virulence as judged by the production of pyocyanin, a redox-active phenazine compound known to kill immune cells. Whole genome transcriptional profiling of P. aeruginosa exposed to fascia demonstrated activation of multiple genes responsible for the synthesis of the iron scavenging molecule pyochelin. Conclusion We conclude that wound elements, in particular fascia, may play a significant role in enhancing the virulence of P. aeruginosa and may contribute to the pathogenesis of clinical wound infection. PMID:25807409

  12. Pectin- Derived Acidic Oligosaccharides Improve the Outcome of Pseudomonas aeruginosa Lung Infection in C57BL/6 Mice

    PubMed Central

    Bernard, Henry; Desseyn, Jean-Luc; Gottrand, Frédéric; Stahl, Bernd; Bartke, Nana; Husson, Marie-Odile

    2015-01-01

    The administration of prebiotics as oligosaccharides (OS), by acting on intestinal microbiota, could modulate the immune and inflammatory response and represent a new strategy to improve the outcome of bacterial infection. The aim of this study was to determine whether pectin-derived acidic oligosaccharides (pAOS) could modulate the outcome of pulmonary P. aeruginosa (PA) infection in C57BL/6 mice, which develop a Th1 response to PA lung infection. Mice were randomized for 5 weeks to consume a control or a 5% pAOS diet and chronically infected by PA. Resistance to a second PA infection was also analyzed by reinfecting the surviving mice 2 weeks after the first infection. Compared with control mice, mice fed pAOS had reduced mortality (P<0.05). This improvement correlated with a better control of the inflammatory response with a lower neutrophil count on day 1 (P<0.05), a sustained neutrophil and macrophage recruitment on days 2 and 3 (P<0.01) a greater and sustained IL-10 release in lung (P<0.05) and a reduction of the Th1 response and M1 activation with a lower IFN-γ/IL-4 (P<0.01) and nos2/arg1 (P<0.05) ratios. These results coincided with a modulation of the intestinal microbiota as shown by an increased butyric acid concentration in feces (P<0.05). Moreover, pAOS decreased the bacterial load (P<0.01) in mice reinfected 2 weeks after the first infection, suggesting that pAOS could reduce pulmonary exacerbations. In conclusion, pAOS improved the outcome of PA infection in C57BL/6 mice by modulating the intestinal microbiota and the inflammatory and immune responses. PMID:26599638

  13. Impact of new water systems on healthcare-associated colonization or infection with Pseudomonas aeruginosa

    PubMed Central

    Lefebvre, Annick; Quantin, Catherine; Vanhems, Philippe; Lucet, Jean-Christophe; Bertrand, Xavier; Astruc, Karine; Chavanet, Pascal; Aho-Glélé, Ludwig S.

    2016-01-01

    Aim: We aimed to study the impact of new water systems, which were less contaminated with P. aeruginosa, on the incidence of healthcare-associated P. aeruginosa cases (colonizations or infections) in care units that moved to a different building between 2005 and 2014. Methods: Generalized Estimated Equations were used to compare the incidence of P. aeruginosa healthcare-associated cases according to the building. Results: Twenty-nine units moved during the study period and 2,759 cases occurred in these units. No difference was observed when the new building was compared with older buildings overall. Conclusion: Our results did not support our hypothesis of a positive association between water system contamination and the incidence of healthcare-associated P. aeruginosa cases. These results must be confirmed by linking results of water samples and patients’ data. PMID:27274443

  14. (1)H NMR spectroscopy in the diagnosis of Pseudomonas aeruginosa-induced urinary tract infection.

    PubMed

    Gupta, Ashish; Dwivedi, Mayank; Nagana Gowda, G A; Ayyagari, Archana; Mahdi, A A; Bhandari, M; Khetrapal, C L

    2005-08-01

    The utility of (1)H NMR spectroscopy is suggested and demonstrated for the diagnosis of Pseudomonas aeruginosa in urinary tract infection (UTI). The specific property of P. aeruginosa of metabolizing nicotinic acid to 6-hydroxynicotinic acid (6-OHNA) is exploited. The quantity of 6-OHNA produced correlates well with the viable bacterial count. Other common bacteria causing UTI such as Escherichia coli, Klebsiella pneumonia, Enterobacter aerogenes, Acinetobacter baumanii, Proteus mirabilis, Citrobacter frundii, Enterococcus faecalis, Streptococcus gp B and Staphylococcus aureus do not metabolize nicotinic acid under similar conditions. The method provides a single-step documentation of P. aeruginosa qualitatively as well as quantitatively. The NMR method is demonstrated on urine samples from 30 patients with UTI caused by P. aeruginosa. PMID:15759292

  15. Meropenem in cystic fibrosis patients infected with resistant Pseudomonas aeruginosa or Burkholderia cepacia and with hypersensitivity to beta-lactam antibiotics.

    PubMed

    Ciofu, Oana; Jensen, Tim; Pressler, Tacjana; Johansen, Helle Krogh; Koch, Christian; Høiby, Niels

    1996-01-01

    OBJECTIVE: To assess the efficacy and safety of meropenem, administered on a compassionate basis to 62 cystic fibrosis (CF) patients (age: 24plus minus6 years) with hypersensitivity reactions to beta-lactam antibiotics and/or infection by bacteria resistant to other antibiotics. METHODS: Fifty-seven patients were chronically infected with Pseudomonas aeruginosa and 5 with Burkholderia cepacia. In total, 124 courses (1 to 6/patient) of meropenem, 2 g three times a day by intravenous infusion (10 to 15 min) for 14 days, were administered. RESULTS: During treatment for P. aeruginosa the mean increase in pulmonary function (as a percentage of the predictive values) was 5.6% for FEV1 (forced expiratory volume in the first second) and 8.6% for FVC (forced vital capacity). C-reactive protein and erythrocyte sedimentation rate (ESR) and leukocyte count decreased significantly. In courses administered for chronic infection with B. cepacia the post treatment FEV1 and FVC values were higher than the pre-treatment values, and all the inflammatory parameters decreased. The geometric means of minimal inhibitory concentration (MICs) (microg/mL) for P. aeruginosa (B. cepacia) were: tobramycin 6 (59), ciprofloxacin 1.2 (9.7), piperacillin 49 (16.3), ceftazidime 26 (23), aztreonam 26 (35), imipenem 6.4 (not determined) and meropenem 5.1 (4.8). No statistically significant increase in the MICs of meropenem for either pathogen occurred during therapy. Of the 124 courses, 115 were tolerated without any clinical complaint. The following side effects were observed: nausea (0.8%), itching (4%), rash (3.2%), drug fever (1.6%). CONCLUSIONS: Meropenem proved to be a valuable drug in the treatment of CF patients with chronic pulmonary infection with multiresistant P. aeruginosa and B. cepacia and with hypersensitivity reactions to other beta-lactam drugs. PMID:11866824

  16. Lung epithelial MyD88 drives early pulmonary clearance of Pseudomonas aeruginosa by a flagellin dependent mechanism.

    PubMed

    Anas, Adam A; van Lieshout, Miriam H P; Claushuis, Theodora A M; de Vos, Alex F; Florquin, Sandrine; de Boer, Onno J; Hou, Baidong; Van't Veer, Cornelis; van der Poll, Tom

    2016-08-01

    Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells. PMID:27288486

  17. Protective efficacy of a peptide derived from a potential adhesin of Pseudomonas aeruginosa against corneal infection.

    PubMed

    Yuan, Qing; Wu, Yuting; Wang, Yiqiang; Chen, Lin; Qu, Mingli; Duan, Kangmin; Zhao, Ge

    2016-02-01

    Dissecting the interactions between Pseudomonas aeruginosa and corneal cells is important to identify a novel target for prevention and treatment of Pseudomonas keratitis. The current study began with a peptide identified by phage display, and was to investigate the protective efficacy against P. aeruginosa infection in cornea. The original peptide Pc-E, with high homology to a hypothetical membrane protein (HmpA) in P. aeruginosa, and the derived peptide Pc-EP, with the same sequence as a region in HmpA, were synthesized. Peptide Pc-EP could directly bind to HCEC, stronger than Pc-E, and specifically activate toll-like receptor 5, and thereby significantly induce the production of pro-inflammatory factors, such as IL-1β, IL-6, IFN-γ and IL-17. Moreover, Pc-EP could act as an antagonist to inhibit the adhesion of wild-type P. aeruginosa to HCEC and mouse corneas. No inhibitory effect was observed on the adhesion of the strain loss of HmpA. When compared to the wild-type strain, the adhesion of the hmpA mutant to corneal cells was significantly decreased. Treatment of infected mouse corneas with Pc-EP before infection significantly decreased the bacterial load in the cornea and attenuated the corneal pathology. These results indicate that Pc-EP can be a useful prophylactic agent for P. aeruginosa keratitis. PMID:26500187

  18. Loss of social behaviours in populations of Pseudomonas aeruginosa infecting lungs of patients with cystic fibrosis.

    PubMed

    Jiricny, Natalie; Molin, Søren; Foster, Kevin; Diggle, Stephen P; Scanlan, Pauline D; Ghoul, Melanie; Johansen, Helle Krogh; Santorelli, Lorenzo A; Popat, Roman; West, Stuart A; Griffin, Ashleigh S

    2014-01-01

    Pseudomonas aeruginosa, is an opportunistic, bacterial pathogen causing persistent and frequently fatal infections of the lung in patients with cystic fibrosis. Isolates from chronic infections differ from laboratory and environmental strains in a range of traits and this is widely interpreted as the result of adaptation to the lung environment. Typically, chronic strains carry mutations in global regulation factors that could effect reduced expression of social traits, raising the possibility that competitive dynamics between cooperative and selfish, cheating strains could also drive changes in P. aeruginosa infections. We compared the expression of cooperative traits - biofilm formation, secretion of exo-products and quorum sensing (QS) - in P. aeruginosa isolates that were estimated to have spent different lengths of time in the lung based on clinical information. All three exo-products involved in nutrient acquisition were produced in significantly smaller quantities with increased duration of infection, and patterns across four QS signal molecules were consistent with accumulation over time of mutations in lasR, which are known to disrupt the ability of cells to respond to QS signal. Pyocyanin production, and the proportion of cells in biofilm relative to motile, free-living cells in liquid culture, did not change. Overall, our results confirm that the loss of social behaviour is a consistent trend with time spent in the lung and suggest that social dynamics are potentially relevant to understanding the behaviour of P. aeruginosa in lung infections. PMID:24454693

  19. Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections

    PubMed Central

    Winstanley, Craig; O’Brien, Siobhan; Brockhurst, Michael A.

    2016-01-01

    Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID:26946977

  20. Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections.

    PubMed

    Winstanley, Craig; O'Brien, Siobhan; Brockhurst, Michael A

    2016-05-01

    Pseudomonas aeruginosa populations undergo a characteristic evolutionary adaptation during chronic infection of the cystic fibrosis (CF) lung, including reduced production of virulence factors, transition to a biofilm-associated lifestyle, and evolution of high-level antibiotic resistance. Populations of P. aeruginosa in chronic CF lung infections typically exhibit high phenotypic diversity, including for clinically important traits such as antibiotic resistance and toxin production, and this diversity is dynamic over time, making accurate diagnosis and treatment challenging. Population genomics studies reveal extensive genetic diversity within patients, including for transmissible strains the coexistence of highly divergent lineages acquired by patient-to-patient transmission. The inherent spatial structure and spatial heterogeneity of selection in the CF lung appears to play a key role in driving P. aeruginosa diversification. PMID:26946977

  1. Virulence Gene Profiles of Multidrug-Resistant Pseudomonas aeruginosa Isolated From Iranian Hospital Infections

    PubMed Central

    Fazeli, Nastaran; Momtaz, Hassan

    2014-01-01

    Background: The most common hospital-acquired pathogen is Pseudomonas aeruginosa. It is a multidrug resistant bacterium causing systemic infections. Objectives: The present study was carried out in order to investigate the distribution of virulence factors and antibiotic resistance properties of Pseudomonas aeruginosa isolated from various types of hospital infections in Iran. Patients and Methods: Two-hundred and seventeen human infection specimens were collected from Baqiyatallah and Payambaran hospitals in Tehran, Iran. The clinical samples were cultured immediately and samples positive for P. aeruginosa were analyzed for the presence of antibiotic resistance and bacterial virulence genes using PCR (polymerase chain reaction). Antimicrobial susceptibility testing was performed using disk diffusion methodology with Müeller–Hinton agar. Results: Fifty-eight out of 127 (45.66%) male infection specimens and 44 out of 90 (48.88%) female infection specimens harbored P. aeruginosa. Also, 65% (in male specimens) and 21% (in female specimens) of respiratory system infections were positive for P. aeruginosa, which was a high rate. The genes encoding exoenzyme S (67.64%) and phospholipases C (45.09%) were the most common virulence genes found among the strains. The incidences of various β-lactams encoding genes, including blaTEM, blaSHV, blaOXA, blaCTX-M, blaDHA, and blaVEB were 94.11%, 16.66%, 15.68%, 18.62%, 21.56%, and 17.64%, respectively. The most commonly detected fluoroquinolones encoding gene was gyrA (15. 68%). High resistance levels to penicillin (100%), tetracycline (90.19%), streptomycin (64.70%), and erythromycin (43.13%) were observed too. Conclusions: Our findings should raise awareness about antibiotic resistance in hospitalized patients in Iran. Clinicians should exercise caution in prescribing antibiotics, especially in cases of human infections. PMID:25763199

  2. Shift in Ribonucleotide Reductase Gene Expression in Pseudomonas aeruginosa during Infection ▿ †

    PubMed Central

    Sjöberg, Britt-Marie; Torrents, Eduard

    2011-01-01

    The roles of different ribonucleotide reductases (RNRs) in bacterial pathogenesis have not been studied systematically. In this work we analyzed the importance of the different Pseudomonas aeruginosa RNRs in pathogenesis using the Drosophila melanogaster host-pathogen interaction model. P. aeruginosa codes for three different RNRs with different environmental requirements. Class II and III RNR chromosomal mutants exhibited reduced virulence in this model. Translational reporter fusions of RNR gene nrdA, nrdJ, or nrdD to the green fluorescent protein were constructed to measure the expression of each class during the infection process. Analysis of the P. aeruginosa infection by flow cytometry revealed increased expression of nrdJ and nrdD and decreased nrdA expression during the infection process. Expression of each RNR class fits with the pathogenicities of the chromosomal deletion mutants. An extended understanding of the pathogenicity and physiology of P. aeruginosa will be important for the development of novel drugs against infections in cystic fibrosis patients. PMID:21502590

  3. Genomic Variation among Contemporary Pseudomonas aeruginosa Isolates from Chronically Infected Cystic Fibrosis Patients

    PubMed Central

    Chung, Jade C. S.; Becq, Jennifer; Fraser, Louise; Schulz-Trieglaff, Ole; Bond, Nicholas J.; Foweraker, Juliet; Bruce, Kenneth D.; Smith, Geoffrey P.

    2012-01-01

    The airways of individuals with cystic fibrosis (CF) often become chronically infected with unique strains of the opportunistic pathogen Pseudomonas aeruginosa. Several lines of evidence suggest that the infecting P. aeruginosa lineage diversifies in the CF lung niche, yet so far this contemporary diversity has not been investigated at a genomic level. In this work, we sequenced the genomes of pairs of randomly selected contemporary isolates sampled from the expectorated sputum of three chronically infected adult CF patients. Each patient was infected by a distinct strain of P. aeruginosa. Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) were identified in the DNA common to the paired isolates from different patients. The paired isolates from one patient differed due to just 1 SNP and 8 indels. The paired isolates from a second patient differed due to 54 SNPs and 38 indels. The pair of isolates from the third patient both contained a mutS mutation, which conferred a hypermutator phenotype; these isolates cumulatively differed due to 344 SNPs and 93 indels. In two of the pairs of isolates, a different accessory genome composition, specifically integrated prophage, was identified in one but not the other isolate of each pair. We conclude that contemporary isolates from a single sputum sample can differ at the SNP, indel, and accessory genome levels and that the cross-sectional genomic variation among coeval pairs of P. aeruginosa CF isolates can be comparable to the variation previously reported to differentiate between paired longitudinally sampled isolates. PMID:22753054

  4. Spanish consensus on the prevention and treatment of Pseudomonas aeruginosa bronchial infections in cystic fibrosis patients.

    PubMed

    Cantón, Rafael; Máiz, Luis; Escribano, Amparo; Olveira, Casilda; Oliver, Antonio; Asensio, Oscar; Gartner, Silvia; Roma, Eva; Quintana-Gallego, Esther; Salcedo, Antonio; Girón, Rosa; Barrio, María Isabel; Pastor, María Dolores; Prados, Concepción; Martínez-Martínez, María Teresa; Barberán, José; Castón, Juan José; Martínez-Martínez, Luis; Poveda, José Luis; Vázquez, Carlos; de Gracia, Javier; Solé, Amparo

    2015-03-01

    Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P.aeruginosa. At initial infection, inhaled colistin (0,5-2MU/tid), tobramycin (300mg/bid) or aztreonam (75mg/tid) with or without oral ciprofloxacin (15-20mg/kg/bid, 2-3weeks) are recommended. In chronic infections, treatment is based on continuous administration of colistin or with a 28-day on-off regimen with tobramycin or aztreonam. During mild-moderate exacerbations oral ciprofloxacin (2-3weeks) can be administered while serious exacerbations must be treated with intravenous combination therapy (beta-lactam with an aminoglycoside or a fluoroquinolone). Future studies will support antibiotic rotation and/or new combination therapies. Epidemiological measures are also recommended to avoid new P.aeruginosa infections and "patient-to-patient transmission" of this pathogen. PMID:25614377

  5. Characterization of Pseudomonas aeruginosa isolated from chronically infected children with cystic fibrosis in India

    PubMed Central

    Agarwal, Gunjan; Kapil, Arti; Kabra, Susheel Kumar; Das, Bimal Kumar; Dwivedi, Sada Nand

    2005-01-01

    Background Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis (CF). With chronicity of infection, the organism resides as a biofilm, shows multi-drug resistance, diversifies its colony morphology and becomes auxotrophic. The patients have been found to be colonized with multiple genotypes. The present work was carried out to characterize P. aeruginosa isolated from children with cystic fibrosis using phenotypic and genotypic methods. Results We studied 56 patients with CF attending the Pediatric Chest clinic at All India Institute of Medical Sciences, New Delhi, India during August 1998-August 2001. These patients were regularly followed up at the clinic. Out of 56 patients, 27 were culture positive for P. aeruginosa where 8 were chronically infected (Group1) and 19 were intermittently colonized with the organism (Group2). Patients under Group1 had significantly higher rates of hospitalization, death and colonization with different colony morphotypes (p < 0.05). The isolates from Group1 patients were the positive producers of extended spectrum beta lactamase. A total of 5 auxotrophs were recovered from 2 patients where one was chronically infected with P. aeruginosa and the other was a recently enrolled patient. The auxotrophs had the specific requirement for methionine and arginine. Molecular typing revealed 33 ERIC-PCR (E1-E33) and 5 PCR-ribotyping (P1-P5) patterns. By ERIC-PCR, 4 patients were colonized with 2–4 genotypes and the remaining 23 patients were colonized with the single genotype. Conclusion With chronicity of infection, P. aeruginosa becomes multidrug resistant, diversifies its colony morphology, acquires mucoidity and shows auxotrophy for amino acids. The chronically infected patients can be colonized with multiple genotypes. Thus in a particular clinical set up, high index of suspicion should be there for diagnosis of CF patients so as to prevent the delay in diagnosis and management of CF

  6. Protein Tyrosine Phosphatase-1B Negatively Impacts Host Defense against Pseudomonas aeruginosa Infection.

    PubMed

    Yue, Lei; Xie, Zhongping; Li, Hua; Pang, Zheng; Junkins, Robert D; Tremblay, Michel L; Chen, Xiaochun; Lin, Tong-Jun

    2016-05-01

    Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated cytokines and chemokines, including chemokine ligand 5 (regulated on activation normal T cell expressed and secreted), CXCL10 (interferon γ-inducible protein 10), and interferon-β production. Further studies reveal that PTP1B deficiency leads to increased interferon regulatory factor 7 (IRF7) expression and activation. These findings demonstrate a novel regulatory mechanism of the immune response to P. aeruginosa infection through PTP1B-IRF7 interaction. This novel PTP1B-IRF7-interferon-stimulated response elements pathway may have broader implications in Toll-like receptor-mediated innate immunity. PMID:27105736

  7. Mimicking the host and its microenvironment in vitro for studying mucosal infections by Pseudomonas aeruginosa

    PubMed Central

    Crabbé, Aurélie; Ledesma, Maria A.; Nickerson, Cheryl A.

    2014-01-01

    Why is a healthy person protected from Pseudomonas aeruginosa infections, while individuals with cystic fibrosis or damaged epithelium are particularly susceptible to this opportunistic pathogen? In order to address this question, it is essential to thoroughly understand the dynamic interplay between the host microenvironment and P. aeruginosa. Therefore, using modeI systems that represent key aspects of human mucosal tissues in health and disease allows recreating in vivo host-pathogen interactions in a physiologically relevant manner. In this review, we discuss how factors of mucosal tissues, such as apical-basolateral polarity, junctional complexes, extracellular matrix proteins, mucus, multicellular complexity (including indigenous microbiota), and other physicochemical factors affect P. aeruginosa pathogenesis and are thus important to mimic in vitro. We highlight in vitro cell and tissue culture model systems of increasing complexity that have been used over the past 35 years to study the infectious disease process of P. aeruginosa, mainly focusing on lung models, and their respective advantages and limitations. Continued improvements of in vitro models based on our expanding knowledge of host microenvironmental factors that participate in P. aeruginosa pathogenesis will help advance fundamental understanding of pathogenic mechanisms and increase the translational potential of research findings from bench to the patient’s bedside. PMID:24737619

  8. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection

    PubMed Central

    Clancy, J P; Dupont, L; Konstan, M W; Billings, J; Fustik, S; Goss, C H; Lymp, J; Minic, P; Quittner, A L; Rubenstein, R C; Young, K R; Saiman, L; Burns, J L; Govan, J R W; Ramsey, B; Gupta, R

    2013-01-01

    Rationale Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. Objectives To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. Methods 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R). Results The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). Conclusions Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection. PMID:23749840

  9. Production of Quorum Sensing Inhibitors in Growing Onion Bulbs Infected with Pseudomonas aeruginosa E (HQ324110)

    PubMed Central

    Abd-Alla, Mohamed H.; Bashandy, Shymaa R.

    2012-01-01

    Eighteen organic compounds were present in growing onion bulbs cultivar Giza 6 infected with P. aeruginosa, but only fourteen of them are present in dry infected onion bulbs; however, four compounds were missing in dry onion. The missing compounds in dry infected onion bulbs are pantolactone, 4,5-dihydro-4,5-dimethylfuran-2(3H)-one, myristic acid, and linoleic acid. All of them were detected in growing onion (living cell) during Pseudomonas aeruginosa infection, and it is hypothesized that it may be produced by plants and act as defence system. Pantolactone and myristic acid were selected to explore their effects on growth and virulence factors of Pseudomonas aeruginosa. Exogenous application of pantolactone and myristic acid significantly inhibited pyocyanin production, protease, and lipase and polygalacturonase activity but did not have any significant effects on bacterial growth. The inhibition of virulence factors without reduction in bacterial growth may be providing strong support that these chemical molecules are general quorum sensing inhibitors than an antibacterial effect. Disruption of quorum sensing of pathogen indicates that this new approach has potential in fighting bacterial infections in human and plants. PMID:23724316

  10. Increased susceptibility to Pseudomonas aeruginosa infection under hindlimb-unloading conditions

    NASA Technical Reports Server (NTRS)

    Aviles, Hernan; Belay, Tesfaye; Fountain, Kimberly; Vance, Monique; Sonnenfeld, Gerald

    2003-01-01

    It has been reported that spaceflight conditions alter the immune system and resistance to infection [Belay T, Aviles H, Vance M, Fountain K, and Sonnenfeld G. J Allergy Clin Immunol 170: 262-268, 2002; Hankins WR and Ziegelschmid JF. In: Biomedical Results of Apollo. Washington, DC: NASA, 1975, p. 43-81. (NASA Spec. Rep. SP-368)]. Ground-based models, including the hindlimb-unloading model, have become important tools for increasing understanding of how spaceflight conditions can influence physiology. The objective of the present study was to determine the effect of hindlimb unloading on the susceptibility of mice to Pseudomonas aeruginosa infection. Hindlimb-unloaded and control mice were subcutaneously infected with 1 LD50 of P. aeruginosa. Survival, bacterial organ load, and antibody and corticosterone levels were compared among the groups. Hindlimb unloading had detrimental effects for infected mice. Animals in the hindlimb-unloaded group, compared with controls, 1). showed significantly increased mortality and reduced time to death, 2). had increased levels of corticosterone, and 3). were much less able to clear bacteria from the organs. These results suggest that hindlimb unloading may induce the production of corticosterone, which may play a critical role in the modulation of the immune system leading to increased susceptibility to P. aeruginosa infection.

  11. Assessing phage therapy against Pseudomonas aeruginosa using a Galleria mellonella infection model.

    PubMed

    Beeton, M L; Alves, D R; Enright, M C; Jenkins, A T A

    2015-08-01

    The Galleria mellonella infection model was used to assess the in vivo efficacy of phage therapy against laboratory and clinical strains of Pseudomonas aeruginosa. In a first series of experiments, Galleria were infected with the laboratory strain P. aeruginosa PAO1 and were treated with varying multiplicity of infection (MOI) of phages either 2h post-infection (treatment) or 2h pre-infection (prevention) via injection into the haemolymph. To address the kinetics of infection, larvae were bled over a period of 24h for quantification of bacteria and phages. Survival rates at 24h when infected with 10 cells/larvae were greater in the prevention versus treatment model (47% vs. 40%, MOI=10; 47% vs. 20%, MOI=1; and 33% vs. 7%, MOI=0.1). This pattern held true when 100 cells/larvae were used (87% vs. 20%, MOI=10; 53% vs. 13%, MOI=1; 67% vs. 7%, MOI=0.1). By 24h post-infection, phages kept bacterial cell numbers in the haemolymph 1000-fold lower than in the non-treated group. In a second series of experiments using clinical strains to further validate the prevention model, phages protected Galleria when infected with both a bacteraemia (0% vs. 85%) and a cystic fibrosis (80% vs. 100%) isolate. Therefore, this study validates the use of G. mellonella as a simple, robust and cost-effective model for initial in vivo examination of P. aeruginosa-targeted phage therapy, which may be applied to other pathogens with similarly low infective doses. PMID:26100212

  12. Effects of Chinese medicinal herbs on a rat model of chronic Pseudomonas aeruginosa lung infection.

    PubMed

    Song, Z; Johansen, H K; Moser, C; Høiby, N

    1996-05-01

    The aim of the study was to evaluate the effects of two kinds of Chinese medicinal herbs, Isatis tinctoria L (ITL) and Daphne giraldii Nitsche (DGN), on a rat model of chronic Pseudomonas aeruginosa lung infection mimicking cystic fibrosis (CF). Compared to the control group, both drugs were able to reduce the incidence of lung abscess (p < 0.05) and to decrease the severity of the macroscopic pathology in lungs (p < 0.05). In the great majority of the rats, the herbs altered the inflammatory response in the lungs from an acute type inflammation, dominated by polymorphonuclear leukocytes (PMN), to a chronic type inflammation, dominated by mononuclear leukocytes (MN). DGN also improved the clearance of P. aeruginosa from the lungs (p < 0.03) compared with the control group. There were no significant differences between the control group and the two herbal groups with regard to serum IgG and IgA anti-P. aeruginosa sonicate antibodies. However, the IgM concentration in the ITL group was significantly lower than in the control group (p < 0.03). These results suggest that the two medicinal herbs might be helpful to CF patients with chronic P. aeruginosa lung infection, DGN being the most favorable. PMID:8703440

  13. Role of small colony variants in persistence of Pseudomonas aeruginosa infections in cystic fibrosis lungs

    PubMed Central

    Malone, Jacob G

    2015-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that predominates during the later stages of cystic fibrosis (CF) lung infections. Over many years of chronic lung colonization, P. aeruginosa undergoes extensive adaptation to the lung environment, evolving both toward a persistent, low virulence state and simultaneously diversifying to produce a number of phenotypically distinct morphs. These lung-adapted P. aeruginosa strains include the small colony variants (SCVs), small, autoaggregative isolates that show enhanced biofilm formation, strong attachment to surfaces, and increased production of exopolysaccharides. Their appearance in the sputum of CF patients correlates with increased resistance to antibiotics, poor lung function, and prolonged persistence of infection, increasing their relevance as a subject for clinical investigation. The evolution of SCVs in the CF lung is associated with overproduction of the ubiquitous bacterial signaling molecule cyclic-di-GMP, with increased cyclic-di-GMP levels shown to be responsible for the SCV phenotype in a number of different CF lung isolates. Here, we review the current state of research in clinical P. aeruginosa SCVs. We will discuss the phenotypic characteristics underpinning the SCV morphotype, the clinical implications of lung colonization with SCVs, and the molecular basis and clinical evolution of the SCV phenotype in the CF lung environment. PMID:26251621

  14. [Pulmonary complications in children with human immunodeficiency virus infection].

    PubMed

    Brockmann V, Pablo; Viviani S, Támara; Peña D, Anamaría

    2007-08-01

    Pulmonary complications in children infected by human immunodeficiency virus (HIV) are common and may be the first manifestation of acquired immunodeficiency syndrome (AIDS). The aim of our study was to review pulmonary diseases and complications in pediatric patients with HIV infection in a large tertiary hospital in Santiago, Chile. We performed a retrospective, descriptive analysis of 17 patients with HIV infection controlled at the Hospital Dr. Sótero del Rio. Respiratory complications/diseases were: overall pneumonia (n: 14), recurrent pneumonia (n: 10), citomegalovirus associated pneumonia (n: 4), Pneumocystis jiroveci associated pneumonia (n: 1) pulmonary tuberculosis (n: 1), lymphoid interstitial pneumonia (n: 3) and chronic pulmonary disease (n: 7). Microorganisms isolated were mostly atypical and frequently associated with severe and chronic pulmonary damage. A high degree of suspicion is required to detect atypical microorganisms promptly, in order to rapidly implement pathogen targeted therapy that could potentially decrease the possibility of sequelae. PMID:17728918

  15. Frequency of Pseudomonas aeruginosa serotypes in burn wound infections and their resistance to antibiotics.

    PubMed

    Estahbanati, Hamid Karimi; Kashani, Parnian Pour; Ghanaatpisheh, Fahimeh

    2002-06-01

    Pseudomonas aeruginosa plays a prominent role as an etiological agent involved in serious infections in burned patients. In this study P. aeruginosa infections were analyzed at the Motahari Burn Center in Tehran (from 22 December 1998 to April 1999) to estimate their frequency, antibiotic susceptibility and serotypes. One hundred and eighty-four positive cultures and 205 bacterial strains were isolated among swabs or biopsy specimens during the study period. Pseudomonas was found to be the most common (57%) followed by Acinetobacter (17%), Escherichia coli (12%), Staphylococcus aureus (8%) and other organisms (6%). The frequency of P. aeruginosa resistance to gentamicin, ceftizoxime, carbenicillin, cephalothin and ceftazidime was over 90%. The antibiotics to which P. aeruginosa was most sensitive were amikacin and tetracyclin. The "O" serotypes isolated from the 117 Pseudomona aeroginosa isolates were serotypes O:2, O:5, O:6, O:8, O:11, O:12 and O:16. The most common serotype was O:6 (20/17%) followed by O:11 (18/15%) and O:5 (14/12%). The serotype most resistant was O:16 (8%) and the most sensitive was O:8 (2%). Since treatment of infection with available antibiotics according to the results attained proved to be difficult, prevention of infection in the burned patients is considered as an appropriate means of conquering overcoming infection problems. The sum of frequencies of serotypes O:6, O:11, O:5 and O:16 was more than 60%, therefore vaccination of burn patients with polyvalent antiserum to these serotypes could possibly produce immunity in more than half of the burned patients. PMID:12052372

  16. Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection

    PubMed Central

    Pastar, Irena; Nusbaum, Aron G.; Gil, Joel; Patel, Shailee B.; Chen, Juan; Valdes, Jose; Stojadinovic, Olivera; Plano, Lisa R.; Tomic-Canic, Marjana; Davis, Stephen C.

    2013-01-01

    Understanding the pathology resulting from Staphylococcus aureus and Pseudomonas aeruginosa polymicrobial wound infections is of great importance due to their ubiquitous nature, increasing prevalence, growing resistance to antimicrobial agents, and ability to delay healing. Methicillin-resistant S. aureus USA300 is the leading cause of community-associated bacterial infections resulting in increased morbidity and mortality. We utilized a well-established porcine partial thickness wound healing model to study the synergistic effects of USA300 and P. aeruginosa on wound healing. Wound re-epithelialization was significantly delayed by mixed-species biofilms through suppression of keratinocyte growth factor 1. Pseudomonas showed an inhibitory effect on USA300 growth in vitro while both species co-existed in cutaneous wounds in vivo. Polymicrobial wound infection in the presence of P. aeruginosa resulted in induced expression of USA300 virulence factors Panton-Valentine leukocidin and α-hemolysin. These results provide evidence for the interaction of bacterial species within mixed-species biofilms in vivo and for the first time, the contribution of virulence factors to the severity of polymicrobial wound infections. PMID:23451098

  17. Les infections à Pseudomonas aeruginosa au service des maladies infectieuses du CHU YO, Burkina Faso: à propos deux cas

    PubMed Central

    Mamoudou, Savadogo; Lassina, Dao; Fla, Koueta

    2015-01-01

    Nous rapportons deux cas d'infection à Pseudomonas aeruginosa: un cas de méningite et un cas d'infection urinaire. Les auteurs rappellent qu’à côté des étiologies classiques des méningites et des infections urinaires, des germes résistants comme Pseudomonas aeruginosa peuvent être responsables d'infections à localisation méningées et urinaires et dont il faut connaître pour une bonne prise en charge. Le traitement de ces infections requiert un antibiogramme au regard de la grande capacité de résistance de Pseudomonas aeruginosa en milieu hospitalier. La limitation des gestes invasifs et l'application rigoureuse des mesures de prévention des infections en milieu hospitalier contribueront à lutter efficacement contre ces infections en milieu de soins. PMID:26491521

  18. Flagellin induces myeloid-derived suppressor cells: implications for Pseudomonas aeruginosa infection in cystic fibrosis lung disease.

    PubMed

    Rieber, Nikolaus; Brand, Alina; Hector, Andreas; Graepler-Mainka, Ute; Ost, Michael; Schäfer, Iris; Wecker, Irene; Neri, Davide; Wirth, Andreas; Mays, Lauren; Zundel, Sabine; Fuchs, Jörg; Handgretinger, Rupert; Stern, Martin; Hogardt, Michael; Döring, Gerd; Riethmüller, Joachim; Kormann, Michael; Hartl, Dominik

    2013-02-01

    Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa-infected CF patient ex vivo-isolated as well as flagellin or P. aeruginosa in vitro-generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell-mediated host defense in CF and other P. aeruginosa-associated chronic lung diseases. PMID:23277486

  19. Novel bacteriophage therapy for controlling metallo-beta-lactamase producing Pseudomonas aeruginosa infection in Catfish

    PubMed Central

    2013-01-01

    Background The bacteriophage therapy is an effective antimicrobial approach with potentially important applications in medicine and biotechnology which can be seen as an additional string in the bow. Emerging drug resistant bacteria in aquaculture industry due to unrestricted use of antibiotics warrants more sustainable and environmental friendly strategies for controlling fish infections. The isolated bacteria from fish lesions was characterised based on isolation on selective and differential medium like Pseudomonas agar, gram staining, biochemical tests and 16SrRNA sequencing. The metallo-beta-lactamase (MBL) producing bacterial isolate was evaluated using Imipenem - Ethylenediaminetetraacetic acid (EDTA) disk method. The specific bacteriophage was isolated and concentrated using coal bed developed in our lab at CSIR-NEERI. The isolated and enriched bacteriophage was characterised by nucleotide sequencing and electron microscopy. The phage therapy was applied for treating ulcerative lesion in fish. Results The pathogenic bacterium responsible for causing ulcerative lesions in catfish species (Clarias gariepinus) was identified as Pseudomonas aeruginosa. One out of twenty P. aeruginosa isolate showing multi drug resistance (MDR) was incidentally found to be MBL producing as determined by Imipenem-EDTA disk method. The phage therapy effectively cured the ulcerative lesions of the infected fish in 8–10 days of treatment, with a sevenfold reduction of the lesion with untreated infection control. Conclusion Bacteriophage therapy can have potential applications soon as an alternative or as a complement to antibiotic treatment in the aquaculture. We present bacteriophage therapy as a treatment method for controlling MDR P. aeruginosa infection in C. gariepinus. To the best of our knowledge this is a first report of application of phage therapy against MBL producing P. aeruginosa isolated from aquatic ecosystem. PMID:24369750

  20. Prevention of bloodstream infections by photodynamic inactivation of multiresistant Pseudomonas aeruginosa in burn wounds

    NASA Astrophysics Data System (ADS)

    Hashimoto, M. C. E.; Prates, R. A.; Toffoli, D. J.; Courrol, L. C.; Ribeiro, M. S.

    2010-02-01

    Bloodstream infections are potentially life-threatening diseases. They can cause serious secondary infections, and may result in endocarditis, severe sepsis or toxic-shock syndrome. Pseudomonas aeruginosa is an opportunistic pathogen and one of the most important etiological factors responsible for nosocomial infections, mainly in immuno-compromissed hosts, characteristic of patients with severe burns. Its multiresistance to antibiotics produces many therapeutic problems, and for this reason, the development of an alternative method to antibiotic therapy is needed. Photodynamic inactivation (PDI) may be an effective and alternative therapeutic option to prevent bloodstream infections in patients with severe burns. In this study we report the use of PDI to prevent bloodstream infections in mice with third-degree burns. Burns were produced on the back of the animals and they were infected with 109 cfu/mL of multi-resistant (MR) P. aeruginosa. Fifteen animals were divided into 3 groups: control, PDT blue and PDT red. PDT was performed thirty minutes after bacterial inoculation using 10μM HB:La+3 and a light-emitting diode (LED) emitting at λ=460nm+/-20nm and a LED emitting at λ=645 nm+/-10nm for 120s. Blood of mice were colected at 7h, 10h, 15h, 18h and 22h pos-infection (p.i.) for bacterial counting. Control group presented 1×104 cfu/mL in bloodstream at 7h p.i. increasing to 1×106 at 22h, while mice PDT-treated did not present any bacteria at 7h; only at 22h p.i. they presented 1×104cfu/mL. These results suggest that HB:La+3 associated to blue LED or red LED is effective to delay and diminish MR P.aeruginosa bloodstream invasion in third-degree-burned mice.

  1. Study on antimicrobial potential of neem oil nanoemulsion against Pseudomonas aeruginosa infection in Labeo rohita.

    PubMed

    Mishra, Prabhakar; R S, Suresh Kumar; Jerobin, Jayakumar; Thomas, John; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2014-01-01

    Presence of several biochemical constituents in neem makes it an efficient antimicrobial agent for pathogenic diseases. The current investigation was aimed to assess the therapeutic potential of neem nanoemulsion as a control measure for Pseudomonas aeruginosa infection in freshwater fish Labeo rohita. The median lethal concentration (LC50) for the neem oil and neem nanoemulsion was 73.9 and 160.3 mg/L, respectively. The biomarker enzymes of treated fish tissues showed a significant difference in the level of glutathione reductase, catalase, and lipid peroxidation in neem oil-treated samples than in neem nanoemulsion-treated samples at P<0.05. The results were corroborative with histopathology and ultrastructural analysis. The bacterial infection of P. aeruginosa treated using neem nanoemulsion was more effective in both in vitro and in vivo methods. Present findings suggest that neem-based nanoemulsion has negligible toxicity to Rohu fishes. This makes neem-based nanoemulsion as an efficient therapeutic agent against P. aeruginosa infection, leading to its possible usage in the aquaculture industry. PMID:24502533

  2. Proteome and carbon flux analysis of Pseudomonas aeruginosa clinical isolates from different infection sites.

    PubMed

    Lassek, Christian; Berger, Antje; Zühlke, Daniela; Wittmann, Christoph; Riedel, Katharina

    2016-05-01

    Pseudomonas aeruginosa is known as opportunistic pathogen frequently isolated from different infection sites. To investigate the expression rates of P. aeruginosa proteins commonly expressed by different clinical isolates, absolute protein quantities were determined employing a gel-free and data-independent LC-IMS(E) approach. Moreover, the metabolic diversity of these isolates was investigated by (13) C-metabolic flux analyses. 812 proteins were reproducibly identified and absolutely quantified for the reference strain P. aeruginosa PAO1, 363 of which were also identified and relatively quantified in all isolates. Whilst the majority of these proteins were expressed in constant amounts, expression rates of 42 proteins were highly variable between the isolates. Notably, the outer membrane protein OprH and the response regulator PhoP were strongly expressed in burned wounds isolates compared to lung/urinary tract isolates. Moreover, proteins involved in iron/amino acids uptake were found to be highly abundant in urinary tract isolates. The fluxome data revealed a conserved glycolysis, and a niche-specific divergence in fluxes through the glyoxylate shunt and the TCA cycle among the isolates. The integrated proteome/fluxome analysis did not indicate straightforward correlation between the protein amount and flux, but rather points to additional layers of regulation that mediate metabolic adaption of P. aeruginosa to different host environments. All MS data have been deposited in the ProteomeXchange with identifier PXD002373 (http://proteomecentral.proteomexchange.org/dataset/PXD002373). PMID:26959854

  3. Successful implementation of infection control strategies prevents P. aeruginosa transmission among cystic fibrosis patients inside the hospital

    PubMed Central

    Matt, Benedikt; Mitteregger, Dieter; Renner, Sabine; Presterl, Elisabeth; Assadian, Ojan; Diab-Elschahawi, Magda

    2014-01-01

    Background: The aim of this study was to characterise the epidemiology of P. aeruginosa isolated from cystic fibrosis (CF) patients at the Vienna General Hospital (VGH) by molecular genetic fingerprinting in order to understand transmission ways and to evaluate the established infection control protocols. Methods: The outpatient clinic for CF patients at the VGH cares for children and adolescents up to the age of 18 years. Among an average of 139 patients cared for at the clinic, 41 were tested positive for P. aeruginosa during the study period. Fifty P. aeruginosa isolates, obtained between August 2010 and March 2012 from routine examinations of CF patients, were subject to molecular characterization using the DiversiLab® method. Results: 42 distinguishable molecular-biological patterns were identified, 7 of which were found multiple times. 40 out of 42 genotypes were retrieved from single patients only, while two patterns were present in two patients each. Nine patients presented with two or more phenotypically diverse P. aeruginosa isolates. In five of these cases the retrieved isolates belonged to the same genotype. Conclusion: The broad genetic heterogeneity of P. aeruginosa in the studied patient population suggests that the majority of CF patients cared for at the VGH acquire P. aeruginosa from environmental sources. It may be concluded that implemented infection control guidelines have been successful in preventing nosocomial transmission of P. aeruginosa among CF patients within the VGH and patient-to-patient transmission outside the hospital. Chronic polyclonal infection/colonization was rare in the study population. PMID:25285264

  4. The Healing Effect of Licorice on Pseudomonas aeruginosa Infected Burn Wounds in Experimental Rat Model

    PubMed Central

    Tanideh, Nader; Rokhsari, Pedram; Mehrabani, Davood; Mohammadi Samani, Soleiman; Sabet Sarvestani, Fatemeh; Ashraf, Mohammad Javad; Koohi Hosseinabadi, Omid; Shamsian, Shahram; Ahmadi, Nasrollah

    2014-01-01

    BACKGROUND Burn is still one of the most devastating injuries in emergency medicine while improvements in wound healing knowledge and technology have resulted into development of new dressings. This study was undertaken to evaluate the healing effect of licorice in Pseudomonas aeruginosa infected burn wounds of experimental rat model. METHODS One hundred and twenty female Sprague-Dawley rats were randomly allocated to 4 equal groups. Group A received silver sulfadiazine ointment, Group B received 10% licorice extract and Group C was considered as control group and received gel base as the base of medication. Group D did not receive any medication and just underwent burn injury. A standard 3rd degree burn wound was produced by a hot plate with similar size about 20% of total body surface area (TBSA) and at identical temperature. After 24 h of burn production, 108 colony forming units (CFU) of toxigenic strains of P. aeruginosa (PA 103) were inoculated subcutaneously into the burnt area. After 3, 7, 14, 21 and 28 days of therapy, the animals were sacrificed and burn areas were macroscopically examined and histologically evaluated. RESULTS Decrease in size of the burn wounds, in inflammation and re-epithelialization were poor in groups B-D. Infection to P. aeruginosa was still visible in groups B-D but was absent in Group A. The mean histological score, tensile strength, maximum stress, yield strength and stiffness in groups B-D were lower compared with Group A. CONCLUSION Licorice extract in 10% concentration was shown not to be effective in healing of P. aeruginosa infected burn wounds. PMID:25489532

  5. Specific Resistance to Pseudomonas aeruginosa Infection in Zebrafish Is Mediated by the Cystic Fibrosis Transmembrane Conductance Regulator ▿ †

    PubMed Central

    Phennicie, Ryan T.; Sullivan, Matthew J.; Singer, John T.; Yoder, Jeffrey A.; Kim, Carol H.

    2010-01-01

    Cystic fibrosis (CF) is a genetic disease caused by recessive mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is associated with prevalent and chronic Pseudomonas aeruginosa lung infections. Despite numerous studies that have sought to elucidate the role of CFTR in the innate immune response, the links between CFTR, innate immunity, and P. aeruginosa infection remain unclear. The present work highlights the zebrafish as a powerful model organism for human infectious disease, particularly infection by P. aeruginosa. Zebrafish embryos with reduced expression of the cftr gene (Cftr morphants) exhibited reduced respiratory burst response and directed neutrophil migration, supporting a connection between cftr and the innate immune response. Cftr morphants were infected with P. aeruginosa or other bacterial species that are commonly associated with infections in CF patients, including Burkholderia cenocepacia, Haemophilus influenzae, and Staphylococcus aureus. Intriguingly, the bacterial burden of P. aeruginosa was found to be significantly higher in zebrafish Cftr morphants than in controls, but this phenomenon was not observed with the other bacterial species. Bacterial burden in Cftr morphants infected with a P. aeruginosa ΔLasR mutant, a quorum sensing-deficient strain, was comparable to that in control fish, indicating that the regulation of virulence factors through LasR is required for enhancement of infection in the absence of Cftr. The zebrafish system provides a multitude of advantages for studying the pathogenesis of P. aeruginosa and for understanding the role that innate immune cells, such as neutrophils, play in the host response to acute bacterial infections commonly associated with cystic fibrosis. PMID:20732993

  6. Role of Nonagglutinating Antibody in the Protracted Immunity of Vaccinated Mice to Pseudomonas aeruginosa Infection

    PubMed Central

    Moody, M. R.; Kessel, R. W. I.; Young, V. M.; Fiset, P.

    1978-01-01

    Effective immunization against infection with Pseudomonas aeruginosa is difficult to evaluate because agglutinin levels decline rapidly. Because fractionation of hyperimmune sera often yields more specific antibody than can be accounted for by direct agglutination tests, an immunoglobulin-specific assay based on antiglobulin augmentation was used to characterize antibody responses of C3H/HeJ mice vaccinated with P. aeruginosa type 2 lipopolysaccharide. Nonagglutinating antibodies, initially detected at 2 weeks post-primary vaccination, were predominantly immunoglobulin G after 5 weeks, and they remained elevated at levels usually 32-fold higher than the direct titer throughout the 4-month study period. The sequential production of immunoglobulin M, then immunoglobulin G, followed that found in orthodox immunological responses. Sera that contained nonagglutinating antibodies but not direct agglutinins (14 to 16 weeks) enhanced phagocytosis of P. aeruginosa type 2 by macrophages from unimmunized mice and passively immunized mice against lethal challenge doses; bactericidal activity of these sera was not demonstrated in the presence or absence of complement. When challenged with 1, 10, and 100 50% lethal doses at 16 weeks, survival rates of actively immunized mice were significantly higher than those of unvaccinated mice (P < 0.001). Thus, at a time when no direct agglutinins were detectable, the augmented system detected nonagglutinating antibodies that could confer protracted resistance in vaccinated mice to pseudomonas infection. PMID:101467

  7. Antibiofilm and Anti-Infection of a Marine Bacterial Exopolysaccharide Against Pseudomonas aeruginosa

    PubMed Central

    Wu, Shimei; Liu, Ge; Jin, Weihua; Xiu, Pengyuan; Sun, Chaomin

    2016-01-01

    Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors, thus leading to major problems in many fields, such as clinical infection, food contamination, and marine biofouling. In this study, we report the purification and characterization of an exopolysaccharide EPS273 from the culture supernatant of marine bacterium P. stutzeri 273. The exopolysaccharide EPS273 not only effectively inhibits biofilm formation but also disperses preformed biofilm of P. aeruginosa PAO1. High performance liquid chromatography traces of the hydrolyzed polysaccharides shows that EPS273 primarily consists of glucosamine, rhamnose, glucose and mannose. Further investigation demonstrates that EPS273 reduces the production of the virulence factors pyocyanin, exoprotease, and rhamnolipid, and the virulence of P. aeruginosa PAO1 to human lung cells A549 and zebrafish embryos is also obviously attenuated by EPS273. In addition, EPS273 also greatly reduces the production of hydrogen peroxide (H2O2) and extracellular DNA (eDNA), which are important factors for biofilm formation. Furthermore, EPS273 exhibits strong antioxidant potential by quenching hydroxyl and superoxide anion radicals. Notably, the antibiofouling activity of EPS273 is observed in the marine environment up to 2 weeks according to the amounts of bacteria and diatoms in the glass slides submerged in the ocean. Taken together, the properties of EPS273 indicate that it has a promising prospect in combating bacterial biofilm-associated infection, food-processing contamination and marine biofouling. PMID:26903981

  8. Antibiofilm and Anti-Infection of a Marine Bacterial Exopolysaccharide Against Pseudomonas aeruginosa.

    PubMed

    Wu, Shimei; Liu, Ge; Jin, Weihua; Xiu, Pengyuan; Sun, Chaomin

    2016-01-01

    Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors, thus leading to major problems in many fields, such as clinical infection, food contamination, and marine biofouling. In this study, we report the purification and characterization of an exopolysaccharide EPS273 from the culture supernatant of marine bacterium P. stutzeri 273. The exopolysaccharide EPS273 not only effectively inhibits biofilm formation but also disperses preformed biofilm of P. aeruginosa PAO1. High performance liquid chromatography traces of the hydrolyzed polysaccharides shows that EPS273 primarily consists of glucosamine, rhamnose, glucose and mannose. Further investigation demonstrates that EPS273 reduces the production of the virulence factors pyocyanin, exoprotease, and rhamnolipid, and the virulence of P. aeruginosa PAO1 to human lung cells A549 and zebrafish embryos is also obviously attenuated by EPS273. In addition, EPS273 also greatly reduces the production of hydrogen peroxide (H2O2) and extracellular DNA (eDNA), which are important factors for biofilm formation. Furthermore, EPS273 exhibits strong antioxidant potential by quenching hydroxyl and superoxide anion radicals. Notably, the antibiofouling activity of EPS273 is observed in the marine environment up to 2 weeks according to the amounts of bacteria and diatoms in the glass slides submerged in the ocean. Taken together, the properties of EPS273 indicate that it has a promising prospect in combating bacterial biofilm-associated infection, food-processing contamination and marine biofouling. PMID:26903981

  9. Multiple roles of Pseudomonas aeruginosa TBCF10839 PilY1 in motility, transport and infection

    PubMed Central

    Bohn, Yu-Sing Tammy; Brandes, Gudrun; Rakhimova, Elza; Horatzek, Sonja; Salunkhe, Prabhakar; Munder, Antje; van Barneveld, Andrea; Jordan, Doris; Bredenbruch, Florian; Häußler, Susanne; Riedel, Kathrin; Eberl, Leo; Jensen, Peter Østrup; Bjarnsholt, Thomas; Moser, Claus; Hoiby, Niels; Tümmler, Burkhard; Wiehlmann, Lutz

    2008-01-01

    Polymorphonuclear neutrophils are the most important mammalian host defence cells against infections with Pseudomonas aeruginosa. Screening of a signature tagged mutagenesis library of the non-piliated P. aeruginosa strain TBCF10839 uncovered that transposon inactivation of its pilY1 gene rendered the bacterium more resistant against killing by neutrophils than the wild type and any other of the more than 3000 tested mutants. Inactivation of pilY1 led to the loss of twitching motility in twitching-proficient wild-type PA14 and PAO1 strains, predisposed to autolysis and impaired the secretion of quinolones and pyocyanin, but on the other hand promoted growth in stationary phase and bacterial survival in murine airway infection models. The PilY1 population consisted of a major full-length and a minor shorter PilY1* isoform. PilY1* was detectable in small extracellular quinolone-positive aggregates, but not in the pilus. P. aeruginosa PilY1 is not an adhesin on the pilus tip, but assists in pilus biogenesis, twitching motility, secretion of secondary metabolites and in the control of cell density in the bacterial population. PMID:19054330

  10. The Healing Effect of Scrophularia Striata on Experimental Burn Wounds Infected to Pseudomonas Aeruginosa in Rat

    PubMed Central

    Tanideh, Nader; Haddadi, Mohammad Hossein; Rokni-Hosseini, Mohammad Hossein; Hossienzadeh, Masood; Mehrabani, Davood; Sayehmiri, Kourosh; Koohi-Hossienabadi, Omid

    2015-01-01

    BACKGROUND The cause of death in burn patients after 48 hours of hospitalization has been reported to be bacterial infections. Recently, due to the compounds accelerating the healing process and the intense reduction of treatment side effects, medicinal plants are used to cure burn wound infections. This study aims to investigate the medicinal effect of the ethanolic extract of Scrophularia striata on burn wound infection in in-vivo and in-vitro in comparison with silver sulfadiazine (SSD). METHODS One hundred and fifty male Sprague Dawley rats were divided into 3 equal groups. A hot plate of 1×1cm was used to create second degree burn wounds. The ethanolic extract of S. striata was provided through percolation method. Group 1 was treated with SSD, group 2 with S. striata, and group 3 was considered as control group. All animals were infected to Pseudomonas aeruginosa. On days 3, 7, 10, 14, and 21 after burn wound injury, the animals were euthanized and were evaluated histologically. The MIC and MBC were determined using the micro dilution method. RESULTS The rate of wound healing was significantly greater in S. striata group in comparison to SSD and control groups. CONCLUSION S. striata contains was shown to have anti-bacterial and wound healing effects while this effect was significantly more than SSD denoting to its use when needed for burn wounds infected to P. aeruginosa. PMID:25606472

  11. Prevalence of Pseudomonas aeruginosa and Acinetobacter spp. in subgingival biofilm and saliva of subjects with chronic periodontal infection.

    PubMed

    Souto, Renata; Silva-Boghossian, Carina M; Colombo, Ana Paula Vieira

    2014-01-01

    P. aeruginosa and Acinetobacter spp. are important pathogens associated with late nosocomial pneumonia in hospitalized and institutionalized individuals. The oral cavity may be a major source of these respiratory pathogens, particularly in the presence of poor oral hygiene and periodontal infection. This study investigated the prevalence of P. aeruginosa and Acinetobacter spp. in subgingival biofilm and saliva of subjects with periodontal disease or health. Samples were obtained from 55 periodontally healthy (PH) and 169 chronic periodontitis (CP) patients. DNA was obtained from the samples and detection of P. aeruginosa and Acinetobacter spp. was carried out by multiplex and nested PCR. P. aeruginosa and Acinetobacter spp. were detected in 40% and 45% of all samples, respectively. No significant differences in the distribution of these microorganisms between men and women, subgingival biofilm and saliva samples, patients ≤ 35 and > 35 years of age, and smokers and non-smokers were observed regardless periodontal status (p > 0.05). In contrast, the frequencies of P. aeruginosa and Acinetobacter spp. in saliva and biofilm samples were significantly greater in CP than PH patients (p < 0.01). Smokers presenting P. aeruginosa and high frequencies of supragingival plaque were more likely to present CP than PH. P. aeruginosa and Acinetobacter spp. are frequently detected in the oral microbiota of CP. Poor oral hygiene, smoking and the presence of P. aeruginosa are strongly associated with periodontitis. PMID:25242933

  12. Opportunistic Pulmonary Bordetella hinzii Infection after Avian Exposure

    PubMed Central

    Dupin, Clarisse; Bénézit, François; Goret, Julien; Piau, Caroline; Jouneau, Stéphane; Guillot, Sophie; Mégraud, Francis; Kayal, Samer; Desrues, Benoit; Le Coustumier, Alain; Guiso, Nicole

    2015-01-01

    We report 2 cases of pulmonary Bordetella hinzii infection in immunodeficient patients. One of these rare cases demonstrated the potential transmission of the bacteria from an avian reservoir through occupational exposure and its persistence in humans. We establish bacteriologic management of these infections and suggest therapeutic options if needed. PMID:26584467

  13. Noninfectious Pulmonary Complications of Human Immunodeficiency Virus Infection

    PubMed Central

    Staitieh, Bashar

    2014-01-01

    Abstract: Human immunodeficiency virus type 1 (HIV-1) is the retrovirus responsible for the development of AIDS. Its profound impact on the immune system leaves the host vulnerable to a wide range of opportunistic infections not seen in individuals with a competent immune system. Pulmonary infections dominated the presentations in the early years of the epidemic, and infectious and noninfectious lung diseases remain the leading causes of morbidity and mortality in persons living with HIV despite the development of effective antiretroviral therapy. In addition to the long known immunosuppression and infection risks, it is becoming increasingly recognized that HIV promotes the risk of noninfectious pulmonary diseases through a number of different mechanisms, including direct tissue toxicity by HIV-related viral proteins and the secondary effects of coinfections. Diseases of the airways, lung parenchyma and the pulmonary vasculature, as well as pulmonary malignancies, are either more frequent in persons living with HIV or have atypical presentations. As the pulmonary infectious complications of HIV are generally well known and have been reviewed extensively, this review will focus on the breadth of noninfectious pulmonary diseases that occur in HIV-infected individuals as these may be more difficult to recognize by general medical physicians and subspecialists caring for this large and uniquely vulnerable population. PMID:24992395

  14. Pulmonary Mycobacterium avium infection demonstrating unusual lobar caseous pneumonia.

    PubMed

    Okuzumi, Shinichi; Minematsu, Naoto; Sasaki, Mamoru; Ohsawa, Kazuma; Murakami, Marohito

    2016-09-01

    Mycobacterium avium complex (MAC) infection is a major medical concern in Japan because of its increased prevalence and associated mortality. A common radiological feature in pulmonary MAC infection is a mixture of two basic patterns: fibrocavitary and nodular bronchiectatic; however, lobar consolidation is rare. We report an 83-year-old man with lobar caseous pneumonia caused by pulmonary MAC infection. Radiological findings were predominantly composed of dense lobar consolidation and ground-glass opacity. A diagnosis was made in accordance with the clinical and microbiological criteria set by the American Thoracic Society. A histological examination of lung specimens obtained by using a bronchoscope revealed a caseous granulomatous inflammation with an appearance of Langhans cells. The patient was treated using combined mycobacterium chemotherapy with an initial positive response for 6 months; however, the disease progressed later. We suggest that an awareness of lobar pneumonic consolidation as a rare radiological finding in pulmonary MAC infection is important. PMID:27516892

  15. A simple alfalfa seedling infection model for Pseudomonas aeruginosa strains associated with cystic fibrosis shows AlgT (sigma-22) and RhlR contribute to pathogenesis

    PubMed Central

    Silo-Suh, Laura; Suh, Sang-Jin; Sokol, Pamela A.; Ohman, Dennis E.

    2002-01-01

    A sensitive plant infection model was developed to identify virulence factors in nontypeable, alginate overproducing (mucoid) Pseudomonas aeruginosa strains isolated from cystic fibrosis (CF) patients with chronic pulmonary disease. Nontypeable strains with defects in lipopolysaccharide O-side chains are common to CF and often exhibit low virulence in animal models of infection. However, 1,000 such bacteria were enough to show disease symptoms in the alfalfa infection. A typical mucoid CF isolate, FRD1, and its isogenic mutants were tested for alfalfa seedling infection. Although defects in the global regulators Vfr, RpoS, PvdS, or LasR had no discernable effect on virulence, a defect in RhlR reduced the infection frequency by >50%. A defect in alginate biosynthesis resulted in plant disease with >3-fold more bacteria per plant, suggesting that alginate overproduction attenuated bacterial growth in planta. FRD1 derivatives lacking AlgT, a sigma factor required for alginate production, were reduced >50% in the frequency of infection. Thus, AlgT apparently regulates factors in FRD1, besides alginate, important for pathogenesis. In contrast, in a non-CF strain, PAO1, an algT mutation did not affect its virulence on alfalfa. Conversely, PAO1 virulence was reduced in a mucA mutant that overproduced alginate. These observations suggested that mucoid conversion in CF may be driven by a selection for organisms with attenuated virulence or growth in the lung, which promotes a chronic infection. These studies also demonstrated that the wounded alfalfa seedling infection model is a useful tool to identify factors contributing to the persistence of P. aeruginosa in CF. PMID:12426404

  16. Fitness of Isogenic Colony Morphology Variants of Pseudomonas aeruginosa in Murine Airway Infection

    PubMed Central

    Rakhimova, Elza; Munder, Antje; Wiehlmann, Lutz; Bredenbruch, Florian; Tümmler, Burkhard

    2008-01-01

    Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called ‘dissociative behaviour’. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of–function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild. PMID:18301762

  17. Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model

    PubMed Central

    Limmer, Stefanie; Haller, Samantha; Drenkard, Eliana; Lee, Janice; Yu, Shen; Kocks, Christine; Ausubel, Frederick M.; Ferrandon, Dominique

    2011-01-01

    An in-depth mechanistic understanding of microbial infection necessitates a molecular dissection of host–pathogen relationships. Both Drosophila melanogaster and Pseudomonas aeruginosa have been intensively studied. Here, we analyze the infection of D. melanogaster by P. aeruginosa by using mutants in both host and pathogen. We show that orally ingested P. aeruginosa crosses the intestinal barrier and then proliferates in the hemolymph, thereby causing the infected flies to die of bacteremia. Host defenses against ingested P. aeruginosa included an immune deficiency (IMD) response in the intestinal epithelium, systemic Toll and IMD pathway responses, and a cellular immune response controlling bacteria in the hemocoel. Although the observed cellular and intestinal immune responses appeared to act throughout the course of the infection, there was a late onset of the systemic IMD and Toll responses. In this oral infection model, P. aeruginosa PA14 did not require its type III secretion system or other well-studied virulence factors such as the two-component response regulator GacA or the protease AprA for virulence. In contrast, the quorum-sensing transcription factor RhlR, but surprisingly not LasR, played a key role in counteracting the cellular immune response against PA14, possibly at an early stage when only a few bacteria are present in the hemocoel. These results illustrate the power of studying infection from the dual perspective of host and pathogen by revealing that RhlR plays a more complex role during pathogenesis than previously appreciated. PMID:21987808

  18. Host Genetic Background Influences the Response to the Opportunistic Pseudomonas aeruginosa Infection Altering Cell-Mediated Immunity and Bacterial Replication

    PubMed Central

    Lorè, Nicola Ivan; Rossi, Giacomo; Cigana, Cristina; De Fino, Ida; Iraqi, Fuad A.; Bragonzi, Alessandra

    2014-01-01

    Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream, urinary tract, and surgical site infections. The clinical outcome of P. aeruginosa infections may be extremely variable among individuals at risk and patients affected by cystic fibrosis. However, risk factors for P. aeruginosa infection remain largely unknown. To identify and track the host factors influencing P. aeruginosa lung infections, inbred immunocompetent mouse strains were screened in a pneumonia model system. A/J, BALB/cJ, BALB/cAnNCrl, BALB/cByJ, C3H/HeOuJ, C57BL/6J, C57BL/6NCrl, DBA/2J, and 129S2/SvPasCRL mice were infected with P. aeruginosa clinical strain and monitored for body weight and mortality up to seven days. The most deviant survival phenotypes were observed for A/J, 129S2/SvPasCRL and DBA/2J showing high susceptibility while BALB/cAnNCrl and C3H/HeOuJ showing more resistance to P. aeruginosa infection. Next, one of the most susceptible and resistant mouse strains were characterized for their deviant clinical and immunological phenotype by scoring bacterial count, cell-mediated immunity, cytokines and chemokines profile and lung pathology in an early time course. Susceptible A/J mice showed significantly higher bacterial burden, higher cytokines and chemokines levels but lower leukocyte recruitment, particularly neutrophils, when compared to C3H/HeOuJ resistant mice. Pathologic scores showed lower inflammatory severity, reduced intraluminal and interstitial inflammation extent, bronchial and parenchymal involvement and diminished alveolar damage in the lungs of A/J when compared to C3H/HeOuJ. Our findings indicate that during an early phase of infection a prompt inflammatory response in the airways set the conditions for a non-permissive environment to P. aeruginosa replication and lock the spread to other organs. Host gene(s) may have a role in the reduction of cell-mediated immunity playing a critical role in the control of P

  19. Host genetic background influences the response to the opportunistic Pseudomonas aeruginosa infection altering cell-mediated immunity and bacterial replication.

    PubMed

    De Simone, Maura; Spagnuolo, Lorenza; Lorè, Nicola Ivan; Rossi, Giacomo; Cigana, Cristina; De Fino, Ida; Iraqi, Fuad A; Bragonzi, Alessandra

    2014-01-01

    Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream, urinary tract, and surgical site infections. The clinical outcome of P. aeruginosa infections may be extremely variable among individuals at risk and patients affected by cystic fibrosis. However, risk factors for P. aeruginosa infection remain largely unknown. To identify and track the host factors influencing P. aeruginosa lung infections, inbred immunocompetent mouse strains were screened in a pneumonia model system. A/J, BALB/cJ, BALB/cAnNCrl, BALB/cByJ, C3H/HeOuJ, C57BL/6J, C57BL/6NCrl, DBA/2J, and 129S2/SvPasCRL mice were infected with P. aeruginosa clinical strain and monitored for body weight and mortality up to seven days. The most deviant survival phenotypes were observed for A/J, 129S2/SvPasCRL and DBA/2J showing high susceptibility while BALB/cAnNCrl and C3H/HeOuJ showing more resistance to P. aeruginosa infection. Next, one of the most susceptible and resistant mouse strains were characterized for their deviant clinical and immunological phenotype by scoring bacterial count, cell-mediated immunity, cytokines and chemokines profile and lung pathology in an early time course. Susceptible A/J mice showed significantly higher bacterial burden, higher cytokines and chemokines levels but lower leukocyte recruitment, particularly neutrophils, when compared to C3H/HeOuJ resistant mice. Pathologic scores showed lower inflammatory severity, reduced intraluminal and interstitial inflammation extent, bronchial and parenchymal involvement and diminished alveolar damage in the lungs of A/J when compared to C3H/HeOuJ. Our findings indicate that during an early phase of infection a prompt inflammatory response in the airways set the conditions for a non-permissive environment to P. aeruginosa replication and lock the spread to other organs. Host gene(s) may have a role in the reduction of cell-mediated immunity playing a critical role in the control of P

  20. The Effect of Infection Control Nurses on the Occurrence of Pseudomonas aeruginosa Healthcare-Acquired Infection and Multidrug-Resistant Strains in Critically-Ill Children

    PubMed Central

    Xu, Wei; He, Linxi; Liu, Chunfeng; Rong, Jian; Shi, Yongyan; Song, Wenliang; Zhang, Tao; Wang, Lijie

    2015-01-01

    Background Healthcare-acquired Pseudomonas aeruginosa (P. aeruginosa) infections in the Pediatric Intensive Care Unit (PICU), which have a high incidence, increase treatment costs and mortality, and seriously threaten the safety of critically ill children. It is essential to seek convenient and effective methods to control and prevent healthcare-acquired infections (HAIs). This research was conducted to study the effect of infection control nurses on the occurrence of P. aeruginosa HAIs and multi-drug resistance (MDR) strains in PICU. Methods The clinical data was divided into two groups, with the age ranging from 1 month to 14 years. One group of the critically ill patients(N = 3,722) was admitted to PICU from 2007 to 2010, without the management of infection control nurses. The other group of the critically ill patients (N = 3,943) was admitted to PICU from 2011 to 2013, with the management of infection control nurses. Compare the mortality, morbidity and the incidence of acquired P. aeruginosa infections to evaluate the effect of infection control nurses. Results After implementation of the post of infection control nurses, the patient's overall mortality fell from 4.81% to 3.73%. Among the patients with endotracheal intubation more than 48 hours, the incidence of endotracheal intubation-related pneumonia decreased from 44.6% to 34.32%. The mortality of patients with endotracheal intubation decreased from 16.96% to 10.17%, and the morbidity of HAIs with P. aeruginosa decreased from 1.89% to 1.07%. The mutual different rate (MDR) dropped from 67.95% to 44.23%. There were remarkable differences in these rates between the two groups (p<0.05). Conclusion Implementing the post of infection control nurses is associated with effectively reducing the HAI rate, especially the incidence and morbidity of P. aeruginosa HAIs, reducing PICU mortality, improving P. aeruginosa drug resistance. PMID:26630032

  1. bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans

    PubMed Central

    Estes, Kathleen A.; Dunbar, Tiffany L.; Powell, Jennifer R.; Ausubel, Frederick M.; Troemel, Emily R.

    2010-01-01

    Very little is known about how animals discriminate pathogens from innocuous microbes. To address this question, we examined infection-response gene induction in the nematode Caenorhabditis elegans. We focused on genes that are induced in C. elegans by infection with the bacterial pathogen Pseudomonas aeruginosa, but are not induced by an isogenic attenuated gacA mutant. Most of these genes are induced independently of known immunity pathways. We generated a GFP reporter for one of these genes, infection response gene 1 (irg-1), which is induced strongly by wild-type P. aeruginosa strain PA14, but not by other C. elegans pathogens or by other wild-type P. aeruginosa strains that are weakly pathogenic to C. elegans. To identify components of the pathway that induces irg-1 in response to infection, we performed an RNA interference screen of C. elegans transcription factors. This screen identified zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes, and is important for defense against infection by P. aeruginosa. These data indicate that zip-2 is part of a specialized pathogen response pathway that is induced by virulent strains of P. aeruginosa and provides defense against this pathogen. PMID:20133860

  2. Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia.

    PubMed

    Cigana, Cristina; Bernardini, Francesca; Facchini, Marcella; Alcalá-Franco, Beatriz; Riva, Camilla; De Fino, Ida; Rossi, Alice; Ranucci, Serena; Misson, Pauline; Chevalier, Eric; Brodmann, Maj; Schmitt, Michel; Wach, Achim; Dale, Glenn E; Obrecht, Daniel; Bragonzi, Alessandra

    2016-08-01

    The clinical development of antibiotics with a new mode of action combined with efficient pulmonary drug delivery is a priority against untreatable Pseudomonas aeruginosa lung infections. POL7001 is a macrocycle antibiotic belonging to the novel class of protein epitope mimetic (PEM) molecules with selective and potent activity against P. aeruginosa We investigated ventilator-associated pneumonia (VAP) and cystic fibrosis (CF) as indications of the clinical potential of POL7001 to treat P. aeruginosa pulmonary infections. MICs of POL7001 and comparators were measured for reference and clinical P. aeruginosa strains. The therapeutic efficacy of POL7001 given by pulmonary administration was evaluated in murine models of P. aeruginosa acute and chronic pneumonia. POL7001 showed potent in vitro activity against a large panel of P. aeruginosa isolates from CF patients, including multidrug-resistant (MDR) isolates with adaptive phenotypes such as mucoid or hypermutable phenotypes. The efficacy of POL7001 was demonstrated in both wild-type and CF mice. In addition to a reduced bacterial burden in the lung, POL7001-treated mice showed progressive body weight recovery and reduced levels of inflammatory markers, indicating an improvement in general condition. Pharmacokinetic studies indicated that POL7001 reached significant concentrations in the lung after pulmonary administration, with low systemic exposure. These results support the further evaluation of POL7001 as a novel therapeutic agent for the treatment of P. aeruginosa pulmonary infections. PMID:27297477

  3. Protective effect of muramyl dipeptide analogs against infections of Pseudomonas aeruginosa or Candida albicans in mice.

    PubMed Central

    Fraser-Smith, E B; Matthews, T R

    1981-01-01

    Two analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) were found to give better protection than muramyl dipeptide against intraperitoneal Pseudomonas aeruginosa infection or intravenous Candida albicans infection in mice. The analogs tested were N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine and N-acetylmuramyl-L-alpha-amino-butyryl-D-isoglutamine. The optimum treatment was 80 mg/kg per day given once daily for 4 consecutive days before infection by the intraperitoneal, intravenous, or subcutaneous route. Dose response was limited. The compounds were not orally active. Synergism was seen between N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine and gentamicin. No postinfection protection was observed. A nonspecific stimulation of macrophage cells by muramyl dipeptide analogs may contribute to the protection because antiinfective activity against Listeria monocytogenes given intraperitoneally was achieved with CBA mice. PMID:7333666

  4. Characterization of corneal damage from Pseudomonas aeruginosa infection by the use of multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Chang, Yu-Lin; Chen, Wei-Liang; Lo, Wen; Chen, Shean-Jen; Tan, Hsin-Yuan; Dong, Chen-Yuan

    2010-11-01

    Using multiphoton autofluorescence (MAF) and second harmonic generation (SHG) microscopy, we investigate the morphology and the structure of the corneal epithelium and stroma collagen of bovine cornea following injection of Pseudomonas aeruginosa. We found that corneal epithelial cells are damaged and stromal collagen becoming increasingly autofluorescent with time. We also characterized infected cornea cultured for 0, 6, 12, and 24 h by quantitative ratiometric MAF to SHG index (MAFSI) analysis. MAFSI results show that the destruction of the stromal collagen corresponds to a decrease in SHG intensity and increase of MAF signal with time.

  5. Interactions between Pseudomonas aeruginosa and Staphylococcus aureus during co-cultivations and polymicrobial infections.

    PubMed

    Nguyen, Angela T; Oglesby-Sherrouse, Amanda G

    2016-07-01

    Pseudomonas aeruginosa and Staphylococcus aureus are versatile bacterial pathogens and common etiological agents in polymicrobial infections. Microbial communities containing both of these pathogens are shaped by interactions ranging from parasitic to mutualistic, with the net impact of these interactions in many cases resulting in enhanced virulence. Polymicrobial communities of these organisms are further defined by multiple aspects of the host environment, with important implications for disease progression and therapeutic outcomes. This mini-review highlights the impact of these interactions on the host and individual pathogens, the molecular mechanisms that underlie these interactions, and host-specific factors that drive interactions between these two important pathogens. PMID:27236810

  6. Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis.

    PubMed

    Vidya, P; Smith, L; Beaudoin, T; Yau, Y C; Clark, S; Coburn, B; Guttman, D S; Hwang, D M; Waters, V

    2016-01-01

    Early eradication treatment with inhaled tobramycin is successful in the majority of children with cystic fibrosis (CF) with incident Pseudomonas aeruginosa infection. However, in 10-40 % of cases, eradication fails and the reasons for this are poorly understood. The purpose of this study was to determine whether specific microbial characteristics could explain eradication treatment failure. This was a cross-sectional study of CF patients (aged 0-18 years) with incident P. aeruginosa infection from 2011 to 2014 at the Hospital for Sick Children, Toronto, Canada. Phenotypic assays were done on all incident P. aeruginosa isolates, and eradicated and persistent isolates were compared using the Mann-Whitney test or the two-sided Chi-square test. A total of 46 children with CF had 51 incident P. aeruginosa infections. In 72 % (33/46) of the patients, eradication treatment was successful, while 28 % failed eradication therapy. Persistent isolates were less likely to be motile, with significantly less twitch motility (p=0.001), were more likely to be mucoid (p=0.002), and more likely to have a tobramycin minimum inhibitory concentration (MIC) ≥ 128 μg/mL (p=0.02) compared to eradicated isolates. Although biofilm production was similar, there was a trend towards more persistent isolates with deletions in quorum-sensing genes compared with eradicated isolates (p=0.06). Initial acquisition of P. aeruginosa with characteristics of chronic infection is associated with failure of eradication treatment. PMID:26492874

  7. Profile of Virulence Factors in the Multi-Drug Resistant Pseudomonas aeruginosa Strains of Human Urinary Tract Infections (UTI)

    PubMed Central

    Habibi, Asghar; Honarmand, Ramin

    2015-01-01

    Background: Putative virulence factors are responsible for the pathogenicity of UTIs caused by Pseudomonas aeruginosa (P. aeruginosa). Resistance of P. aeruginosa to commonly used antibiotics is caused by the extreme overprescription of those antibiotics. Objectives: The goal of the present study was to investigate the prevalence of virulence factors and the antibiotic resistance patterns of P. aeruginosa isolates in UTI cases in Iran. Patients and Methods: Two hundred and fifty urine samples were collected from patients who suffered from UTIs. Samples were cultured immediately, and those that were P. aeruginosa-positive were analyzed for the presence of virulence genes using polymerase chain reaction (PCR) testing. Antimicrobial susceptibility testing (AST) was performed using the disk diffusion method. Results: Of the 250 urine samples analyzed, 8 samples (3.2%) were positive for P. aeruginosa. The prevalence of P. aeruginosa in male and female patients was 2.7% and 3.5%, respectively, (P = 0.035). In patients less than 10 years old, it was 4.2%, and in patients more than 55 years old, it was 4.2%. These were the most commonly infected groups. The highest levels of resistance were seen against ampicillin (87.5%), norfloxacin (62.5%), gentamycin (62.5%), amikacin (62.5%), and aztreonam (62.5%), while the lowest were seen for meropenem (0%), imipenem (12.5%), and polymyxin B (12.5%). LasB (87.5%), pclH (75%), pilB (75%), and exoS (75%) were the most commonly detected virulence factors in the P. aeruginosa isolates. Conclusions: It is logical to first prescribe meropenem, imipenem, and polymyxin B in cases of UTIs caused by P. aeruginosa. Medical practitioners should be aware of the presence of levels of antibiotic resistance in hospitalized UTI patients in Iran. PMID:26756017

  8. Seeking the source of Pseudomonas aeruginosa infections in a recently opened hospital: an observational study using whole-genome sequencing

    PubMed Central

    Quick, Joshua; Cumley, Nicola; Wearn, Christopher M; Niebel, Marc; Constantinidou, Chrystala; Thomas, Chris M; Pallen, Mark J; Moiemen, Naiem S; Bamford, Amy; Oppenheim, Beryl; Loman, Nicholas J

    2014-01-01

    Objectives Pseudomonas aeruginosa is a common nosocomial pathogen responsible for significant morbidity and mortality internationally. Patients may become colonised or infected with P. aeruginosa after exposure to contaminated sources within the hospital environment. The aim of this study was to determine whether whole-genome sequencing (WGS) can be used to determine the source in a cohort of burns patients at high risk of P. aeruginosa acquisition. Study design An observational prospective cohort study. Setting Burns care ward and critical care ward in the UK. Participants Patients with >7% total burns by surface area were recruited into the study. Methods All patients were screened for P. aeruginosa on admission and samples taken from their immediate environment, including water. Screening patients who subsequently developed a positive P. aeruginosa microbiology result were subject to enhanced environmental surveillance. All isolates of P. aeruginosa were genome sequenced. Sequence analysis looked at similarity and relatedness between isolates. Results WGS for 141 P. aeruginosa isolates were obtained from patients, hospital water and the ward environment. Phylogenetic analysis revealed eight distinct clades, with a single clade representing the majority of environmental isolates in the burns unit. Isolates from three patients had identical genotypes compared with water isolates from the same room. There was clear clustering of water isolates by room and outlet, allowing the source of acquisitions to be unambiguously identified. Whole-genome shotgun sequencing of biofilm DNA extracted from a thermostatic mixer valve revealed this was the source of a P. aeruginosa subpopulation previously detected in water. In the remaining two cases there was no clear link to the hospital environment. Conclusions This study reveals that WGS can be used for source tracking of P. aeruginosa in a hospital setting, and that acquisitions can be traced to a specific source within a

  9. In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections.

    PubMed

    Mardirossian, Mario; Pompilio, Arianna; Crocetta, Valentina; De Nicola, Serena; Guida, Filomena; Degasperi, Margherita; Gennaro, Renato; Di Bonaventura, Giovanni; Scocchi, Marco

    2016-09-01

    Patients with cystic fibrosis require pharmacological treatment against chronic lung infections. The alpha-helical antimicrobial peptides BMAP-27 and BMAP-28 have shown to be highly active in vitro against planktonic and sessile forms of multidrug-resistant Pseudomonas aeruginosa, Staphylococcus aureus, and Stenotrophomonas maltophilia cystic fibrosis strains. To develop small antibacterial peptides for therapeutic use, we tested shortened/modified BMAP fragments, and selected the one with the highest in vitro antibacterial activity and lowest in vivo acute pulmonary toxicity. All the new peptides have shown to roughly maintain their antibacterial activity in vitro. The 1-18 N-terminal fragment of BMAP-27, showing MIC90 of 16 µg/ml against P. aeruginosa isolates and strain-dependent anti-biofilm effects, showed the lowest pulmonary toxicity in mice. However, when tested in a murine model of acute lung infection by P. aeruginosa, BMAP-27(1-18) did not show any curative effect. If exposed to murine broncho-alveolar lavage fluid BMAP-27(1-18) was degraded within 10 min, suggesting it is not stable in pulmonary environment, probably due to murine proteases. Our results indicate that shortened BMAP peptides could represent a starting point for antibacterial drugs, but they also indicate that they need a further optimization for effective in vivo use. PMID:27270571

  10. Infection control in the pulmonary function test laboratory

    PubMed Central

    Rasam, Shweta Amol; Apte, Komalkirti Keshavkiran; Salvi, Sundeep Santosh

    2015-01-01

    Pulmonary function testing plays a crucial role in the diagnostic evaluation of patients with lung diseases. Cases of cross infection acquired from the pulmonary function laboratory, although rare, have been reported from various countries. It is therefore imperative to identify the risks and potential organisms implicated in cross infections in a pulmonary function test (PFT) laboratory and implement better and more effective infection control procedures, which will help in preventing cross infections. The infrastructure, the daily patient flow, and the prevalent disinfection techniques used in a PFT laboratory, all play a significant role in transmission of infections. Simple measures to tackle the cross infection potential in a PFT laboratory can help reduce this risk to a bare minimum. Use of specialized techniques and equipment can also be of much use in a set up that has a high turnover of patients. This review aims at creating awareness about the possible pathogens and situations commonly encountered in a PFT laboratory. We have attempted to suggest some relevant and useful infection control measures with regard to disinfection, sterilization, and patient planning and segregation to help minimize the risk of cross infections in a PFT laboratory. The review also highlights the lacuna in the current scenario of PFT laboratories in India and the need to develop newer and better methods of infection control, which will be more user-friendly and cost effective. Further studies to study the possible pathogens in a PFT laboratory and evaluate the prevalent infection control strategies will be needed to enable us to draw more precious conclusions, which can lead to more relevant, contextual recommendations for cross infections control in PFT lab in India. PMID:26180386

  11. Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1

    PubMed Central

    Nusbaum, Rebecca J.; Calderon, Veronica E.; Huante, Matthew B.; Sutjita, Putri; Vijayakumar, Sudhamathi; Lancaster, Katrina L.; Hunter, Robert L.; Actor, Jeffrey K.; Cirillo, Jeffrey D.; Aronson, Judith; Gelman, Benjamin B.; Lisinicchia, Joshua G.; Valbuena, Gustavo; Endsley, Janice J.

    2016-01-01

    Co-infection with HIV increases the morbidity and mortality associated with tuberculosis due to multiple factors including a poorly understood microbial synergy. We developed a novel small animal model of co-infection in the humanized mouse to investigate how HIV infection disrupts pulmonary containment of Mtb. Following dual infection, HIV-infected cells were localized to sites of Mtb-driven inflammation and mycobacterial replication in the lung. Consistent with disease in human subjects, we observed increased mycobacterial burden, loss of granuloma structure, and increased progression of TB disease, due to HIV co-infection. Importantly, we observed an HIV-dependent pro-inflammatory cytokine signature (IL-1β, IL-6, TNFα, and IL-8), neutrophil accumulation, and greater lung pathology in the Mtb-co-infected lung. These results suggest that in the early stages of acute co-infection in the humanized mouse, infection with HIV exacerbates the pro-inflammatory response to pulmonary Mtb, leading to poorly formed granulomas, more severe lung pathology, and increased mycobacterial burden and dissemination. PMID:26908312

  12. Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1.

    PubMed

    Nusbaum, Rebecca J; Calderon, Veronica E; Huante, Matthew B; Sutjita, Putri; Vijayakumar, Sudhamathi; Lancaster, Katrina L; Hunter, Robert L; Actor, Jeffrey K; Cirillo, Jeffrey D; Aronson, Judith; Gelman, Benjamin B; Lisinicchia, Joshua G; Valbuena, Gustavo; Endsley, Janice J

    2016-01-01

    Co-infection with HIV increases the morbidity and mortality associated with tuberculosis due to multiple factors including a poorly understood microbial synergy. We developed a novel small animal model of co-infection in the humanized mouse to investigate how HIV infection disrupts pulmonary containment of Mtb. Following dual infection, HIV-infected cells were localized to sites of Mtb-driven inflammation and mycobacterial replication in the lung. Consistent with disease in human subjects, we observed increased mycobacterial burden, loss of granuloma structure, and increased progression of TB disease, due to HIV co-infection. Importantly, we observed an HIV-dependent pro-inflammatory cytokine signature (IL-1β, IL-6, TNFα, and IL-8), neutrophil accumulation, and greater lung pathology in the Mtb-co-infected lung. These results suggest that in the early stages of acute co-infection in the humanized mouse, infection with HIV exacerbates the pro-inflammatory response to pulmonary Mtb, leading to poorly formed granulomas, more severe lung pathology, and increased mycobacterial burden and dissemination. PMID:26908312

  13. Normal and Cystic Fibrosis Human Bronchial Epithelial Cells Infected with Pseudomonas aeruginosa Exhibit Distinct Gene Activation Patterns

    PubMed Central

    Balloy, Viviane; Varet, Hugo; Dillies, Marie-Agnès; Proux, Caroline; Jagla, Bernd; Coppée, Jean-Yves; Tabary, Olivier; Corvol, Harriet; Chignard, Michel; Guillot, Loïc

    2015-01-01

    Background and Aims In cystic fibrosis (CF), Pseudomonas aeruginosa is not eradicated from the lower respiratory tract and is associated with epithelial inflammation that eventually causes tissue damage. To identify the molecular determinants of an effective response to P. aeruginosa infection, we performed a transcriptomic analysis of primary human bronchial epithelial cells from healthy donors (CTRL) 2, 4, and 6 h after induced P. aeruginosa infection. Compared to noninfected cells, infected cells showed changes in gene activity, which were most marked 6 h postinfection and usually consisted in upregulation. Results By comparing for each time point of infection, the transcriptomic response of epithelial cells from CF patients and healthy donors, we identified 851, 638, 667, and 980 differentially expressed genes 0, 2, 4, and 6 h postinfection, respectively. Gene selection followed by bioinformatic analysis showed that most of the differentially expressed genes, either up- or downregulated, were in the protein-binding and catalytic gene-ontology categories. Finally, we established that the protein products of the genes exhibiting the greatest differential upregulation (CSF2, CCL2, TNF, CSF3, MMP1, and MMP10) between CF patients and CTRL were produced in higher amounts by infected cells from CF patients versus CTRL. Conclusions The differentially expressed genes in CF patients may constitute a signature for a detrimental inflammatory response and for an inefficient P. aeruginosa host-cell response. PMID:26485688

  14. The B Lymphocyte Differentiation Factor (BAFF) Is Expressed in the Airways of Children with CF and in Lungs of Mice Infected with Pseudomonas aeruginosa

    PubMed Central

    Bricio-Moreno, Laura; Fothergill, Joanne L.; Southern, Kevin W.; Winstanley, Craig; Christmas, Stephen E.; Slupsky, Joseph R.; McNamara, Paul S.; Kadioglu, Aras; Flanagan, Brian F.

    2014-01-01

    Background Chronic lung infection with Pseudomonas aeruginosa remains a major cause of mortality and morbidity among individuals with CF. Expression of mediators promoting recruitment and differentiation of B cells, or supporting antibody production is poorly understood yet could be key to controlling infection. Methods BAFF was measured in BAL from children with CF, both with and without P. aeruginosa, and controls. Mice were intra-nasally infected with P. aeruginosa strain LESB65 for up to 7 days. Cellular infiltration and expression of B cell chemoattractants and B cell differentiation factor, BAFF were measured in lung tissue. Results BAFF expression was elevated in both P. aeruginosa negative and positive CF patients and in P. aeruginosa infected mice post infection. Expression of the B cell chemoattractants CXCL13, CCL19 and CCL21 increased progressively post infection. Conclusions In a mouse model, infection with P. aeruginosa was associated with elevated expression of BAFF and other B cell chemoattractants suggesting a role for airway B cell recruitment and differentiation in the local adaptive immune response to P. aeruginosa. The paediatric CF airway, irrespective of pseudomonal infection, was found to be associated with an elevated level of BAFF implying that BAFF expression is not specific to pseudomonas infection and may be a feature of the CF airway. Despite the observed presence of a potent B cell activator, chronic colonisation is common suggesting that this response is ineffective. PMID:24847941

  15. Effect of airway Pseudomonas aeruginosa isolation and infection on steady-state bronchiectasis in Guangzhou, China

    PubMed Central

    Guan, Wei-Jie; Gao, Yong-Hua; Xu, Gang; Lin, Zhi-Ya; Tang, Yan; Li, Hui-Min; Li, Zhi-Min; Zheng, Jin-Ping

    2015-01-01

    Background Current status of Pseudomonas aeruginosa (PA) infection in clinically stable bronchiectasis in mainland China remains unclear. Objective To compare the inflammation and lung function impairment in bronchiectasis patients isolated or infected with PA, potentially pathogenic microorganisms (PPMs) and commensals, and to identify factors associated with PA isolation and infection. Methods Patients with steady-state bronchiectasis and healthy subjects were recruited. Peripheral blood and sputum were sampled to determine inflammatory markers and bacterial loads in steady-state bronchiectasis and health. Spirometry and diffusing capacity were also measured. Results We enrolled 144 bronchiectasis patients and 23 healthy subjects. PA isolation and infection accounted for 44 and 39 patients, who demonstrated significant inflammatory responses and markedly impaired spirometry, but not diffusing capacity, compared with healthy subjects and patients isolated with other PPMs and commensals (all P<0.05). Except for heightened sputum inflammatory responses, there were no notable differences in serum inflammation and lung function as with the increased density of PA. Female gender [odds ratio (OR): 3.10 for PA isolation; OR: 3.74 for PA infection], 4 or more exacerbations within 2 years (OR: 3.74 for PA isolation, OR: 2.95 for PA infection) and cystic bronchiectasis (OR: 3.63 for PA isolation, OR: 4.47 for PA infection) were the factors consistently associated with PA isolation and infection. Conclusions PA elicits intense inflammation and lung function impairment in steady-state bronchiectasis. The density of PA does not correlate with most clinical indices. PA infection is associated with females, frequent exacerbations and cystic bronchiectasis. PMID:25973228

  16. Evolution of metabolic divergence in Pseudomonas aeruginosa during long-term infection facilitates a proto-cooperative interspecies interaction.

    PubMed

    Frydenlund Michelsen, Charlotte; Hossein Khademi, Seyed Mohammad; Krogh Johansen, Helle; Ingmer, Hanne; Dorrestein, Pieter C; Jelsbak, Lars

    2016-06-01

    The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa-S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa-S. aureus relationship. PMID:26684729

  17. Effects of a human antiflagellar monoclonal antibody in combination with antibiotics on Pseudomonas aeruginosa infection.

    PubMed Central

    Uezumi, I; Terashima, M; Kohzuki, T; Kato, M; Irie, K; Ochi, H; Noguchi, H

    1992-01-01

    The in vivo activity of human immunoglobulin M monoclonal antibody IN-2A8, which is specific for flagellum type b of Pseudomonas aeruginosa, was evaluated in comparison to anti-O antigen (serotype B) MAb KO-2F2 and in combination with antibiotics. IN-2A8 showed stronger activity than KO-2F2 against subcutaneous infection in burned mice, while it was much less active against intraperitoneal infection in normal mice. In a burn infection model, IN-2A8 inhibited the increase of bacteria in skin lesions weakly and that in blood significantly, suggesting that it strongly suppressed bacterial spread to blood. The activity of IN-2A8 in combination with 10 antipseudomonal antibiotics against intraperitoneal infection was examined. Clear additive effect was observed with a combination of either carbapenem or aminoglycoside antibiotics in terms of mouse survival. The administration of an antibiotic, imipenem-cilastatin, simultaneously with or before that of IN-2A8 gave a combined effect, but the reverse order did not. The combination of IN-2A8 with imipenem-cilastatin decreased numbers of viable bacteria in the peritoneal cavity and blood and kept them low for a longer time than did either treatment alone. These results suggest that an antiflagellar monoclonal antibody would be effective against systemic infection in combination with some kinds of antibiotics. Images PMID:1416830

  18. Opportunistic Pulmonary Infections in Immunocompromised Hosts.

    PubMed

    Rali, Parth; Veer, Manik; Gupta, Nupur; Singh, Anil C; Bhanot, Nitin

    2016-01-01

    Infections that are typically innocuous in immunocompetent persons may cause significant disease states in immunocompromised hosts. These individuals may be immunosuppressed secondary to many different causes such as drugs, malignancy, solid-organ or hematopoietic stem cell transplantation, HIV/AIDS, or anatomic reasons (asplenia). These immunocompromised hosts are at high risk for developing opportunistic infections. Here, we discuss some of these infections caused by bacteria, fungi, viruses, and parasites. Clinicians should be aware of the risk factors, common clinical presentations, diagnostic modalities, and treatment options for these potentially fatal illnesses. PMID:26919677

  19. Effects of phosphate supplementation on Pseudomonas aeruginosa invasive behavior in burn wound infections: A simple approach to a big problem.

    PubMed

    Mohammadi-Samani, Soliman; Kouroshfard, Shahriyar; Azarpira, Negar

    2016-03-01

    This study was designed to investigate the effect of inorganic phosphate supplementation on invasive behavior of Pseudomonas aeruginosa in burn wound infections. An emulsion-based lotion containing sodium dihydrogen phosphate was formulated and then 50 female Sprague-Dawley rats with burn wounds were used to assess the effect of phosphate supplementation on swarming motility of P. aeruginosa. On the second day after burn, four groups of rats were inoculated with P. aeruginosa and one group was left as negative control. The treatment was started on day 3 and the animals were followed up for 4 weeks. Significant improvement in wound healing was observed in the phosphate-receiving group after the 4-week follow-up, compared to the negative control, positive control, and silver sulfadiazine-receiving groups. Histopathological assessment of the tissue samples also indicated the healing process in phosphate-enriched lotion receiving group. The results showed that inorganic phosphate supplementation results in alteration of the virulence behavior of P. aeruginosa and improvement in the wound healing process. In conclusion, phosphate supplementation would be a rational strategy in the eradication of P. aeruginosa wound infection. PMID:26787129

  20. Aloe vera Gel: Effective Therapeutic Agent against Multidrug-Resistant Pseudomonas aeruginosa Isolates Recovered from Burn Wound Infections

    PubMed Central

    Goudarzi, Mehdi; Fazeli, Maryam; Azad, Mehdi; Seyedjavadi, Sima Sadat; Mousavi, Reza

    2015-01-01

    Objective. Aloe vera is an herbal medicinal plant with biological activities, such as antimicrobial, anticancer, anti-inflammatory, and antidiabetic ones, and immunomodulatory properties. The purpose of this study was investigation of in vitro antimicrobial activity of A. vera gel against multidrug-resistant (MDR) Pseudomonas aeruginosa isolated from patients with burn wound infections. Methods. During a 6-month study, 140 clinical isolates of P. aeruginosa were collected from patients admitted to the burn wards of a hospital in Tehran, Iran. Antimicrobial susceptibility test was carried out against the pathogens using the A. vera gel and antibiotics (imipenem, gentamicin, and ciprofloxacin). Results. The antibiogram revealed that 47 (33.6%) of all isolates were MDR P. aeruginosa. The extract isolated from A. vera has antibacterial activity against all of isolates. Also, 42 (89.4%) isolates were inhibited by A. vera gel extract at minimum inhibitory concentration (MIC) ≤ 200 µg/mL. MIC value of A. vera gel for other isolates (10.6%) was 800 µg/mL. All of MDR P. aeruginosa strains were inhibited by A. vera at similar MIC50 and MIC90 200 µg/mL. Conclusion. Based on our results, A. vera gel at various concentrations can be used as an effective antibacterial agent in order to prevent wound infection caused by P. aeruginosa. PMID:26266047

  1. Pseudomonas aeruginosa infection in embryonated hen's eggs. An alternative in vivo model for the screening of antibacterial substances.

    PubMed

    Härtl, A; Möllmann, U; Schrinner, E; Stelzner, A

    1997-09-01

    Embryonated hens' eggs can be reliably infected by Pseudomonas aeruginosa in laboratory experiments. Therapy tests with the antibiotics azlocillin (CAS 37091-66-0) and gentamicin (CAS 13291-74-2) on this type of infected hens' eggs demonstrate that this test system offers a realistic alternative to septic experiments with small laboratory rodents. Chick embryos survive a lethal Pseudomonas infection when azlocillin or gentamicin in a relevant therapeutic dose are administered immediately after the infective agent. The use of Pseudomonas infected chick embryos in the screening for new antiinfectives allows, therefore, a considerable reduction of the number of laboratory rodents required. PMID:9342424

  2. Blue Light Rescues Mice from Potentially Fatal Pseudomonas aeruginosa Burn Infection: Efficacy, Safety, and Mechanism of Action

    PubMed Central

    Dai, Tianhong; Gupta, Asheesh; Huang, Ying-Ying; Yin, Rui; Murray, Clinton K.; Vrahas, Mark S.; Sherwood, Margaret E.; Tegos, George P.

    2013-01-01

    Blue light has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. However, the use of blue light for wound infections has not been established yet. In this study, we demonstrated the efficacy of blue light at 415 nm for the treatment of acute, potentially lethal Pseudomonas aeruginosa burn infections in mice. Our in vitro studies demonstrated that the inactivation rate of P. aeruginosa cells by blue light was approximately 35-fold higher than that of keratinocytes (P = 0.0014). Transmission electron microscopy revealed blue light-mediated intracellular damage to P. aeruginosa cells. Fluorescence spectroscopy suggested that coproporphyrin III and/or uroporphyrin III are possibly the intracellular photosensitive chromophores associated with the blue light inactivation of P. aeruginosa. In vivo studies using an in vivo bioluminescence imaging technique and an area-under-the-bioluminescence-time-curve (AUBC) analysis showed that a single exposure of blue light at 55.8 J/cm2, applied 30 min after bacterial inoculation to the infected mouse burns, reduced the AUBC by approximately 100-fold in comparison with untreated and infected mouse burns (P < 0.0001). Histological analyses and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays indicated no significant damage in the mouse skin exposed to blue light at the effective antimicrobial dose. Survival analyses revealed that blue light increased the survival rate of the infected mice from 18.2% to 100% (P < 0.0001). In conclusion, blue light therapy might offer an effective and safe alternative to conventional antimicrobial therapy for P. aeruginosa burn infections. PMID:23262998

  3. Blue light rescues mice from potentially fatal Pseudomonas aeruginosa burn infection: efficacy, safety, and mechanism of action.

    PubMed

    Dai, Tianhong; Gupta, Asheesh; Huang, Ying-Ying; Yin, Rui; Murray, Clinton K; Vrahas, Mark S; Sherwood, Margaret E; Tegos, George P; Hamblin, Michael R

    2013-03-01

    Blue light has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. However, the use of blue light for wound infections has not been established yet. In this study, we demonstrated the efficacy of blue light at 415 nm for the treatment of acute, potentially lethal Pseudomonas aeruginosa burn infections in mice. Our in vitro studies demonstrated that the inactivation rate of P. aeruginosa cells by blue light was approximately 35-fold higher than that of keratinocytes (P = 0.0014). Transmission electron microscopy revealed blue light-mediated intracellular damage to P. aeruginosa cells. Fluorescence spectroscopy suggested that coproporphyrin III and/or uroporphyrin III are possibly the intracellular photosensitive chromophores associated with the blue light inactivation of P. aeruginosa. In vivo studies using an in vivo bioluminescence imaging technique and an area-under-the-bioluminescence-time-curve (AUBC) analysis showed that a single exposure of blue light at 55.8 J/cm(2), applied 30 min after bacterial inoculation to the infected mouse burns, reduced the AUBC by approximately 100-fold in comparison with untreated and infected mouse burns (P < 0.0001). Histological analyses and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays indicated no significant damage in the mouse skin exposed to blue light at the effective antimicrobial dose. Survival analyses revealed that blue light increased the survival rate of the infected mice from 18.2% to 100% (P < 0.0001). In conclusion, blue light therapy might offer an effective and safe alternative to conventional antimicrobial therapy for P. aeruginosa burn infections. PMID:23262998

  4. Complete Genome Sequence of Pseudomonas aeruginosa PA1, Isolated from a Patient with a Respiratory Tract Infection

    PubMed Central

    Lu, Shuguang; Le, Shuai; Li, Gang; Shen, Mengyu; Tan, Yinling; Zhao, Xia; Wang, Jing; Shen, Wei; Guo, Keke; Yang, Yuhui; Zhu, Hongbin; Li, Shu; Li, Ming; Zhu, Junmin; Rao, Xiancai

    2015-01-01

    We report the 6,498,072-bp complete genome sequence of Pseudomonas aeruginosa PA1, which was isolated from a patient with a respiratory tract infection in Chongqing, People's Republic of China. Whole-genome sequencing was performed using single-molecule real-time (SMRT) technology, and de novo assembly revealed a single contig with 396-fold sequence coverage. PMID:26659688

  5. Insights into the respiratory tract microbiota of patients with cystic fibrosis during early Pseudomonas aeruginosa colonization

    DOE PAGESBeta

    Keravec, Marlène; Mounier, Jérôme; Prestat, Emmanuel; Vallet, Sophie; Jansson, Janet K.; Burgaud, Gaëtan; Rosec, Sylvain; Gouriou, Stéphanie; Rault, Gilles; Coton, Emmanuel; et al

    2015-08-09

    Pseudomonas aeruginosa plays a major role in cystic fibrosis (CF) progression. Therefore, it is important to understand the initial steps of P. aeruginosa infection. The structure and dynamics of CF respiratory tract microbial communities during the early stages of P. aeruginosa colonization were characterized by pyrosequencing and cloning-sequencing. The respiratory microbiota showed high diversity, related to the young age of the CF cohort (mean age 10 years). Wide inter- and intra-individual variations were revealed. A common core microbiota of 5 phyla and 13 predominant genera was found, the majority of which were obligate anaerobes. A few genera were significantly moremore » prevalent in patients never infected by P. aeruginosa. Persistence of an anaerobic core microbiota regardless of P. aeruginosa status suggests a major role of certain anaerobes in the pathophysiology of lung infections in CF. Some genera may be potential biomarkers of pulmonary infection state.« less

  6. Insights into the respiratory tract microbiota of patients with cystic fibrosis during early Pseudomonas aeruginosa colonization

    SciTech Connect

    Keravec, Marlene; Mounier, Jerome; Prestat , Emmanuel; Vallet, Sophie; Jansson, Janet K.; Bergaud , Gaetaqn; Rosec, Silvain; Gourious, Stephanie; Rault, Gilles; Coton, Emmanuel; Barbier, George; Hery-Arnaud, Geneveieve

    2015-08-09

    Abstract Pseudomonas aeruginosa plays a major role in cystic fibrosis (CF) progression. Therefore, it is important to understand the initial steps of P. aeruginosa infection. The structure and dynamics of CF respiratory tract microbial communities during the early stages of P. aeruginosa colonization were characterized by pyrosequencing and cloning-sequencing. The respiratory microbiota showed high diversity, related to the young age of the CF cohort (mean age 10 years). Wide inter- and intra-individual variations were revealed. A common core microbiota of 5 phyla and 13 predominant genera was found, the majority of which were obligate anaerobes. A few genera were significantly more prevalent in patients never infected by P. aeruginosa. Persistence of an anaerobic core microbiota regardless of P. aeruginosa status suggests a major role of certain anaerobes in the pathophysiology of lung infections in CF. Some genera may be potential biomarkers of pulmonary infection state.

  7. Insights into the respiratory tract microbiota of patients with cystic fibrosis during early Pseudomonas aeruginosa colonization.

    PubMed

    Keravec, Marlène; Mounier, Jérôme; Prestat, Emmanuel; Vallet, Sophie; Jansson, Janet K; Burgaud, Gaëtan; Rosec, Sylvain; Gouriou, Stéphanie; Rault, Gilles; Coton, Emmanuel; Barbier, Georges; Héry-Arnaud, Geneviève

    2015-01-01

    Pseudomonas aeruginosa plays a major role in cystic fibrosis (CF) progression. Therefore, it is important to understand the initial steps of P. aeruginosa infection. The structure and dynamics of CF respiratory tract microbial communities during the early stages of P. aeruginosa colonization were characterized by pyrosequencing and cloning-sequencing. The respiratory microbiota showed high diversity, related to the young age of the CF cohort (mean age 10 years). Wide inter- and intra-individual variations were revealed. A common core microbiota of 5 phyla and 13 predominant genera was found, the majority of which were obligate anaerobes. A few genera were significantly more prevalent in patients never infected by P. aeruginosa. Persistence of an anaerobic core microbiota regardless of P. aeruginosa status suggests a major role of certain anaerobes in the pathophysiology of lung infections in CF. Some genera may be potential biomarkers of pulmonary infection state. PMID:26266076

  8. Draft genome sequence of blaVeb-1, blaoxa-10 producing multi-drug resistant (MDR) Pseudomonas aeruginosa strain VRFPA09 recovered from bloodstream infection.

    PubMed

    Murugan, Nandagopal; Malathi, Jambulingam; Umashankar, Vetrivel; Madhavan, Hajib NarahariRao

    2015-01-01

    Pseudomonas aeruginosa (P. aeruginosa) bacteremia causes significant mortality rate due to emergence of multidrug resistant (MDR) nosocomial infections. We report the draft genome sequence of P. aeruginosa strain VRFPA09, a human bloodstream isolate, phenotypically proven as MDR strain. Whole genome sequencing on VRFPA09, deciphered betalactamase encoding blav(eb-1) and bla(OXA-10) genes and multiple drug resistance, virulence factor encoding genes. PMID:26413042

  9. Pseudomonas aeruginosa Exploits Lipid A and Muropeptides Modification as a Strategy to Lower Innate Immunity during Cystic Fibrosis Lung Infection

    PubMed Central

    Ieranò, Teresa; Lorè, Nicola Ivan; Bianconi, Irene; Silipo, Alba; Cozzolino, Flora; Lanzetta, Rosa; Molinaro, Antonio; Bernardini, Maria Lina; Bragonzi, Alessandra

    2009-01-01

    Pseudomonas aeruginosa can establish life-long airways chronic infection in patients with cystic fibrosis (CF) with pathogenic variants distinguished from initially acquired strain. Here, we analysed chemical and biological activity of P. aeruginosa Pathogen-Associated Molecular Patterns (PAMPs) in clonal strains, including mucoid and non-mucoid phenotypes, isolated during a period of up to 7.5 years from a CF patient. Chemical structure by MS spectrometry defined lipopolysaccharide (LPS) lipid A and peptidoglycan (PGN) muropeptides with specific structural modifications temporally associated with CF lung infection. Gene sequence analysis revealed novel mutation in pagL, which supported lipid A changes. Both LPS and PGN had different potencies when activating host innate immunity via binding TLR4 and Nod1. Significantly higher NF-kB activation, IL-8 expression and production were detected in HEK293hTLR4/MD2-CD14 and HEK293hNod1 after stimulation with LPS and PGN respectively, purified from early P. aeruginosa strain as compared to late strains. Similar results were obtained in macrophages-like cells THP-1, epithelial cells of CF origin IB3-1 and their isogenic cells C38, corrected by insertion of cystic fibrosis transmembrane conductance regulator (CFTR). In murine model, altered LPS structure of P. aeruginosa late strains induces lower leukocyte recruitment in bronchoalveolar lavage and MIP-2, KC and IL-1β cytokine levels in lung homogenates when compared with early strain. Histopathological analysis of lung tissue sections confirmed differences between LPS from early and late P. aeruginosa. Finally, in this study for the first time we unveil how P. aeruginosa has evolved the capacity to evade immune system detection, thus promoting survival and establishing favourable conditions for chronic persistence. Our findings provide relevant information with respect to chronic infections in CF. PMID:20037649

  10. Excessive pediatric fasciitis necrotisans due to Pseudomonas aeruginosa infection successfully treated with negative pressure wound therapy.

    PubMed

    Szabó, Levente; Szegedi, István; Kiss, Csongor; Szikszay, Edit; Remenyik, Éva; Csízy, István; Juhász, István

    2015-01-01

    The case of a 10-year old female child is described with a history of myeloproliferative disorder having skin, bone and visceral involvement. Bone marrow biopsy revealed histiocytosis X. During chemotherapy necrotizing fasciitis of the lower abdominal wall was diagnosed. Multiple microbiological cultures taken from the wound base revealed Pseudomonas aeruginosa infection. Surgical necrectomy and application of negative pressure wound therapy (NPWT) was started together with intensive care treatment for sepsis. As both wound and general condition of the patient improved, autologous split thickness skin grafting was carried out in two sitting under continuing NPWT application. The applied skin grafts showed excellent take, the perilesional subcutaneous recesses resolved and complete healing was achieved after 28 days of NPWT treatment. Proper dermatological diagnosis and immediate escharectomy complemented with application of NPWT can be life-saving in the treatment of necrotizing fasciitis. PMID:26032296

  11. Microbial growth inhibition by alternating electric fields in mice with Pseudomonas aeruginosa lung infection.

    PubMed

    Giladi, Moshe; Porat, Yaara; Blatt, Alexandra; Shmueli, Esther; Wasserman, Yoram; Kirson, Eilon D; Palti, Yoram

    2010-08-01

    High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2 degrees C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality. PMID:20547811

  12. Novel inhaled combined antibiotic formulations in the treatment of Pseudomonas aeruginosa airways infections in cystic fibrosis.

    PubMed

    Antoniu, Sabina

    2015-07-01

    In cystic fibrosis, chronic airways infection caused by Pseudomonas aeruginosa can be treated with inhaled antibiotics such as inhaled tobramycin, aztreonam or colistin. However, biofilm formation induced by this bacterium can reduce the effectiveness of such therapies and can contribute to antibiotic resistance. Inhaled antibiotic combination might represent an optimal antibiofilm strategy in this setting. This review discusses the rationale for combining the antibiotics as well as some emerging or existing combinations. Most of the combinations except for fosfomycin/tobramycin are at an early stage of development. The latter combination was found to be effective in Phase II clinical studies and is planned to be tested in Phase III trials. The clinical data on long-term efficacy are currently missing, but the existing evidence as well as the unmet therapeutic need can prompt the further evaluation of such compounds. PMID:25921312

  13. Protective effect of recombinant murine granulocyte-macrophage colony-stimulating factor against Pseudomonas aeruginosa infection in leukocytopenic mice.

    PubMed Central

    Tanaka, T.; Okamura, S.; Okada, K.; Suga, A.; Shimono, N.; Ohhara, N.; Hirota, Y.; Sawae, Y.; Niho, Y.

    1989-01-01

    The effects of recombinant murine granulocyte-macrophage colony-stimulating factor (rmGM-CSF) against Pseudomonas aeruginosa infection in ICR mice were investigated. Mice were treated with cyclophosphamide (CPA) and were then injected intraperitoneally with rmGM-CSF three times daily, beginning on the day after CPA treatment, for 7 days. The number of peripheral blood leukocytes in both CPA- and rmGM-CSF-treated mice and control CPA-treated mice reached a nadir on day 4, when P. aeruginosa was injected intraperitoneally. The administration of rmGM-CSF significantly increased the proportion of survivors among mice infected with a lethal dose of P. aeruginosa. This effect was further analyzed by monitoring sequential changes in leukocyte count and bacterial growth in various organs. The number of bacteria in the peritoneal cavities, peripheral blood samples, and livers of GM-CSF-treated mice decreased to an undetectable level after a transient increase, and the number was significantly lower than that in control mice. In GM-CSF-treated mice, the neutrophil levels in peripheral blood started to increase 5 days after CPA administration and were consistently higher than those in controls. Furthermore, the neutrophils in GM-CSF-treated mice were more mature morphologically. Thus, the prophylactic effect of rmGM-CSF against P. aeruginosa infection may result from a rapid recovery of myelopoiesis and a partial enhancement of mature neutrophil function. PMID:2656523

  14. Large Porous Particles for Sustained Release of a Decoy Oligonucelotide and Poly(ethylenimine): Potential for Combined Therapy of Chronic Pseudomonas aeruginosa Lung Infections.

    PubMed

    d'Angelo, Ivana; Perfetto, Brunella; Costabile, Gabriella; Ambrosini, Veronica; Caputo, Pina; Miro, Agnese; d'Emmanuele di Villa Bianca, Roberta; Sorrentino, Raffaella; Donnarumma, Giovanna; Quaglia, Fabiana; Ungaro, Francesca

    2016-05-01

    We have recently demonstrated that the specific inhibition of nuclear factor-κB by a decoy oligonucleotide (dec-ODN) delivered through inhalable large porous particles (LPP) made of poly(lactic-co-glycolic acid) (PLGA) may be highly beneficial for long-term treatment of lung inflammation. Nevertheless, besides chronic inflammation, multifunctional systems aimed to control also infection are required in chronic lung diseases, such as cystic fibrosis (CF). In this work, we tested the hypothesis that engineering PLGA-based LPP with branched poly(ethylenimine) (PEI) may improve LPP properties for pulmonary delivery of dec-ODN, with particular regard to the treatment of Pseudomonas aeruginosa lung infections. After getting insight into the role of PEI on the technological properties of PLGA-based LPP for delivery of dec-ODN, the putative synergistic effect of PEI free or PEI released from LPP on in vitro antimicrobial activity of tobramycin (Tb) and aztreonam (AZT) against P. aeruginosa was elucidated. Meanwhile, cytotoxicity studies on A549 cells were carried out. Results clearly demonstrate that the dry powders have promising aerosolization properties and afford a prolonged in vitro release of both dec-ODN and PEI. The encapsulation of PEI into LPP results in a 2-fold reduction of the minimum inhibitory concentration of AZT, while reducing the cytotoxic effect of PEI. Of note, the developed ODN/PLGA/PEI LPP persisted at lung at least for 14 days after intratracheal administration in rats where they can provide sustained and combined release of dec-ODN and PEI. dec-ODN will likely act as an anti-inflammatory drug, while PEI may enhance the therapeutic activity of inhaled antibiotics, which are commonly employed for the treatment of concomitant lung infections. PMID:27002689

  15. In Vitro Analysis of Pseudomonas aeruginosa Virulence Using Conditions That Mimic the Environment at Specific Infection Sites.

    PubMed

    Colmer-Hamood, J A; Dzvova, N; Kruczek, C; Hamood, A N

    2016-01-01

    Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes chronic lung infection in patients with cystic fibrosis (CF) and acute systemic infections in severely burned patients and immunocompromised patients including cancer patients undergoing chemotherapy and HIV infected individuals. In response to the environmental conditions at specific infection sites, P. aeruginosa expresses certain sets of cell-associated and extracellular virulence factors that produce tissue damage. Analyzing the mechanisms that govern the production of these virulence factors in vitro requires media that closely mimic the environmental conditions within the infection sites. In this chapter, we review studies based on media that closely resemble three in vivo conditions, the thick mucus accumulated within the lung alveoli of CF patients, the serum-rich wound bed and the bloodstream. Media resembling the CF alveolar mucus include standard laboratory media supplemented with sputum obtained from CF patients as well as prepared synthetic mucus media formulated to contain the individual components of CF sputum. Media supplemented with serum or individual serum components have served as surrogates for the soluble host components of wound infections, while whole blood has been used to investigate the adaptation of pathogens to the bloodstream. Studies using these media have provided valuable information regarding P. aeruginosa gene expression in different host environments as varying sets of genes were differentially regulated during growth in each medium. The unique effects observed indicate the essential role of these in vitro media that closely mimic the in vivo conditions in providing accurate information regarding the pathogenesis of P. aeruginosa infections. PMID:27571695

  16. A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection

    PubMed Central

    Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; van der Plas, Mariena J. A.; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

    2014-01-01

    Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections. PMID:25047075

  17. The pulmonary involvement in Theileria lestoquardi naturally infected sheep.

    PubMed

    El Imam, Ahmed H; Hassan, Shawgi M; Gameel, Ahmed A; El Hussein, Abdelrahim M; Taha, Khalid M

    2016-01-01

    Malignant Ovine Theileriosis (MOT) caused by Theileria lestoquardi is considered a major constraint for sheep production in many areas of the world including Sudan. Pulmonary oedema is thought to be the main cause of animal death, but the mechanism, the cell types involved and/or the probable cause of this pneumonia has yet to be defined. The present study was carried out to investigate the pulmonary involvement post T. lestoquardi infection and to identify the cell types involved in pneumonia. Apparently healthy sheep were exposed to ticks challenge in T. lestoquardi endemic area. Lungs impression smears and tissue sections for histopathology were processed. At necropsy, fifteen infected sheep revealed severe pneumonia associated with oedema and accumulation of creamy-grayish frothy exudates. The microscopic findings of examined lungs showed emphysema, congestion, collapse and proliferation of immense amount of different kinds of cells. The current study indicates that T. lestoquardi infections are accompanied with remarkable pulmonary involvements and may lead to respiratory failure and death. PMID:27262956

  18. Immunopathogenesis of Staphylococcus aureus pulmonary infection

    PubMed Central

    Parker, Dane; Prince, Alice

    2013-01-01

    Staphylococcus aureus is a common human pathogen highly evolved as both a component of the commensal flora and as a major cause of invasive infection. Severe respiratory infection due to staphylococci has been increasing due to the prevalence of more virulent USA300 CA-MRSA strains in the general population. The ability of S. aureus to adapt to the milieu of the respiratory tract has facilitated its emergence as a respiratory pathogen. Its metabolic versatility, the ability to scavenge iron, coordinate gene expression, and the horizontal acquisition of useful genetic elements have all contributed to its success as a component of the respiratory flora, in hospitalized patients, as a complication of influenza and in normal hosts. The expression of surface adhesins facilitates its persistence in the airways. In addition, the highly sophisticated interactions of the multiple S. aureus virulence factors, particularly the α-hemolysin and protein A, with diverse immune effectors in the lung such as ADAM10, TNFR1, EGFR, immunoglobulin, and complement all contribute to the pathogenesis of staphylococcal pneumonia. PMID:22037948

  19. [Chemotherapy of pulmonary Mycobacterium kansasii infection].

    PubMed

    Mizutani, S

    1996-09-01

    the former author demonstrated the potent activities of both CS-940* and sparfloxacin (SPFX), followed by AM-1155*, ciprofloxacin (CPFX), levofloxacin (LVFX), OPC-17116*, NM-394* in sequence. The author gave attention also to a high Cmax in CS-940*. In vitro activities with 7 H 11 agar medium reported by Dr. Kawahara demonstrated generally higher activities against M. avium than M. intracellulare, and reported potent activities of CPFX, SPFX, LVFX, grepafloxacin (GPFX), AM-1155*, and DU-6859 a* among 14 NQs tested. The author reported a rather potent activity of CAM against MAC followed by RXM and AZM in sequence. There was an impression that the MICs in both liquid and agar medium were comparable. (* : under development). The present status in the treatment of MAC lung disease was precisely reported by Dr. Harada, who summarized the results of survey both in 13 National Chest Hospitals (by questionnaire) and in the author's Hospital. The former survey demonstrated that 73% of the cases with the initial chemotherapy became consecutively negative for 6 months in the span of 9 months observation, which clearly showed the early response of MAC disease was rather favorable, in spite of very few cases with 4 drug-or more combinations. However, longer the follow up, the percentage of negative cases went down, which suggested bacteriological relapse occurred in relatively high percentage of the early converted cases. The evaluation of 117 cases of pulmonary MAC disease in the author's Hospital disclosed 2 drug-combination, RFP and INH, was clearly less potent than 3-drug combination, RFP.IHN.SM or EB, and 1 year after the begining of initial chemotherapy, around 60% of cases were negative, while only a little more than 40% of cases were negative in retreatments. The author suggested that around 50% of MAC lung disease may progress with episodes of "relapse". Death occurred 20% in the cases PMID:8914388

  20. High coverage metabolomics analysis reveals phage-specific alterations to Pseudomonas aeruginosa physiology during infection.

    PubMed

    De Smet, Jeroen; Zimmermann, Michael; Kogadeeva, Maria; Ceyssens, Pieter-Jan; Vermaelen, Wesley; Blasdel, Bob; Bin Jang, Ho; Sauer, Uwe; Lavigne, Rob

    2016-08-01

    Phage-mediated metabolic changes in bacteria are hypothesized to markedly alter global nutrient and biogeochemical cycles. Despite their theoretic importance, experimental data on the net metabolic impact of phage infection on the bacterial metabolism remains scarce. In this study, we tracked the dynamics of intracellular metabolites using untargeted high coverage metabolomics in Pseudomonas aeruginosa cells infected with lytic bacteriophages from six distinct phage genera. Analysis of the metabolomics data indicates an active interference in the host metabolism. In general, phages elicit an increase in pyrimidine and nucleotide sugar metabolism. Furthermore, clear phage-specific and infection stage-specific responses are observed, ranging from extreme metabolite depletion (for example, phage YuA) to complete reorganization of the metabolism (for example, phage phiKZ). As expected, pathways targeted by the phage-encoded auxiliary metabolic genes (AMGs) were enriched among the metabolites changing during infection. The effect on pyrimidine metabolism of phages encoding AMGs capable of host genome degradation (for example, YuA and LUZ19) was distinct from those lacking nuclease-encoding genes (for example, phiKZ), which demonstrates the link between the encoded set of AMGs of a phage and its impact on host physiology. However, a large fraction of the profound effect on host metabolism could not be attributed to the phage-encoded AMGs. We suggest a potentially crucial role for small, 'non-enzymatic' peptides in metabolism take-over and hypothesize on potential biotechnical applications for such peptides. The highly phage-specific nature of the metabolic impact emphasizes the potential importance of the 'phage diversity' parameter when studying metabolic interactions in complex communities. PMID:26882266

  1. Pseudomonas aeruginosa Infection in a Group of Captive Humboldt Penguins ( Spheniscus humboldti ).

    PubMed

    Widmer, Dimitri; Ziemssen, Eva; Schade, Benjamin; Kappe, Eva; Schmitt, Ferdinand; Kempf, Hermann; Wibbelt, Gudrun

    2016-06-01

    Nine Humboldt penguins ( Spheniscus humboldti ), between 1 and 1.5 years old and kept at Zoo Dresden, developed local and systemic infections with various opportunistic pathogens within a period of 4 months. Affected birds died peracutely without preceding symptoms or showed various clinical signs, including separation from conspecifics, reduced food intake, lethargy, dyspnea, swelling of the salt glands, and ocular discharge. One bird showed central nervous signs, including seizures. Pathologic examination of deceased birds revealed severe necrotizing inflammation of the mucous membranes and deep structures of the glottis, trachea, nasal sinus, and conchae and granulomatous inflammation of the salt glands. Further findings were airsacculitis, pneumonia, hepatitis, conjunctivitis, and myositis. Pseudomonas aeruginosa was the predominant pathogen in 7 cases. Six penguins died or were euthanatized, whereas 3 penguins that received systemic antibiotic treatment with tobramycin (10 mg/kg IM q24h for 10 days) showed rapid clinical improvement. Insufficient turnover rate of the filtration system, biofilm formation on pipe surfaces, and other factors are assumed to have promoted pathogen buildup in the pool water and subsequent infection. PMID:27315388

  2. Cystic Fibrosis Transmembrane Conductance Regulator is an Epithelial Cell Receptor for Clearance of Pseudomonas aeruginosa from the Lung

    NASA Astrophysics Data System (ADS)

    Pier, Gerald B.; Grout, Martha; Zaidi, Tanweer S.

    1997-10-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel, but its relationship to the primary clinical manifestation of CF, chronic Pseudomonas aeruginosa pulmonary infection, is unclear. We report that CFTR is a cellular receptor for binding, endocytosing, and clearing P. aeruginosa from the normal lung. Murine cells expressing recombinant human wild-type CFTR ingested 30-100 times as many P. aeruginosa as cells lacking CFTR or expressing mutant Δ F508 CFTR protein. Purified CFTR inhibited ingestion of P. aeruginosa by human airway epithelial cells. The first extracellular domain of CFTR specifically bound to P. aeruginosa and a synthetic peptide of this region inhibited P. aeruginosa internalization in vivo, leading to increased bacterial lung burdens. CFTR clears P. aeruginosa from the lung, indicating a direct connection between mutations in CFTR and the clinical consequences of CF.

  3. The TAK1→IKKβ→TPL2→MKK1/MKK2 Signaling Cascade Regulates IL-33 Expression in Cystic Fibrosis Airway Epithelial Cells Following Infection by Pseudomonas aeruginosa

    PubMed Central

    Farias, Raquel; Rousseau, Simon

    2016-01-01

    In cystic fibrosis (CF), chronic respiratory infections result in an exaggerated and uncontrolled inflammatory response that ultimately lead to a decrease in pulmonary function. We have previously described the presence of the alarmin IL-33 in lung explants from CF patients. The signals regulating IL-33 expression in the airway epithelium following a gram-negative bacterial infection are currently unknown. Our objective was to characterize the pathways in CF airway epithelial cells (AECs) leading to an increase in IL-33 expression. We found that, in CF AECs expressing a deletion of a phenylalanine at position 508 of the gene coding for Cystic Fibrosis Transmembrane Conductance Regulator (CFTRdelF508), exposure to live Pseudomonas aeruginosa upregulates IL-33 via the TLR2 and TLR5 signaling pathways. This up-regulation can be partially or fully reverted by pre-incubating CFTRdelF508 AECs with a CFTR corrector (VX-809) and/or a CFTR potentiator (VX-770). Similarly, incubation with the CFTR corrector and/or the CFTR potentiator also decreased IL-8 expression in response to infection. Moreover, using different protein kinase inhibitors that target elements downstream of TLR signaling, we show that the TAK1→IKKβ→TPL2→MKK1/MKK2 pathway regulates IL-33 expression following an infection with P. aeruginosa. Our findings represent the first characterization of the signals regulating IL-33 expression in CF airway epithelial cells in response to a bacterial infection. PMID:26793709

  4. Helical Carbon Nanotubes Enhance the Early Immune Response and Inhibit Macrophage-Mediated Phagocytosis of Pseudomonas aeruginosa

    PubMed Central

    Walling, Brent E.; Kuang, Zhizhou; Hao, Yonghua; Estrada, David; Wood, Joshua D.; Lian, Feifei; Miller, Lou Ann; Shah, Amish B.; Jeffries, Jayme L.; Haasch, Richard T.; Lyding, Joseph W.; Pop, Eric; Lau, Gee W.

    2013-01-01

    Aerosolized or aspirated manufactured carbon nanotubes have been shown to be cytotoxic, cause pulmonary lesions, and demonstrate immunomodulatory properties. CD-1 mice were used to assess pulmonary toxicity of helical carbon nanotubes (HCNTs) and alterations of the immune response to subsequent infection by Pseudomonas aeruginosa in mice. HCNTs provoked a mild inflammatory response following either a single exposure or 2X/week for three weeks (multiple exposures) but were not significantly toxic. Administering HCNTs 2X/week for three weeks resulted in pulmonary lesions including granulomas and goblet cell hyperplasia. Mice exposed to HCNTs and subsequently infected by P. aeruginosa demonstrated an enhanced inflammatory response to P. aeruginosa and phagocytosis by alveolar macrophages was inhibited. However, clearance of P. aeruginosa was not affected. HCNT exposed mice depleted of neutrophils were more effective in clearing P. aeruginosa compared to neutrophil-depleted control mice, accompanied by an influx of macrophages. Depletion of systemic macrophages resulted in slightly inhibited bacterial clearance by HCNT treated mice. Our data indicate that pulmonary exposure to HCNTs results in lesions similar to those caused by other nanotubes and pre-exposure to HCNTs inhibit alveolar macrophage phagocytosis of P. aeruginosa. However, clearance was not affected as exposure to HCNTs primed the immune system for an enhanced inflammatory response to pulmonary infection consisting of an influx of neutrophils and macrophages. PMID:24324555

  5. CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense.

    PubMed

    Carevic, M; Öz, H; Fuchs, K; Laval, J; Schroth, C; Frey, N; Hector, A; Bilich, T; Haug, M; Schmidt, A; Autenrieth, S E; Bucher, K; Beer-Hammer, S; Gaggar, A; Kneilling, M; Benarafa, C; Gao, J L; Murphy, P M; Schwarz, S; Moepps, B; Hartl, D

    2016-01-01

    Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases. PMID:26950764

  6. Protective role of Th17 cells in pulmonary infection.

    PubMed

    Rathore, Jitendra Singh; Wang, Yan

    2016-03-18

    Th17 cells are characterized as preferential producer of interleukins including IL-17A, IL-17F, IL-21 and IL-22. Corresponding receptors of these cytokines are expressed on number of cell types found in the mucosa, including epithelial cells and fibroblasts which constitute the prime targets of the Th17-associated cytokines. Binding of IL-17 family members to their corresponding receptors lead to modulation of antimicrobial functions of target cells including alveolar epithelial cells. Stimulated alveolar epithelial cells produce antimicrobial peptides and are involved in granulepoesis, neutrophil recruitment and tissue repair. Mucosal immunity mediated by Th17 cells is protective against numerous pulmonary pathogens including extracellular bacterial and fungal pathogens. This review focuses on the protective role of Th17 cells during pulmonary infection, highlighting subset differentiation, effector cytokines production, followed by study of the binding of these cytokines to their corresponding receptors, the subsequent signaling pathway they engender and their effector role in host defense. PMID:26878294

  7. Efficacy of species-specific protein antibiotics in a murine model of acute Pseudomonas aeruginosa lung infection

    PubMed Central

    McCaughey, Laura C.; Ritchie, Neil. D.; Douce, Gillian R.; Evans, Thomas J.; Walker, Daniel

    2016-01-01

    Protein antibiotics, known as bacteriocins, are widely produced by bacteria for intraspecies competition. The potency and targeted action of bacteriocins suggests that they could be developed into clinically useful antibiotics against highly drug resistant Gram-negative pathogens for which there are few therapeutic options. Here we show that Pseudomonas aeruginosa specific bacteriocins, known as pyocins, show strong efficacy in a murine model of P. aeruginosa lung infection, with the concentration of pyocin S5 required to afford protection from a lethal infection at least 100-fold lower than the most commonly used inhaled antibiotic tobramycin. Additionally, pyocins are stable in the lung, poorly immunogenic at high concentrations and efficacy is maintained in the presence of pyocin specific antibodies after repeated pyocin administration. Bacteriocin encoding genes are frequently found in microbial genomes and could therefore offer a ready supply of highly targeted and potent antibiotics active against problematic Gram-negative pathogens. PMID:27444885

  8. ANTI-PCRV ANTIBODY IN CYSTIC FIBROSIS: A NOVEL APPROACH TARGETING PSEUDOMONAS AERUGINOSA AIRWAY INFECTION

    PubMed Central

    Milla, Carlos E.; Chmiel, James F.; Accurso, Frank J.; VanDevanter, Donald R.; Konstan, Michael W.; Yarranton, Geoffrey; Geller, David E.

    2014-01-01

    SUMMARY Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality in cystic fibrosis (CF). The type III secretion system is one of the factors responsible for the increased virulence and pro-inflammatory effects of Pa. KB001 is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab’ fragment that blocks the function of Pa TTSS. We studied the safety, pharmacokinetic (PK), and pharmacodynamic properties of KB001 in CF subjects with chronic Pa infection. Twenty-seven eligible CF subjects (≥ 12 years of age, FEV1 ≥ 40% of predicted, and sputum Pa density >105 CFU/gm) received a single intravenous dose of KB001 (3 mg/kg or 10 mg/kg) or placebo. Safety, PK, Pa density, clinical outcomes and inflammatory markers were assessed. KB001 had an acceptable safety profile and a mean serum half-life of 11.9 days. All subjects had Pa TTSS expression in sputum. There were no significant differences between KB001 and placebo for changes in Pa density, symptoms, or spirometry after a single dose. However, compared to baseline, at Day 28 there was a trend towards a dose-dependent reduction in sputum myeloperoxidase, IL-1, and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001 10 mg/kg group versus placebo (−0.61 log10 and −0.63 log10 respectively; p<0.05). These results support targeting Pa TTSS with KB001 as a non-antibiotic strategy to reduce airway inflammation and damage in CF patients with chronic Pa infection. Repeat-dosing studies are necessary to evaluate the durability of the anti-inflammatory effects and how that may translate into clinical benefit. (NCT00638365) PMID:24019259

  9. Anti-PcrV antibody in cystic fibrosis: a novel approach targeting Pseudomonas aeruginosa airway infection.

    PubMed

    Milla, Carlos E; Chmiel, James F; Accurso, Frank J; VanDevanter, Donald R; Konstan, Michael W; Yarranton, Geoffrey; Geller, David E

    2014-07-01

    Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality in cystic fibrosis (CF). The type III secretion system is one of the factors responsible for the increased virulence and pro-inflammatory effects of Pa. KB001 is a PEGylated, recombinant, anti-Pseudomonas-PcrV antibody Fab' fragment that blocks the function of Pa TTSS. We studied the safety, pharmacokinetic (PK), and pharmacodynamic properties of KB001 in CF subjects with chronic Pa infection. Twenty-seven eligible CF subjects (≥12 years of age, FEV1 ≥40% of predicted, and sputum Pa density >10(5)  CFU/g) received a single intravenous dose of KB001 (3 mg/kg or 10 mg/kg) or placebo. Safety, PK, Pa density, clinical outcomes, and inflammatory markers were assessed. KB001 had an acceptable safety profile and a mean serum half-life of 11.9 days. All subjects had Pa TTSS expression in sputum. There were no significant differences between KB001 and placebo for changes in Pa density, symptoms, or spirometry after a single dose. However, compared to baseline, at Day 28 there was a trend towards a dose-dependent reduction in sputum myeloperoxidase, IL-1, and IL-8, and there were significant overall differences in change in sputum neutrophil elastase and neutrophil counts favoring the KB001 10 mg/kg group versus placebo (-0.61 log(10) and -0.63 log(10) , respectively; P < 0.05). These results support targeting Pa TTSS with KB001 as a nonantibiotic strategy to reduce airway inflammation and damage in CF patients with chronic Pa infection. Repeat-dosing studies are necessary to evaluate the durability of the anti-inflammatory effects and how that may translate into clinical benefit. (NCT00638365). PMID:24019259

  10. Baicalein attenuates the quorum sensing-controlled virulence factors of Pseudomonas aeruginosa and relieves the inflammatory response in P. aeruginosa-infected macrophages by downregulating the MAPK and NFκB signal-transduction pathways

    PubMed Central

    Luo, Jing; Kong, Jin-liang; Dong, Bi-ying; Huang, Hong; Wang, Ke; Wu, Li-hong; Hou, Chang-chun; Liang, Yue; Li, Bing; Chen, Yi-qiang

    2016-01-01

    Burgeoning antibiotic resistance and unfavorable outcomes of inflammatory injury after Pseudomonas aeruginosa infection have necessitated the development of novel agents that not only target quorum sensing (QS) but also combat inflammatory injury with the least risk of resistance. This study aimed to assess the anti-QS and anti-inflammatory activities of baicalein, a traditional herbal medicine that is widely used in the People’s Republic of China, against P. aeruginosa infection. We found that subminimum inhibitory concentrations of baicalein efficiently interfered with the QS-signaling pathway of P. aeruginosa via downregulation of the transcription of QS-regulated genes and the translation of QS-signaling molecules. This interference resulted in the global attenuation of QS-controlled virulence factors, such as motility and biofilm formation, and the secretion into the culture supernatant of extracellular virulence factors, including pyocyanin, LasA protease, LasB elastase, and rhamnolipids. Moreover, we examined the anti-inflammatory activity of baicalein and its mode of action via a P. aeruginosa-infected macrophage model to address its therapeutic effect. Baicalein reduced the P. aeruginosa-induced secretion of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNFα. In addition, baicalein suppressed P. aeruginosa-induced activation of the MAPK and NFκB signal-transduction pathways in cocultured macrophages; this may be the mechanism by which baicalein inhibits the production of proinflammatory cytokines. Therefore, our study demonstrates that baicalein represents a potential treatment for P. aeruginosa infection because it clearly exhibits both antibacterial and anti-inflammatory activities. PMID:26792984

  11. Bundled strategies against infection after liver transplantation: Lessons from multidrug-resistant Pseudomonas aeruginosa.

    PubMed

    Sato, Asahi; Kaido, Toshimi; Iida, Taku; Yagi, Shintaro; Hata, Koichiro; Okajima, Hideaki; Takakura, Shunji; Ichiyama, Satoshi; Uemoto, Shinji

    2016-04-01

    Infection is a life-threatening complication after liver transplantation (LT). A recent outbreak of multidrug-resistant Pseudomonas aeruginosa triggered changes in our infection control measures. This study investigated the usefulness of our bundled interventions against postoperative infection after LT. This before-and-after analysis enrolled 130 patients who underwent living donor or deceased donor LT between January 2011 and October 2014. We initiated 3 measures after January 2013: (1) we required LT candidates to be able to walk independently; (2) we increased the hand hygiene compliance rate and contact precautions; and (3) we introduced procalcitonin (PCT) measurement for a more precise determination of empirical antimicrobial treatment. We compared factors affecting the emergence of drug-resistant microorganisms, such as the duration of antimicrobial and carbapenem therapy and hospital stay, and outcomes such as bacteremia and death from infection between before (n = 77) and after (n = 53) the LT suspension period. The utility of PCT measurement was also evaluated. Patients' backgrounds were not significantly different before and after the protocol revision. Incidence of bacteremia (44% versus 25%; P = 0.02), detection rate of multiple bacteria (18% versus 4%; P = 0.01), and deaths from infections (12% versus 2%; P =  0.04) significantly decreased after the protocol revision. Duration of antibiotic (42.3 versus 25.1 days; P =  0.002) and carbapenem administration (15.1 versus 5.2 days; P < 0.001) and the length of postoperative hospital stay (85.4 versus 63.5 days; P =  0.048) also decreased after the protocol revision. PCT mean values were significantly higher in the bacteremia group (10.10 ng/mL), compared with the uneventful group (0.65 ng/mL; P =  0.002) and rejection group (2.30 ng/mL; P =  0.02). One-year overall survival after LT significantly increased in the latter period (71% versus 94%; P =  0

  12. Membranous glomerulonephritis associated with Mycobacterium shimoidei pulmonary infection

    PubMed Central

    Kanaji, Nobuhiro; Kushida, Yoshio; Bandoh, Shuji; Ishii, Tomoya; Haba, Reiji; Tadokoro, Akira; Watanabe, Naoki; Takahama, Takayuki; Kita, Nobuyuki; Dobashi, Hiroaki; Matsunaga, Takuya

    2013-01-01

    Patient: Male, 83 Final Diagnosis: Membranous glomerulonephritis Symptoms: Producting cough Medication: — Clinical Procedure: — Specialty: Nephrology Objective: Rare disease Background: Membranous glomerulonephritis can occur secondarily from infectious diseases. There are no reports describing membranous glomerulonephritis caused by non-tuberculous mycobacterium infection. However, several cases with membranous glomerulonephritis due to Mycobacterium tuberculosis have been reported. Mycobacterium shimoidei is an uncommon pathogen, and less than 20 cases with this species have been reported. A therapeutic regimen for this infection has not been established yet. Case Report: An 83-year-old Japanese man presented with productive cough for 6 months. Computed tomography scan showed multiple cavities in the bilateral pulmonary fields. Acid-fast bacilli were evident in his sputum by Ziehl-Neelsen staining (Gaffky 3). PCR amplifications for Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium intracellulare were all negative. Finally, Mycobacterium shimoidei was identified by rpoB sequencing and 16S rRNA sequencing. Urine examination showed a sub-nephrotic range of proteinuria and histology of the kidney showed membranous glomerulonephritis. Antimycobacterial treatment with clarithromycin, rifampicin, and ethambutol dramatically improved not only the pulmonary disease, but also the proteinuria. Conclusions: To the best of our knowledge, the presented case is the first report showing non-tuberculous mycobacterium-induced secondary membranous glomerulonephritis. A combination with clarithromycin, ethambutol, and rifampicin might be effective for treatment of Mycobacterium shimoidei infection. PMID:24367720

  13. Full-thickness porcine burns infected with Staphylococcus aureus or Pseudomonas aeruginosa can be effectively treated with topical antibiotics.

    PubMed

    Tsai, David M; Tracy, Lauren E; Lee, Cameron C Y; Hackl, Florian; Kiwanuka, Elizabeth; Minasian, Raquel A; Onderdonk, Andrew; Junker, Johan P E; Eriksson, Elof; Caterson, E J

    2016-03-01

    Burn and blast injuries are frequently complicated by invasive infections, which lead to poor wound healing, delay in treatment, disability, or death. Traditional approach centers on early debridement, fluid resuscitation, and adjunct intravenous antibiotics. These modalities often prove inadequate in burns, where compromised local vasculature limits the tissue penetration of systemic antibiotics. Here, we demonstrate the treatment of infected burns with topical delivery of ultrahigh concentrations of antibiotics. Standardized burns were inoculated with Staphylococcus aureus or Pseudomonas aeruginosa. After debridement, burns were treated with either gentamicin (2 mg/mL) or minocycline (1 mg/mL) at concentrations greater than 1,000 times the minimum inhibitory concentration. Amount of bacteria was quantified in tissue biopsies and wound fluid following treatment. After six days of gentamicin or minocycline treatment, S. aureus counts decreased from 4.2 to 0.31 and 0.72 log CFU/g in tissue, respectively. Similarly, P. aeruginosa counts decreased from 2.5 to 0.0 and 1.5 log CFU/g in tissue, respectively. Counts of both S. aureus and P. aeruginosa remained at a baseline of 0.0 log CFU/mL in wound fluid for both treatment groups. The findings here demonstrate that super-therapeutic concentrations of antibiotics delivered topically can rapidly reduce bacterial counts in infected full-thickness porcine burns. This treatment approach may aid wound bed preparation and accelerate time to grafting. PMID:26800421

  14. Antibiotic resistance pattern of Pseudomonas aeruginosa isolated from urine samples of Urinary Tract Infections patients in Karachi, Pakistan

    PubMed Central

    Shah, Dania Aijaz; Wasim, Shehnaz; Essa Abdullah, Farhan

    2015-01-01

    Objective: The aim of this study was to evaluate the antibiotic resistance pattern of Psedomonas aeruginosa and its prevalence in patients with urinary tract infections (UTI) for effective treatment in a developing country like Pakistan. Methods: This is an observational study conducted for a period of ten months which ended on December 2013 at the Dr. Essa Laboratory and Diagnostic Centre in Karachi. A total of 4668 urine samples of UTI patients were collected and standard microbiological techniques were performed to identify the organisms in urine cultures. Antibiotic susceptibility testing was performed by Kirby-Bauer technique for twenty five commonly used antimicrobials and then analyzed on SPSS version 17. Results: P. aeruginosa was isolated in 254 cultures (5.4%). The most resistant drugs included Ceclor(100%) and Cefizox (100%) followed by Amoxil/Ampicillin (99.6%), Ceflixime (99.6%), Doxycycline (99.6%), Cefuroxime (99.2%), Cephradine (99.2%), Cotrimoxazole (99.2%), Nalidixic acid (98.8%), Pipemidic acid (98.6%) and Augmentin (97.6%). Conclusion: Emerging resistant strains of Pseudomonas aeruginosa are potentially linked to injudicious use of drugs leading to ineffective empirical therapy and in turn, appearance of even more resistant strains of the bacterium. Therefore, we recommend culture and sensitivity testing to determine the presence of P.aeruginosa prior to specific antimicrobial therapy. PMID:26101487

  15. Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment.

    PubMed

    Silva Filho, Luiz Vicente Ribeiro Ferreira da; Ferreira, Flavia de Aguiar; Reis, Francisco José Caldeira; Britto, Murilo Carlos Amorim de; Levy, Carlos Emilio; Clark, Otavio; Ribeiro, José Dirceu

    2013-01-01

    Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO-an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group. PMID:24068273

  16. Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment*

    PubMed Central

    da Silva, Luiz Vicente Ribeiro Ferreira; Ferreira, Flavia de Aguiar; Reis, Francisco José Caldeira; de Britto, Murilo Carlos Amorim; Levy, Carlos Emilio; Clark, Otavio; Ribeiro, José Dirceu

    2013-01-01

    Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO–an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group. PMID:24068273

  17. Ciprofloxacin-Loaded Keratin Hydrogels Prevent Pseudomonas aeruginosa Infection and Support Healing in a Porcine Full-Thickness Excisional Wound

    PubMed Central

    Roy, Daniel C.; Tomblyn, Seth; Burmeister, David M.; Wrice, Nicole L.; Becerra, Sandra C.; Burnett, Luke R.; Saul, Justin M.; Christy, Robert J.

    2015-01-01

    Objective: Cutaneous wound infection can lead to impaired healing, multiple surgical procedures, and increased hospitalization time. We tested the effectiveness of keratin-based hydrogels (termed “keratose”) loaded with ciprofloxacin to inhibit infection and support healing when topically administered to porcine excision wounds infected with Pseudomonas aeruginosa. Approach: Using a porcine excisional wound model, 10 mm full-thickness wounds were inoculated with 106 colony-forming units of P. aeruginosa and treated on days 1 and 3 postinoculation with ciprofloxacin-loaded keratose hydrogels. Bacteria enumeration and wound healing were assessed on days 3, 7, and 11 postinjury. Results: Ciprofloxacin-loaded keratose hydrogels reduced the amount of P. aeruginosa in the wound bed by 99.9% compared with untreated wounds on days 3, 7, and 11 postinjury. Ciprofloxacin-loaded keratose hydrogels displayed decreased wound contraction and reepithelialization at day 7 postinjury. By day 11, wounds treated with ciprofloxacin-keratose hydrogels contained collagen-rich granulation tissue and myofibroblasts. Wounds treated with ciprofloxacin-loaded keratose hydrogels exhibited a transient increase in macrophages in the wound bed at day 7 postinjury that subsided by day 11. Innovation: Current therapies for wound infection include systemic antibiotics, which could lead to antibiotic resistance, and topical antimicrobial treatments, which require multiple applications and can delay healing. Here, we show that ciprofloxacin-loaded keratose hydrogels inhibit cutaneous wound infection without interfering with key aspects of the healing process including granulation tissue deposition and remodeling. Conclusions: Ciprofloxacin-loaded keratose hydrogels have the potential to serve as a point-of-injury antibiotic therapy that prevents infection and supports healing following cutaneous injury. PMID:26244102

  18. Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Calabrese, Fiorella; Kipar, Anja; Lunardi, Francesca; Balestro, Elisabetta; Perissinotto, Egle; Rossi, Emanuela; Nannini, Nazarena; Marulli, Giuseppe; Stewart, James P.; Rea, Federico

    2013-01-01

    Background Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed. Methods Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice. Results A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients. Conclusion

  19. Simple Sequence Repeats Together with Mismatch Repair Deficiency Can Bias Mutagenic Pathways in Pseudomonas aeruginosa during Chronic Lung Infection

    PubMed Central

    Moyano, Alejandro J.; Feliziani, Sofía; Di Rienzo, Julio A.; Smania, Andrea M.

    2013-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the airways of cystic fibrosis (CF) patients and undergoes a process of genetic adaptation based on mutagenesis. We evaluated the role of mononucleotide G:C and A:T simple sequence repeats (SSRs) in this adaptive process. An in silico survey of the genome sequences of 7 P. aeruginosa strains showed that mononucleotide G:C SSRs but not A:T SSRs were greatly under-represented in coding regions, suggesting a strong counterselection process for G:C SSRs with lengths >5 bp but not for A:T SSRs. A meta-analysis of published whole genome sequence data for a P. aeruginosa strain from a CF patient with chronic airway infection showed that G:C SSRs but not A:T SSRs were frequently mutated during the infection process through the insertion or deletion of one or more SSR subunits. The mutation tendency of G:C SSRs was length-dependent and increased exponentially as a function of SSR length. When this strain naturally became a stable Mismatch Repair System (MRS)-deficient mutator, the degree of increase of G:C SSRs mutations (5-fold) was much higher than that of other types of mutation (2.2-fold or less). Sequence analysis of several mutated genes reported for two different collections, both containing mutator and non-mutator strains of P. aeruginosa from CF chronic infections, showed that the proportion of G:C SSR mutations was significantly higher in mutators than in non-mutators, whereas no such difference was observed for A:T SSR mutations. Our findings, taken together, provide genome-scale evidences that under a MRS-deficient background, long G:C SSRs are able to stochastically bias mutagenic pathways by making the genes in which they are harbored more prone to mutation. The combination of MRS deficiency and virulence-related genes that contain long G:C SSRs is therefore a matter of concern in P. aeruginosa CF chronic infection. PMID:24278287

  20. Simple sequence repeats together with mismatch repair deficiency can bias mutagenic pathways in Pseudomonas aeruginosa during chronic lung infection.

    PubMed

    Moyano, Alejandro J; Feliziani, Sofía; Di Rienzo, Julio A; Smania, Andrea M

    2013-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the airways of cystic fibrosis (CF) patients and undergoes a process of genetic adaptation based on mutagenesis. We evaluated the role of mononucleotide G:C and A:T simple sequence repeats (SSRs) in this adaptive process. An in silico survey of the genome sequences of 7 P. aeruginosa strains showed that mononucleotide G:C SSRs but not A:T SSRs were greatly under-represented in coding regions, suggesting a strong counterselection process for G:C SSRs with lengths >5 bp but not for A:T SSRs. A meta-analysis of published whole genome sequence data for a P. aeruginosa strain from a CF patient with chronic airway infection showed that G:C SSRs but not A:T SSRs were frequently mutated during the infection process through the insertion or deletion of one or more SSR subunits. The mutation tendency of G:C SSRs was length-dependent and increased exponentially as a function of SSR length. When this strain naturally became a stable Mismatch Repair System (MRS)-deficient mutator, the degree of increase of G:C SSRs mutations (5-fold) was much higher than that of other types of mutation (2.2-fold or less). Sequence analysis of several mutated genes reported for two different collections, both containing mutator and non-mutator strains of P. aeruginosa from CF chronic infections, showed that the proportion of G:C SSR mutations was significantly higher in mutators than in non-mutators, whereas no such difference was observed for A:T SSR mutations. Our findings, taken together, provide genome-scale evidences that under a MRS-deficient background, long G:C SSRs are able to stochastically bias mutagenic pathways by making the genes in which they are harbored more prone to mutation. The combination of MRS deficiency and virulence-related genes that contain long G:C SSRs is therefore a matter of concern in P. aeruginosa CF chronic infection. PMID:24278287

  1. Antimicrobial resistance and genetic characterization of fluoroquinolone resistance of Pseudomonas aeruginosa isolated from canine infections.

    PubMed

    Rubin, J; Walker, R D; Blickenstaff, K; Bodeis-Jones, S; Zhao, S

    2008-09-18

    Infections with antimicrobial-resistant bacteria are a great challenge in both human and veterinary medicine. The purpose of this study was to determine antimicrobial susceptibility of 106 strains of Pseudomonas aeruginosa isolated from dogs with otitis and pyoderma from 2003 to 2006 in the United States. Three antimicrobial panels, including 6 classes and 32 antimicrobial agents, were used. A wide range of susceptibility patterns were noted with some isolates being resistant to between 8 and 28 (mean 16) of the antimicrobials tested. Among the beta-lactams, all isolates were resistant to ampicillin, cefoxitin, cefpodoxime, cephalothin and cefazolin followed by amoxicillin/clavulanic acid (99%), ceftiofur (97%), ceftriaxone (39%), cefotaxime (26%), and cefotaxime/clavulanic acid (20%), whereas less than 7% of isolates were resistant to ceftazidime/clavulanic acid, ceftazidime, piperacillin/tazobactam or cefepime. Two isolates were resistant to the carbapenems. Among the quinolones and fluoroquinolones, the most isolates were resistant to naladixic acid (96%), followed by orbifloxacin (52%), difloxacin (43%), enrofloxacin (31%), marbofloxacin (27%), gatifloxacin (23%), levofloxacin (21%), and ciprofloxacin (16%). Among the aminoglycosides, the most resistance was seen to kanamycin (90%), followed by streptomycin (69%), gentamicin (7%), and amikacin (3%). Of the remaining antimicrobials 100% of the isolates were resistant to chloramphenicol followed by tetracycline (98%), trimethoprim/sulfamethoxazole (57%), and sulfisoxazole (51%). Point mutations were present in gyrA, gyrB, parC, and/or parE genes among 34 of the 102 naladixic acid-resistant isolates. Two isolates contained class 1 integrons carrying aadA gene conferring streptomycin and spectinomycin resistance. The findings suggest that many antimicrobial agents commonly used in companion animals may not constitute appropriate therapy for canine pseudomonas infections. PMID:18395369

  2. Colistimethate sodium for the treatment of chronic pulmonary infection in cystic fibrosis: an evidence-based review of its place in therapy

    PubMed Central

    Koerner-Rettberg, Cordula; Ballmann, Manfred

    2014-01-01

    Chronic bacterial respiratory-tract infections are a major driving force in the pathogenesis of cystic fibrosis (CF) lung disease and promote chronic lung-function decline, destruction, and progression to respiratory failure at a premature age. Gram-negative bacteria colonizing the airways in CF are a major problem in CF therapy due to their tendency to develop a high degree of resistance to antibiotic agents over time. Pseudomonas aeruginosa is the dominating bacterial strain infecting the CF lung from early childhood on, and multiresistant strains frequently develop after years of therapy. Colistin has been used for treating pulmonary bacterial infections in CF for decades due to its very good Gram-negative activity. However, drawbacks include concerns regarding toxicity when being applied systemically, and the lack of approval for application by inhalation in the USA for many years. Other antibiotic substances for systemic use are available with good to excellent Gram-negative and anti-Pseudomonas activity, while there are only three substances approved for inhalation use in the treatment of chronic pulmonary infection with proven benefit in CF. The emergence of multiresistant strains leaving nearly no antibiotic substance as a treatment option, the limited number of antibiotics with high activity against P. aeruginosa, the concerns about increasing the risk of antibiotic resistance by continuous antibiotic therapy, the development of new drug formulations and drug-delivery devices, and, finally, the differing treatment strategies used in CF centers call for defining the place of this “old” drug, colistimethate, in today’s CF therapy. This article reviews the available evidence to reflect on the place of colistimethate sodium in the therapy of chronic pulmonary infection in CF. PMID:25278817

  3. Tasco®: A Product of Ascophyllum nodosum Enhances Immune Response of Caenorhabditis elegans Against Pseudomonas aeruginosa Infection

    PubMed Central

    Kandasamy, Saveetha; Khan, Wajahatullah; Evans, Franklin; Critchley, Alan T.; Prithiviraj, Balakrishnan

    2012-01-01

    The effects of Tasco®, a product made from the brown seaweed (Ascophyllum nodosum) were tested for the ability to protect Caenorhabditis elegans against Pseudomonas aeruginosa infection. A water extract of Tasco® (TWE) reduced P. aeruginosa inflicted mortality in the nematode. The TWE, at a concentration of 300 µg/mL, offered the maximum protection and induced the expression of innate immune response genes viz.; zk6.7 (Lypases), lys-1 (Lysozyme), spp-1 (Saponin like protein), f28d1.3 (Thaumatin like protein), t20g5.7 (Matridin SK domain protein), abf-1 (Antibacterial protein) and f38a1.5 (Lectin family protein). Further, TWE treatment also affected a number of virulence components of the P. aeuroginosa and reduced its secreted virulence factors such as lipase, proteases and toxic metabolites; hydrogen cyanide and pyocyanin. Decreased virulence factors were associated with a significant reduction in expression of regulatory genes involved in quorum sensing, lasI, lasR, rhlI and rhlR. In conclusion, the TWE-treatment protected the C. elegans against P. aeruginosa infection by a combination of effects on the innate immunity of the worms and direct effects on the bacterial quorum sensing and virulence factors. PMID:22363222

  4. Twenty-Five-Year Outbreak of Pseudomonas aeruginosa Infecting Individuals with Cystic Fibrosis: Identification of the Prairie Epidemic Strain

    PubMed Central

    Glezerson, Bryan A.; Sibley, Christopher D.; Sibley, Kristen A.; Duong, Jessica; Purighalla, Swathi; Mody, Christopher H.; Workentine, Matthew L.; Storey, Douglas G.; Surette, Michael G.; Rabin, Harvey R.

    2014-01-01

    Transmissible strains of Pseudomonas aeruginosa have been described for cystic fibrosis (CF) and may be associated with a worse prognosis. Using a comprehensive strain biobank spanning 3 decades, we sought to determine the prevalence and stability of chronic P. aeruginosa infection in an adult population. P. aeruginosa isolates from sputum samples collected at initial enrollment in our adult clinic and at the most recent clinic visit were examined by a combination of pulsed-field gel electrophoresis and multilocus sequence typing and compared against a collection of established transmissible and local non-CF bronchiectasis (nCFB) isolates. A total of 372 isolates from 107 patients, spanning 674 patient-years, including 66 patients with matched isolates from initial and final encounters, were screened. A novel clone with increased antibacterial resistance, termed the prairie epidemic strain (PES), was found in 29% (31/107 patients) of chronically infected patients referred from multiple prairie-based CF centers. This isolate was not found in those diagnosed with CF as adults or in a control population with nCFB. While 90% (60/66 patients) of patients had stable infection over a mean of 10.8 years, five patients experienced strain displacement of unique isolates, with PES occurring within 2 years of transitioning to adult care. PES has been present in our cohort since at least 1987, is unique to CF, generally establishes chronic infection during childhood, and has been found in patients at the time of transition of patients from multiple prairie-based CF clinics, suggesting broad endemicity. Studies are under way to evaluate the clinical implications of PES infection. PMID:24452167

  5. Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections.

    PubMed

    Feliziani, Sofía; Marvig, Rasmus L; Luján, Adela M; Moyano, Alejandro J; Di Rienzo, Julio A; Krogh Johansen, Helle; Molin, Søren; Smania, Andrea M

    2014-10-01

    The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ∼100 SNPs/year-∼40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections. PMID:25330091

  6. Coexistence and Within-Host Evolution of Diversified Lineages of Hypermutable Pseudomonas aeruginosa in Long-term Cystic Fibrosis Infections

    PubMed Central

    Feliziani, Sofía; Moyano, Alejandro J.; Di Rienzo, Julio A.; Krogh Johansen, Helle; Molin, Søren; Smania, Andrea M.

    2014-01-01

    The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ∼100 SNPs/year–∼40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections. PMID:25330091

  7. Toward Repositioning Niclosamide for Antivirulence Therapy of Pseudomonas aeruginosa Lung Infections: Development of Inhalable Formulations through Nanosuspension Technology.

    PubMed

    Costabile, Gabriella; d'Angelo, Ivana; Rampioni, Giordano; Bondì, Roslen; Pompili, Barbara; Ascenzioni, Fiorentina; Mitidieri, Emma; d'Emmanuele di Villa Bianca, Roberta; Sorrentino, Raffaella; Miro, Agnese; Quaglia, Fabiana; Imperi, Francesco; Leoni, Livia; Ungaro, Francesca

    2015-08-01

    Inhaled antivirulence drugs are currently considered a promising therapeutic option to treat Pseudomonas aeruginosa lung infections in cystic fibrosis (CF). We have recently shown that the anthelmintic drug niclosamide (NCL) has strong quorum sensing (QS) inhibiting activity against P. aeruginosa and could be repurposed as an antivirulence drug. In this work, we developed dry powders containing NCL nanoparticles that can be reconstituted in saline solution to produce inhalable nanosuspensions. NCL nanoparticles were produced by high-pressure homogenization (HPH) using polysorbate 20 or polysorbate 80 as stabilizers. After 20 cycles of HPH, all formulations showed similar properties in the form of needle-shape nanocrystals with a hydrodynamic diameter of approximately 450 nm and a zeta potential of -20 mV. Nanosuspensions stabilized with polysorbate 80 at 10% w/w to NCL (T80_10) showed an optimal solubility profile in simulated interstitial lung fluid. T80_10 was successfully dried into mannitol-based dry powder by spray drying. Dry powder (T80_10 DP) was reconstituted in saline solution and showed optimal in vitro aerosol performance. Both T80_10 and T80_10 DP were able to inhibit P. aeruginosa QS at NCL concentrations of 2.5-10 μM. NCL, and these formulations did not significantly affect the viability of CF bronchial epithelial cells in vitro at microbiologically active concentrations (i.e., ≤10 μM). In vivo acute toxicity studies in rats confirmed no observable toxicity of the NCL T80_10 DP formulation upon intratracheal administration at a concentration 100-fold higher than the anti-QS activity concentration. These preliminary results suggest that NCL repurposed in the form of inhalable nanosuspensions has great potential for the local treatment of P. aeruginosa lung infections as in the case of CF patients. PMID:25974285

  8. GM-CSF modulates pulmonary resistance to influenza A infection

    PubMed Central

    Sever-Chroneos, Zvjezdana; Murthy, Aditi; Davis, Jeremy; Florence, Jon Matthew; Kurdowska, Anna; Krupa, Agnieszka; Tichelaar, Jay W.; White, Mitchell R.; Hartshorn, Kevan L.; Kobzik, Lester; Whitsett, Jeffrey A.; Chroneos, Zissis C.

    2016-01-01

    Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9 × 104 ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM−/−) mice compared to GM−/− mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO−/− alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza. PMID:21925209

  9. Pseudomonas aeruginosa biofilms in disease.

    PubMed

    Mulcahy, Lawrence R; Isabella, Vincent M; Lewis, Kim

    2014-07-01

    Pseudomonas aeruginosa is a ubiquitous organism that is the focus of intense research because of its prominent role in disease. Due to its relatively large genome and flexible metabolic capabilities, this organism exploits numerous environmental niches. It is an opportunistic pathogen that sets upon the human host when the normal immune defenses are disabled. Its deadliness is most apparent in cystic fibrosis patients, but it also is a major problem in burn wounds, chronic wounds, chronic obstructive pulmonary disorder, surface growth on implanted biomaterials, and within hospital surface and water supplies, where it poses a host of threats to vulnerable patients (Peleg and Hooper, N Engl J Med 362:1804-1813, 2010; Breathnach et al., J Hosp Infect 82:19-24, 2012). Once established in the patient, P. aeruginosa can be especially difficult to treat. The genome encodes a host of resistance genes, including multidrug efflux pumps (Poole, J Mol Microbiol Biotechnol 3:255-264, 2001) and enzymes conferring resistance to beta-lactam and aminoglycoside antibotics (Vahdani et al., Annal Burns Fire Disast 25:78-81, 2012), making therapy against this gram-negative pathogen particularly challenging due to the lack of novel antimicrobial therapeutics (Lewis, Nature 485: 439-440, 2012). This challenge is compounded by the ability of P. aeruginosa to grow in a biofilm, which may enhance its ability to cause infections by protecting bacteria from host defenses and chemotherapy. Here, we review recent studies of P. aeruginosa biofilms with a focus on how this unique mode of growth contributes to its ability to cause recalcitrant infections. PMID:24096885

  10. Cooperative pathogenicity in cystic fibrosis: Stenotrophomonas maltophilia modulates Pseudomonas aeruginosa virulence in mixed biofilm

    PubMed Central

    Pompilio, Arianna; Crocetta, Valentina; De Nicola, Serena; Verginelli, Fabio; Fiscarelli, Ersilia; Di Bonaventura, Giovanni

    2015-01-01

    The present study was undertaken in order to understand more about the interaction occurring between S. maltophilia and P. aeruginosa, which are frequently co-isolated from CF airways. For this purpose, S. maltophilia RR7 and P. aeruginosa RR8 strains, co-isolated from the lung of a chronically infected CF patient during a pulmonary exacerbation episode, were evaluated for reciprocal effect during planktonic growth, adhesion and biofilm formation onto both polystyrene and CF bronchial cell monolayer, motility, as well as for gene expression in mixed biofilms. P. aeruginosa significantly affected S. maltophilia growth in both planktonic and biofilm cultures, due to an inhibitory activity probably requiring direct contact. Conversely, no effect was observed on P. aeruginosa by S. maltophilia. Compared with monocultures, the adhesiveness of P. aeruginosa on CFBE41o- cells was significantly reduced by S. maltophilia, which probably acts by reducing P. aeruginosa's swimming motility. An opposite trend was observed for biofilm formation, confirming the findings obtained using polystyrene. When grown in mixed biofilm with S. maltophilia, P. aeruginosa significantly over-expressed aprA, and algD—codifying for protease and alginate, respectively—while the quorum sensing related rhlR and lasI genes were down-regulated. The induced alginate expression by P. aeruginosa might be responsible for the protection of S. maltophilia against tobramycin activity we observed in mixed biofilms. Taken together, our results suggest that the existence of reciprocal interference of S. maltophilia and P. aeruginosa in CF lung is plausible. In particular, S. maltophilia might confer some selective “fitness advantage” to P. aeruginosa under the specific conditions of chronic infection or, alternatively, increase the virulence of P. aeruginosa thus leading to pulmonary exacerbation. PMID:26441885

  11. Use of Ceftolozane/Tazobactam in the Treatment of Multidrug-resistant Pseudomonas aeruginosa Bloodstream Infection in a Pediatric Leukemia Patient.

    PubMed

    Aitken, Samuel L; Kontoyiannis, Dimitrios P; DePombo, April M; Bhatti, Micah M; Tverdek, Frank P; Gettys, Suzanne C; Nicolau, David P; Nunez, Cesar A

    2016-09-01

    Multidrug-resistant Pseudomonas aeruginosa is of increasing concern in pediatric patients. Ceftolozane/tazobactam is a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant Pseudomonas; however, no data exist on its use in children. This report summarizes the treatment of a multidrug-resistant P. aeruginosa bloodstream infection in a pediatric leukemia patient with ceftolozane/tazobactam and provides the first description of its pharmacokinetics in pediatrics. PMID:27254038

  12. Effects of Quorum Sensing Systems on Regulatory T Cells in Catheter-Related Pseudomonas aeruginosa Biofilm Infection Rat Models

    PubMed Central

    Feng, Lei; Xiang, Qingqing; Ai, Qing; Wang, Zhengli; Zhang, Yunhui; Lu, Qi

    2016-01-01

    Background. Quorum sensing (QS) systems play an important role in modulating biofilm formation. Recent studies have found that the QS molecules had complex effects on the host immune systems. In addition, regulatory T cells (Tregs), known as important negative regulators in the immune system, have been found upregulated in multiple chronic infections. Therefore, the QS systems were hypothesized to be involved in modulating Tregs in biofilm-associated infections. Object. To explore the effects of QS systems on Tregs in catheter-related Pseudomonas aeruginosa biofilm infection rat models. Method. Catheter-related Pseudomonas aeruginosa biofilm infection rat models were established; the bacterial clearance rates, total cell counts in bronchoalveolar lavage (BAL) fluid, pathological changes of lungs, and the levels of Foxp3, TGF-β1, and IL-10 in PAO1 strain group were examined and compared with the QS-mutant ΔlasRΔrhlR and ΔlasIΔrhlI groups. Results. In PAO1 group, the bacterial clearance rates were lower, total cell counts were higher, pathological changes were severer, and the levels of Foxp3, TGF-β1, and IL-10 were significantly higher compared with QS-mutant groups (p < 0.05). No significant difference was observed between the two QS-mutant groups (p > 0.05). Conclusion. QS systems can trigger host immune system, accompanied with the upregulation of Tregs. PMID:27069314

  13. Chronic lung infection by Pseudomonas aeruginosa biofilm is cured by L-Methionine in combination with antibiotic therapy

    PubMed Central

    Gnanadhas, Divya Prakash; Elango, Monalisha; Datey, Akshay; Chakravortty, Dipshikha

    2015-01-01

    Bacterial biofilms are associated with 80–90% of infections. Within the biofilm, bacteria are refractile to antibiotics, requiring concentrations >1,000 times the minimum inhibitory concentration. Proteins, carbohydrates and DNA are the major components of biofilm matrix. Pseudomonas aeruginosa (PA) biofilms, which are majorly associated with chronic lung infection, contain extracellular DNA (eDNA) as a major component. Herein, we report for the first time that L-Methionine (L-Met) at 0.5 μM inhibits Pseudomonas aeruginosa (PA) biofilm formation and disassembles established PA biofilm by inducing DNase expression. Four DNase genes (sbcB, endA, eddB and recJ) were highly up-regulated upon L-Met treatment along with increased DNase activity in the culture supernatant. Since eDNA plays a major role in establishing and maintaining the PA biofilm, DNase activity is effective in disrupting the biofilm. Upon treatment with L-Met, the otherwise recalcitrant PA biofilm now shows susceptibility to ciprofloxacin. This was reflected in vivo, in the murine chronic PA lung infection model. Mice treated with L-Met responded better to antibiotic treatment, leading to enhanced survival as compared to mice treated with ciprofloxacin alone. These results clearly demonstrate that L-Met can be used along with antibiotic as an effective therapeutic against chronic PA biofilm infection. PMID:26521707

  14. Mixed pulmonary infection in an immunocompromised patient: a rare case report.

    PubMed

    Qureshi, S; Pandey, A; Sirohi, T R; Verma, S R; Sardana, V; Agrawal, C; Asthana, A K; Madan, M

    2014-01-01

    Patients who are immunocompromised are predisposed to a variety of common and uncommon pulmonary infections. We report a case of mixed pulmonary infection by drug resistant tuberculosis with a nocardiosis in a 49-year-old man who was a known case of chronic obstructive pulmonary disease, on prolonged corticosteroid use with diabetes mellitus. Chronic use of corticosteroids is a predisposing factor for opportunistic infections, such as nocardiosis or tuberculosis. Since such a mixed infection is rare, maybe a combined approach to therapy early in the course of disease would be effective in such cases. PMID:24399397

  15. Pulmonary uptake in Indium-111 leukocyte imaging: clinical significance in patients with suspected occult infections

    SciTech Connect

    Cook, P.S.; Datz, F.L.; Disbro, M.A.; Alazraki, N.P.; Taylor, A.T.

    1984-02-01

    A retrospective review was undertaken to evaluate the frequency and significance of pulmonary activity noted on 306 indium-111 leukocyte studies involving 232 patients with suspected occult infections. Forty-eight studies showed pulmonary activity in one of two patterns of uptake, focal or diffuse. Fourteen of 27 studies (52%) with focal uptake and two of 21 studies (10%) with diffuse uptake were associated with infectious processes. Lung uptake of indium-111-labeled leukocytes was a poor predictor of pulmonary infection in patients studied for occult infection, although the focal pattern was more likely than the diffuse pattern to be associated with infection.

  16. Application of Dual Inhibition Concept within Looped Autoregulatory Systems toward Antivirulence Agents against Pseudomonas aeruginosa Infections.

    PubMed

    Thomann, Andreas; de Mello Martins, Antonio G G; Brengel, Christian; Empting, Martin; Hartmann, Rolf W

    2016-05-20

    Pseudomonas aeruginosa quorum-sensing (QS) is a sophisticated network of genome-wide regulation triggered in response to population density. A major component is the self-inducing pseudomonas quinolone signal (PQS) QS system that regulates the production of several nonvital virulence- and biofilm-related determinants. Hence, QS circuitry is an attractive target for antivirulence agents with lowered resistance development potential and a good model to study the concept of polypharmacology in autoloop-regulated systems per se. Based on the finding that a combination of PqsR antagonist and PqsD inhibitor synergistically lowers pyocyanin, we have developed a dual-inhibitor compound of low molecular weight and high solubility that targets PQS transcriptional regulator (PqsR) and PqsD, a key enzyme in the biosynthesis of PQS-QS signal molecules (HHQ and PQS). In vitro, this compound markedly reduced virulence factor production and biofilm formation accompanied by a diminished content of extracellular DNA (eDNA). Additionally, coadministration with ciprofloxacin increased susceptibility of PA14 to antibiotic treatment under biofilm conditions. Finally, disruption of pathogenicity mechanisms was also assessed in vivo, with significantly increased survival of challenged larvae in a Galleria mellonella infection model. Favorable physicochemical properties and effects on virulence/biofilm establish a promising starting point for further optimization. In particular, the ability to address two targets of the PQS autoinduction cycle at the same time with a single compound holds great promise in achieving enhanced synergistic cellular effects while potentially lowering rates of resistance development. PMID:26882081

  17. Questions on causality and responsibility arising from an outbreak of Pseudomonas aeruginosa infections in Norway

    PubMed Central

    Iversen, Bjørn G; Hofmann, Bjørn; Aavitsland, Preben

    2008-01-01

    In 2002, Norway experienced a large outbreak of Pseudomonas aeruginosa infections in hospitals with 231 confirmed cases. This fuelled intense public and professional debates on what were the causes and who were responsible. In epidemiology, other sciences, in philosophy and in law there is a long tradition of discussing the concept of causality. We use this outbreak as a case; apply various theories of causality from different disciplines to discuss the roles and responsibilities of some of the parties involved. Mackie's concept of INUS conditions, Hill's nine viewpoints to study association for claiming causation, deterministic and probabilistic ways of reasoning, all shed light on the issues of causality in this outbreak. Moreover, applying legal theories of causation (counterfactual reasoning and the "but-for" test and the NESS test) proved especially useful, but the case also illustrated the weaknesses of the various theories of causation. We conclude that many factors contributed to causing the outbreak, but that contamination of a medical device in the production facility was the major necessary condition. The reuse of the medical device in hospitals contributed primarily to the size of the outbreak. The unintended error by its producer – and to a minor extent by the hospital practice – was mainly due to non-application of relevant knowledge and skills, and appears to constitute professional negligence. Due to criminal procedure laws and other factors outside the discourse of causality, no one was criminally charged for the outbreak which caused much suffering and shortening the life of at least 34 people. PMID:18947429

  18. Catheter-related infections caused by Pseudomonas aeruginosa: virulence factors involved and their relationships.

    PubMed

    Olejnickova, Katerina; Hola, Veronika; Ruzicka, Filip

    2014-11-01

    The nosocomial pathogen Pseudomonas aeruginosa is equipped with a large arsenal of cell-associated and secreted virulence factors which enhance its invasive potential. The complex relationships among virulence determinants have hitherto not been fully elucidated. In the present study, 175 catheter-related isolates were observed for the presence of selected virulence factors, namely extracellular enzymes and siderophore production, biofilm formation, resistance to antibiotics, and motility. A high percentage of the strains produced most of the tested virulence factors. A positive correlation was identified between the production of several exoproducts, and also between the formation of both types of biofilm. An opposite trend was observed between the two types of biofilm and the production of siderophores. Whereas the relationship between the submerged biofilm production (i.e. the biofilm formed on the solid surface below the water level) and the siderophore secretion was negative, the production of air-liquid interface (A-L) biofilm (i.e. the biofilm floating on the surface of the cultivation medium) and the siderophore secretion were positively correlated. All correlations were statistically significant at the level P = 0.05 with the correlation coefficient γ ≥ 0.50. Our results suggest that: (1) the co-production of the lytic enzymes and siderophores can play an important role in the pathogenesis of the catheter-related infections and should be taken into account when the virulence potential is assessed; (2) biofilm-positive strains are capable of forming both submerged and non-attached A-L biofilms; and (3) the different micro-environment in the submerged biofilm and A-L biofilm layers have opposite consequences for the production of other virulence factors. PMID:24842562

  19. A proof-of-concept model for the identification of the key events in the infection process with specific reference to Pseudomonas aeruginosa in corneal infections

    PubMed Central

    Soumpasis, Ilias; Knapp, Laura; Pitt, Tyrone

    2015-01-01

    Background It is a common medical practice to characterise an infection based on the causative agent and to adopt therapeutic and prevention strategies targeting the agent itself. However, from an epidemiological perspective, exposure to a microbe can be harmless to a host as a result of low-level exposure or due to host immune response, with opportunistic infection only occurring as a result of changes in the host, pathogen, or surrounding environment. Methods We have attempted to review systematically the key host, pathogen, and environmental factors that may significantly impact clinical outcomes of exposure to a pathogen, using Pseudomonas aeruginosa eye infection as a case study. Results and discussion Extended contact lens wearing and compromised hygiene may predispose users to microbial keratitis, which can be a severe and vision-threatening infection. P. aeruginosa has a wide array of virulence-associated genes and sensing systems to initiate and maintain cell populations at the corneal surface and beyond. We have adapted the well-known concept of the epidemiological triangle in combination with the classic risk assessment framework (hazard identification, characterisation, and exposure) to develop a conceptual pathway-based model that demonstrates the overlapping relationships between the host, the pathogen, and the environment; and to illustrate the key events in P. aeruginosa eye infection. Conclusion This strategy differs from traditional approaches that consider potential risk factors in isolation, and hopefully will aid the identification of data and models to inform preventive and therapeutic measures in addition to risk assessment. Furthermore, this may facilitate the identification of knowledge gaps to direct research in areas of greatest impact to avert or mitigate adverse outcomes of infection. PMID:26546946

  20. Invasive Pulmonary Aspergillosis with Disseminated Infection in Immunocompetent Patient.

    PubMed

    Moreno-González, Gabriel; Ricart de Mesones, Antoni; Tazi-Mezalek, Rachid; Marron-Moya, Maria Teresa; Rosell, Antoni; Mañez, Rafael

    2016-01-01

    Invasive pulmonary aspergillosis (IPA) is a rare pathology with increasing incidence mainly in critical care settings and recently in immunocompetent patients. The mortality of the disease is very high, regardless of an early diagnosis and aggressive treatment. Here, we report a case of a 56 yr old previously healthy woman who was found unconscious at home and admitted to the emergency room with mild respiratory insufficiency. In the first 24 hours she developed an acute respiratory failure with new radiographic infiltrates requiring Intensive Care Unit admission. A severe obstructive pattern with impossibility of ventilation because of bilateral atelectasis was observed, requiring emergent venovenous extracorporeal membrane oxygenator device insertion. Bronchoscopy revealed occlusion of main bronchi, demonstrating by biopsy an invasive infection by Aspergillus fumigatus and A. flavus. Despite an aggressive treatment and vital support the patient had a fatal outcome. The forensic study confirms the diagnosis of IPA but also revealed the presence of disseminated aspergillosis. PMID:27445566

  1. A fatal case of pulmonary infection by Mycobacterium colombiense in Para State, Amazon Region, Brazil.

    PubMed

    Barretto, Adriana Rodrigues; Felício, João Soares; Sales, Lucia Helena Messias; Yamada, Elizabeth Sumi; Lopes, Maria Luiza; da Costa, Ana Roberta Fusco

    2016-07-01

    Mycobacterium avium complex (MAC) is a heterogeneous group of species found in several environmental sources and that exhibit variable degrees of pathogenicity. Among the MAC members, Mycobacterium colombiense has been related to pulmonary disease and disseminated infection in HIV-infected patients in Colombia. Lymphadenopathy cases have also been reported. We have described a fatal case of M. colombiense pulmonary disease in a Brazilian patient without evidence of HIV infection or other known causes of immunosuppression. PMID:27133309

  2. Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice.

    PubMed

    Nakamura, Shigeki; Iwanaga, Naoki; Seki, Masafumi; Fukudome, Kenji; Oshima, Kazuhiro; Miyazaki, Taiga; Izumikawa, Koichi; Yanagihara, Katsunori; Miyazaki, Yoshitsugu; Mukae, Hiroshi; Kohno, Shigeru

    2016-07-01

    Chronic lower respiratory tract infection with Pseudomonas aeruginosa is difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response to Pseudomonas infection in mice. We implanted sterile plastic tubes precoated with P. aeruginosa in the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assays in vitro using UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G(+) neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P < 0.05). Depletion of CD4(+) T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function. PMID:27091927

  3. A genetic approach to the development of new therapeutic phages to fight pseudomonas aeruginosa in wound infections.

    PubMed

    Krylov, Victor; Shaburova, Olga; Krylov, Sergey; Pleteneva, Elena

    2013-01-01

    Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent ("lytic") and temperate ("lysogenic") bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID:23344559

  4. A Genetic Approach to the Development of New Therapeutic Phages to Fight Pseudomonas Aeruginosa in Wound Infections

    PubMed Central

    Krylov, Victor; Shaburova, Olga; Krylov, Sergey; Pleteneva, Elena

    2012-01-01

    Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent (“lytic”) and temperate (“lysogenic”) bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID:23344559

  5. Epidemiology of human pulmonary infection with nontuberculous mycobacteria.

    PubMed

    Marras, Theodore K; Daley, Charles L

    2002-09-01

    A great deal of study has gone into the assessment of the epidemiology of NTM infection and disease in many different parts of the world. Review of the available studies provides insight into the frequency of this clinical problem as well as important limitations in current data. Study methods have varied greatly, undoubtedly leading to differing biases. In general, reported rates of infection and disease are likely underestimates, with the former probably less accurate than the latter, given that people without significant symptoms are not likely to have intensive investigations to detect infection. Pulmonary NTM is a problem with differing rates in various parts of the world. North American rates of infection and disease have been reported to range from approximately 1-15 per 100,000 and 0.1-2 per 100,000, respectively (see Table 1). Rates have been observed to increase with coincident decreases in TB. MAC has been reported most commonly, followed by rapid growers and M kansasii. Generally similar rates have been reported in European studies, with the exception of extremely high rates in an area of the Czech Republic where mining is the dominant industry (see Table 2). These studies have also shown marked geographic variability in prevalence. The only available population-based studies have been in South Africa and report extremely high rates of infection, three orders of magnitude greater than studies from other parts of the world (see Table 3). This undoubtedly reflects the select population with an extremely high rate of TB and resultant bronchiectasis leading to NTM infection. Rates in Japan and Australia were similar to those reported in Europe and North America and also show significant increases over time (see Table 3). Specific risk factors have been identified in several studies. CF and HIV, mentioned above, are two important high-risk groups. Other important factors include underlying chronic lung disease, work in the mining industry, warm climate

  6. Role of Adherence in the Pathogenesis of Pseudomonas aeruginosa Lung Infection in Cystic Fibrosis Patients

    PubMed Central

    Woods, Donald E.; Bass, Joe A.; Johanson, W. G.; Straus, David C.

    1980-01-01

    A correlation has been demonstrated between the in vitro adherence of Pseudomonas aeruginosa to upper respiratory tract epithelium and colonization of the respiratory tract by this organism. Twenty patients with cystic fibrosis (CF) and 20 age-matched controls were examined in this study. All of the CF patients but none of the controls were colonized with P. aeruginosa at the time of study. P. aeruginosa adherence to isolated epithelial cells, as determined by an in vitro assay, was 19.1 ± 1.1 bacteria per buccal epithelial cell in the CF patients and 2.3 ± 0.3 bacteria per cell in the controls (P < 0.01). P. aeruginosa strains of the mucoid colony type adhered in significantly lower numbers to buccal epithelial cells than did strains of the rough colony type (1.8 + 0.1 versus 24.8 ± 0.9, P < 0.001). This difference might explain the common observation that the initial pseudomonas colonization of the respiratory tract of CF patients is due to organisms of the rough colony type. We have further demonstrated that increased P. aeruginosa adherence in vitro varies directly with the loss of a protease-sensitive glycoprotein, fibronectin, from the cell surface, as well as increased levels of salivary proteases in CF patients. When examined by a direct radioimmune binding assay, buccal cells from CF patients possessed only 17% of the total cell surface fibronectin present on similar cells obtained from controls. Salivary protease levels, as measured by 125I release from an 125I-labeled insoluble fibrin matrix, were increased about threefold in CF patients versus controls. Thus, colonization of the respiratory tract by P. aeruginosa in CF patients correlates well with buccal cell adherence of this organism; increased adherence is associated with decreased amounts of fibronectin on respiratory epithelial cell surfaces and increased levels of salivary proteases. PMID:7014444

  7. Treatment for patients with multidrug resistant Acinetobacter baumannii pulmonary infection

    PubMed Central

    PAN, TAO; LIU, XIAOYUN; XIANG, SHOUGUI; JI, WENLI

    2016-01-01

    Bacterial infections are common but have become increasingly resistant to drugs. The aim of the present study was to examine the combined treatment of traditional Chinese and Western medicine in 30 cases of pulmonary infection with multidrug resistant Acinetobacter baumannii. Patients were divided into groups A and B according to drug treatments. Cefoperazone or sulbactam and tanreqing were administered in group A, and cefoperazone or sulbactam in group B. The curative effect and prognosis of the two groups were recorded and the remaining treatments were performed routinely in the clinic. For the combined therapy group, which was administered sulperazone and tanreqing, 8 patients were recovered, 6 patients had significant effects, 3 patients exhibited some improvement and 1 patient had no response. One of the patients did not survive after 28 days. By contrast, there were 4 patients that were successfully treated, 3 patients with significant effects, 2 patients with some improvement and 2 patients had no response in the sulperazone group, and 4 patients did not survive after 28 days. In conclusion, the combined therapy of cefoperazone or sulbactam supplemented with tanreqing was identified to be more effective than cefoperazone or sulbactam as monotherapy, for treating multidrug resistant Acinetobacter baumannii. PMID:27073447

  8. Right-Sided Infective Endocarditis and Pulmonary Infiltrates: An Update.

    PubMed

    Chahoud, Jad; Sharif Yakan, Ahmad; Saad, Hala; Kanj, Souha S

    2016-01-01

    Sixty years after its initial description, right-sided infective endocarditis (RSIE) still poses a challenge to all medical practitioners. Epidemiological data reveal a rising incidence attributable to the global surge in the number of intravenous drug users and the increased use of central vascular catheters and implantable cardiac devices. RSIE differs from left-sided infective endocarditis in more than just the location of the involved cardiac valve. They have different clinical presentations, diagnostic findings, and prognoses; hence, they require different management strategies. Cardiac murmurs and systemic emboli are usually absent in RSIE, whereas pulmonary embolism and its related complications dominate the clinical picture. Diagnostic delay of RSIE is secondary to the similarity in its initial presentation to other entities. Complications may ensue as a result of this delay. Diagnosis can be initially confirmed by using transthoracic echocardiography, except in patients with implanted cardioverter defibrillator, where a transesophageal echocardiogram is necessary. Various factors may increase mortality and morbidity in RSIE such as tricuspid valve vegetation size, fungal etiology, and low CD4 cell count in HIV patients. Oxacillin and vancomycin had been the traditionally used agents for the treatment of methicillin-susceptible and methicillin-resistant Staphylococcus aureus, respectively. More recently, daptomycin has shown promising results, which has led to its Food and Drug Administration (FDA) approval for the treatment of S. aureus bacteremia and associated RSIE. The aim of this article is to provide a comprehensive update on RSIE including epidemiology, pathogenesis, microbiology, diagnosis, management, and prognosis. PMID:26501991

  9. Recombinant outer membrane protein F-B subunit of LT protein as a prophylactic measure against Pseudomonas aeruginosa burn infection in mice

    PubMed Central

    Farsani, Hassan Heydari; Rasooli, Iraj; Gargari, Seyed Latif Mousavi; Nazarian, Shahram; Astaneh, Shakiba Darwish Alipour

    2015-01-01

    AIM: To study immunogenicity of outer membrane protein F (OprF) fused with B subunit of LT (LTB), against Pseudomonas aeruginosa (P. aeruginosa). METHODS: The OprF, a major surface exposed outer membrane protein that is antigenically conserved in various strains of P. aeruginosa, is a promising immunogen against P. aeruginosa. In the present study recombinant OprF and OprF-LTB fusion gene was cloned, expressed and purified. BALB/c mice and rabbits were immunized using recombinant OprF and OprF-LTB and challenged at the burn site with P. aeruginosa lethal dose of 104 CFU. The protective efficacy of rabbit anti OprF IgG against P. aeruginosa burn infection was investigated by passive immunization. RESULTS: It has been well established that the LTB is a powerful immunomodulator with strong adjuvant activity. LTB as a bacterial adjuvant enhanced immunogenicity of OprF and anti OprF IgG titer in serum was increased. Experimental findings showed significantly higher average survival rate in burned mice immunized with OprF-LTB than immunized with OprF or the control group. Rabbits anti OprF IgG brought about 75% survival of mice following challenge with P. aeruginosa. Post challenge hepatic and splenic tissues of mice group immunized with OprF-LTB had significantly lower bacterial load than those immunized with OprF or the control groups. CONCLUSION: These results demonstrate that LTB-fused OprF might be a potential candidate protein for a prophylactic measure against P. aeruginosa in burn infection. PMID:26713284

  10. Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide.

    PubMed

    d'Angelo, Ivana; Casciaro, Bruno; Miro, Agnese; Quaglia, Fabiana; Mangoni, Maria Luisa; Ungaro, Francesca

    2015-11-01

    Cationic antimicrobial peptides (CAMPs) are very promising in the treatment of multi-drug resistant Pseudomonas aeruginosa lung infections experienced by cystic fibrosis (CF) patients. Nevertheless, there is an urgent need of inhalable formulations able to deliver the intact CAMP in conductive airways and to shield its interactions with airway mucus/bacterial biofilm, thus enhancing CAMP/bacteria interactions. Along these lines, the aim of this work was the design and development of nano-embedded microparticles (NEM) for sustained delivery of CAMPs in the lung. To this purpose, nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) containing a model CAMP, colistin (Col), were produced by emulsion/solvent diffusion technique. Engineering NPs with chitosan (CS) and poly(vinyl alcohol) (PVA) allowed to modulate surface properties and, in so doing, to improve NP transport through artificial CF mucus. In order to achieve a long-term stable dosage form useful for NP inhalation, NPs were spray-dried in different carriers (lactose or mannitol), thus producing NEM. The most promising NEM formulations were selected on the basis of bulk and flow properties, distribution of NPs in the carrier and aerosolization performance upon delivery through a breath-actuated dry powder inhaler. Of note, selected Col-loaded NEM were found to kill P. aeruginosa biofilm and to display a prolonged efficacy in biofilm eradication compared to the free Col. This effect was likely ascribable to the ability of NPs to penetrate into bacterial biofilm, as demonstrated by confocal analysis, and to sustain Col release inside it. Taken all together, our results indicate that adequate engineering of PLGA NPs represents an enticing technological approach to harness novel antimicrobials for P. aeruginosa lung infection, such as CAMPs, especially in CF. PMID:26340361

  11. Systemic inflammatory responses and multiple organ dysfunction syndrome following skin burn wound and Pseudomonas aeruginosa infection in mice.

    PubMed

    Li, Na; Hu, Xiaolong; Liu, Yang; Wang, Yaojun; Wang, Yunchuan; Liu, Jiaqi; Cai, Weixia; Bai, Xiaozhi; Zhu, Xiongxiang; Han, Juntao; Hu, Dahai

    2013-08-01

    Burn wound-related sepsis is associated with the development of systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). This study is aimed at investigating the development and progression of SIS and MODS in a mouse model of skin burn sepsis. C57BL/6J mice were randomly divided into the sham, burn, Pseudomonas, and burn/Pseudomonas groups. The back skin of the sham, burn, and burn/Pseudomonas groups was burned about 10% of total area with using 37°C or 98°C water for 8 s, respectively, followed by inoculating with Pseudomonas aeruginosa. The Pseudomonas group was infected with P. aeruginosa without burn injury. Their body weights, mortality, organ histology, and function as well as systemic inflammation were measured longitudinally. The burn/Pseudomonas mice lost more body weights than did mice from the other groups and had a significantly higher mortality rate (P < 0.05). The burn/Pseudomonas mice exhibited significantly higher levels of bacterial loads in different organs and serum endotoxin, interleukin 1β, interleukin 6, tumor necrosis factor α, and C-reactive protein than those in mice from the other groups (P < 0.05). The burn/Pseudomonas mice also displayed more severe liver, lung, and kidney tissue damage and impaired organ functions, particularly at 72 h after inoculation than did the burn and Pseudomonas groups of mice. Our data indicate that burn and P. aeruginosa infection induced severe sepsis and rapidly progressed into systemic inflammatory response syndrome and MODS in mice. PMID:23707977

  12. Pore-forming activity of type III system-secreted proteins leads to oncosis of Pseudomonas aeruginosa-infected macrophages.

    PubMed

    Dacheux, D; Goure, J; Chabert, J; Usson, Y; Attree, I

    2001-04-01

    The Pseudomonas aeruginosa cystic fibrosis isolate CHA induces type III secretion system-dependent but ExoU-independent oncosis of neutrophils and macrophages. Time-lapse microscopy of the infection process revealed the rapid accumulation of motile bacteria around infected cells undergoing the process of oncosis, a phenomenon we termed pack swarming. Characterization of the non-chemotactic CHAcheZ mutant showed that pack swarming is a bacterial chemotactic response to infected macrophages. A non-cytotoxic mutant, lacking the type III-secreted proteins PcrV, PopB and PopD, was able to pack swarm only in the presence of the parental strain CHA or when macrophages were pretreated with the pore-forming toxin streptolysin O. Interaction of P. aeruginosa with red blood cells (RBCs) showed that the contact-dependent haemolysis provoked by CHA requires secretion via the type III system and the PcrV, PopB/PopD proteins. The pore inserted into RBC membrane was estimated from osmoprotection experiments to be between 2.8 and 3.5 nm. CHA-infected macrophages could be protected from cell lysis with PEG3350, indicating that the pore introduced into RBC and macrophage membranes is of similar size. The time course uptake of the vital fluorescent dye, Yo-Pro-1, into infected macrophages confirmed that the formation of transmembrane pores by CHA precedes cellular oncosis. Therefore, CHA-induced macrophage death results from a pore-forming activity that is dependent on the intact pcrGVHpopBD operon. PMID:11298277

  13. Cyanide in bronchoalveolar lavage is not diagnostic for Pseudomonas aeruginosa in children with cystic fibrosis.

    PubMed

    Stutz, M D; Gangell, C L; Berry, L J; Garratt, L W; Sheil, B; Sly, P D

    2011-03-01

    Early detection of the cyanobacterium Pseudomonas aeruginosa in the lungs of young children with cystic fibrosis (CF) is considered the key to delaying chronic pulmonary disease. We investigated whether cyanide in bronchoalveolar lavage (BAL) fluid could be used as an early diagnostic biomarker of infection. Cyanide was measured in 226 BAL samples (36 P. aeruginosa infected) obtained from 96 infants and young children with CF participating in an early surveillance programme involving annual BAL. Cyanide was detected in 97.2% of P. aeruginosa infected and 60.5% of uninfected samples. Cyanide concentrations were significantly higher in BALs infected with P. aeruginosa (median (25th-75th percentile) 27.3 (22.1-33.3) μM) than those which were not (17.2 (7.85-23.0) μM, p<0.001). The best sensitivity, specificity, positive and negative predictive values were obtained with a cut-off concentration of 20.6 μM, and were 83%, 66%, 32% and 96%, respectively. Neutrophil number in BAL was a significant predictor of cyanide concentration (p<0.001). Cyanide concentration can distinguish between P. aeruginosa infected and uninfected BALs as a group, but not individually; therefore, cyanide is a poor diagnostic biomarker of P. aeruginosa infection. Cyanide levels in BAL are related to the level of neutrophilic inflammation. PMID:20562125

  14. Interruption of pulmonary arterial flow with inadequate ventilation leads to pulmonary infection.

    PubMed

    Urano; Shibayama, Y; Fukunshi, K; Nariyama, K; Ohsawa, N

    1996-03-01

    We examined the effect of interruption of pulmonary arterial flow and inadequate ventilation on the development of pulmonary infarction in rats. Pulmonary arterial flow was blocked by the injection of agar into the inferior vena cava and inadequate ventilation was produced by obstructing the left main bronchus with a polypropylene tip. Histological and angiographic examination of the lung demonstrated that: pulmonary artery embolism alone does not induce pulmonary infarction; obstruction of a bronchus does not induce significant changes, but that pulmonary infarction develops when pulmonary artery embolism and obstruction of a bronchus occur simultaneously. It has been thought that pulmonary infarction is caused by acute obstruction of a pulmonary artery, however, the alveolar walls are supplied with oxygen by both the pulmonary circulation and by ventilation. Interruption of pulmonary arterial flow alone is probably not sufficient to induce pulmonary infarction, which is probably caused by deficiency of oxygen supply to the alveolar walls by a synergy between interruption of pulmonary arterial flow and inadequate ventilation. PMID:8605572

  15. Recombination is a key driver of genomic and phenotypic diversity in a Pseudomonas aeruginosa population during cystic fibrosis infection.

    PubMed

    Darch, Sophie E; McNally, Alan; Harrison, Freya; Corander, Jukka; Barr, Helen L; Paszkiewicz, Konrad; Holden, Stephen; Fogarty, Andrew; Crusz, Shanika A; Diggle, Stephen P

    2015-01-01

    The Cystic Fibrosis (CF) lung harbors a complex, polymicrobial ecosystem, in which Pseudomonas aeruginosa is capable of sustaining chronic infections, which are highly resistant to multiple antibiotics. Here, we investigate the phenotypic and genotypic diversity of 44 morphologically identical P. aeruginosa isolates taken from a single CF patient sputum sample. Comprehensive phenotypic analysis of isolates revealed large variances and trade-offs in growth, virulence factors and quorum sensing (QS) signals. Whole genome analysis of 22 isolates revealed high levels of intra-isolate diversity ranging from 5 to 64 SNPs and that recombination and not spontaneous mutation was the dominant driver of diversity in this population. Furthermore, phenotypic differences between isolates were not linked to mutations in known genes but were statistically associated with distinct recombination events. We also assessed antibiotic susceptibility of all isolates. Resistance to antibiotics significantly increased when multiple isolates were mixed together. Our results highlight the significant role of recombination in generating phenotypic and genetic diversification during in vivo chronic CF infection. We also discuss (i) how these findings could influence how patient-to-patient transmission studies are performed using whole genome sequencing, and (ii) the need to refine antibiotic susceptibility testing in sputum samples taken from patients with CF. PMID:25578031

  16. Recombination is a key driver of genomic and phenotypic diversity in a Pseudomonas aeruginosa population during cystic fibrosis infection

    PubMed Central

    Darch, Sophie E.; McNally, Alan; Harrison, Freya; Corander, Jukka; Barr, Helen L.; Paszkiewicz, Konrad; Holden, Stephen; Fogarty, Andrew; Crusz, Shanika A.; Diggle, Stephen P.

    2015-01-01

    The Cystic Fibrosis (CF) lung harbors a complex, polymicrobial ecosystem, in which Pseudomonas aeruginosa is capable of sustaining chronic infections, which are highly resistant to multiple antibiotics. Here, we investigate the phenotypic and genotypic diversity of 44 morphologically identical P. aeruginosa isolates taken from a single CF patient sputum sample. Comprehensive phenotypic analysis of isolates revealed large variances and trade-offs in growth, virulence factors and quorum sensing (QS) signals. Whole genome analysis of 22 isolates revealed high levels of intra-isolate diversity ranging from 5 to 64 SNPs and that recombination and not spontaneous mutation was the dominant driver of diversity in this population. Furthermore, phenotypic differences between isolates were not linked to mutations in known genes but were statistically associated with distinct recombination events. We also assessed antibiotic susceptibility of all isolates. Resistance to antibiotics significantly increased when multiple isolates were mixed together. Our results highlight the significant role of recombination in generating phenotypic and genetic diversification during in vivo chronic CF infection. We also discuss (i) how these findings could influence how patient-to-patient transmission studies are performed using whole genome sequencing, and (ii) the need to refine antibiotic susceptibility testing in sputum samples taken from patients with CF. PMID:25578031

  17. Pulmonary immunostimulation with MALP-2 in influenza virus-infected mice increases survival after pneumococcal superinfection.

    PubMed

    Reppe, Katrin; Radünzel, Peter; Dietert, Kristina; Tschernig, Thomas; Wolff, Thorsten; Hammerschmidt, Sven; Gruber, Achim D; Suttorp, Norbert; Witzenrath, Martin

    2015-12-01

    Pulmonary infection with influenza virus is frequently complicated by bacterial superinfection, with Streptococcus pneumoniae being the most prevalent causal pathogen and hence often associated with high morbidity and mortality rates. Local immunosuppression due to pulmonary influenza virus infection has been identified as a major cause of the pathogenesis of secondary bacterial lung infection. Thus, specific local stimulation of the pulmonary innate immune system in subjects with influenza virus infection might improve the host defense against secondary bacterial pathogens. In the present study, we examined the effect of pulmonary immunostimulation with Toll-like receptor 2 (TLR-2)-stimulating macrophage-activating lipopeptide 2 (MALP-2) in influenza A virus (IAV)-infected mice on the course of subsequent pneumococcal superinfection. Female C57BL/6N mice infected with IAV were treated with MALP-2 on day 5 and challenged with S. pneumoniae on day 6. Intratracheal MALP-2 application increased proinflammatory cytokine and chemokine release and enhanced the recruitment of leukocytes, mainly neutrophils, into the alveolar space of IAV-infected mice, without detectable systemic side effects. Local pulmonary instillation of MALP-2 in IAV-infected mice 24 h before transnasal pneumococcal infection considerably reduced the bacterial number in the lung tissue without inducing exaggerated inflammation. The pulmonary viral load was not altered by MALP-2. Clinically, MALP-2 treatment of IAV-infected mice increased survival rates and reduced hypothermia and body weight loss after pneumococcal superinfection compared to those of untreated coinfected mice. In conclusion, local immunostimulation with MALP-2 in influenza virus-infected mice improved pulmonary bacterial elimination and increased survival after subsequent pneumococcal superinfection. PMID:26371127

  18. Pulmonary Immunostimulation with MALP-2 in Influenza Virus-Infected Mice Increases Survival after Pneumococcal Superinfection

    PubMed Central

    Reppe, Katrin; Radünzel, Peter; Dietert, Kristina; Tschernig, Thomas; Wolff, Thorsten; Hammerschmidt, Sven; Gruber, Achim D.; Suttorp, Norbert

    2015-01-01

    Pulmonary infection with influenza virus is frequently complicated by bacterial superinfection, with Streptococcus pneumoniae being the most prevalent causal pathogen and hence often associated with high morbidity and mortality rates. Local immunosuppression due to pulmonary influenza virus infection has been identified as a major cause of the pathogenesis of secondary bacterial lung infection. Thus, specific local stimulation of the pulmonary innate immune system in subjects with influenza virus infection might improve the host defense against secondary bacterial pathogens. In the present study, we examined the effect of pulmonary immunostimulation with Toll-like receptor 2 (TLR-2)-stimulating macrophage-activating lipopeptide 2 (MALP-2) in influenza A virus (IAV)-infected mice on the course of subsequent pneumococcal superinfection. Female C57BL/6N mice infected with IAV were treated with MALP-2 on day 5 and challenged with S. pneumoniae on day 6. Intratracheal MALP-2 application increased proinflammatory cytokine and chemokine release and enhanced the recruitment of leukocytes, mainly neutrophils, into the alveolar space of IAV-infected mice, without detectable systemic side effects. Local pulmonary instillation of MALP-2 in IAV-infected mice 24 h before transnasal pneumococcal infection considerably reduced the bacterial number in the lung tissue without inducing exaggerated inflammation. The pulmonary viral load was not altered by MALP-2. Clinically, MALP-2 treatment of IAV-infected mice increased survival rates and reduced hypothermia and body weight loss after pneumococcal superinfection compared to those of untreated coinfected mice. In conclusion, local immunostimulation with MALP-2 in influenza virus-infected mice improved pulmonary bacterial elimination and increased survival after subsequent pneumococcal superinfection. PMID:26371127

  19. OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model.

    PubMed

    Hengzhuang, Wang; Song, Zhijun; Ciofu, Oana; Onsøyen, Edvar; Rye, Philip D; Høiby, Niels

    2016-05-01

    Biofilm growth is a universal survival strategy for bacteria, providing an effective and resilient approach for survival in an otherwise hostile environment. In the context of an infection, a biofilm provides resistance and tolerance to host immune defenses and antibiotics, allowing the biofilm population to survive and thrive under conditions that would destroy their planktonic counterparts. Therefore, the disruption of the biofilm is a key step in eradicating persistent bacterial infections, as seen in many types of chronic disease. In these studies, we used both in vitro minimum biofilm eradication concentration (MBEC) assays and an in vivo model of chronic biofilm infection to demonstrate the biofilm-disrupting effects of an alginate oligomer, OligoG CF-5/20. Biofilm infections were established in mice by tracheal instillation of a mucoid clinical isolate of Pseudomonas aeruginosa embedded in alginate polymer beads. The disruption of the biofilm by OligoG CF-5/20 was observed in a dose-dependent manner over 24 h, with up to a 2.5-log reduction in CFU in the infected mouse lungs. Furthermore, in vitro assays showed that 5% OligoG CF-5/20 significantly reduced the MBEC for colistin from 512 μg/ml to 4 μg/ml after 8 h. These findings support the potential for OligoG CF-5/20 as a biofilm disruption agent which may have clinical value in reducing the microbial burden in chronic biofilm infections. PMID:26833153

  20. Next-Generation "-omics" Approaches Reveal a Massive Alteration of Host RNA Metabolism during Bacteriophage Infection of Pseudomonas aeruginosa.

    PubMed

    Chevallereau, Anne; Blasdel, Bob G; De Smet, Jeroen; Monot, Marc; Zimmermann, Michael; Kogadeeva, Maria; Sauer, Uwe; Jorth, Peter; Whiteley, Marvin; Debarbieux, Laurent; Lavigne, Rob

    2016-07-01

    As interest in the therapeutic and biotechnological potentials of bacteriophages has grown, so has value in understanding their basic biology. However, detailed knowledge of infection cycles has been limited to a small number of model bacteriophages, mostly infecting Escherichia coli. We present here the first analysis coupling data obtained from global next-generation approaches, RNA-Sequencing and metabolomics, to characterize interactions between the virulent bacteriophage PAK_P3 and its host Pseudomonas aeruginosa. We detected a dramatic global depletion of bacterial transcripts coupled with their replacement by viral RNAs over the course of infection, eventually leading to drastic changes in pyrimidine metabolism. This process relies on host machinery hijacking as suggested by the strong up-regulation of one bacterial operon involved in RNA processing. Moreover, we found that RNA-based regulation plays a central role in PAK_P3 lifecycle as antisense transcripts are produced mainly during the early stage of infection and viral small non coding RNAs are massively expressed at the end of infection. This work highlights the prominent role of RNA metabolism in the infection strategy of a bacteriophage belonging to a new characterized sub-family of viruses with promising therapeutic potential. PMID:27380413

  1. First Pulmonary Case Reported in Argentina of Infection with Mycobacterium szulgai, a Rare Pathogen▿

    PubMed Central

    Gutierrez, M.; Feola, M.; Lenge, L.; Rey, R.; Hoffman, M.

    2007-01-01

    Mycobacterium szulgai is a rare pathogen. Nontuberculous mycobacteria usually produce disease in people with some kind of immunosuppression or another predisposing condition. A case of pulmonary Mycobacterium szulgai infection is described. PMID:17596359

  2. Outbreak of nosocomial urinary tract infections due to Pseudomonas aeruginosa in a paediatric surgical unit associated with tap-water contamination.

    PubMed

    Ferroni, A; Nguyen, L; Pron, B; Quesne, G; Brusset, M C; Berche, P

    1998-08-01

    An outbreak of 14 cases of urinary tract infections by Pseudomonas aeruginosa, including six symptomatic infections, occurred from September to November 1994 in a paediatric surgical unit. During the outbreak, urine samples from patients and multiple samples from the environment of patients were tested for the presence of P. aeruginosa. Bacterial isolates were studied by pulsed-field gel electrophoresis. Genotypic analysis showed that most of the isolates from children were different. Multiple P. aeruginosa isolates were also found in the tap water, as the only putative source of contamination. Two of these isolates were identified in two infected patients, indicating possible direct contamination of patients via tap water and this was related to the distal colonization of faucets. Bacteria were eradicated from tap water by replacement of taps. The cluster of cases of P. aeruginosa urinary infection was, therefore, related to multiple contaminations through tap water. These results illustrate an unexpected risk of nosocomial infection and emphasizes the importance of checking tap water to prevent bacterial contamination through handwashing in contaminated water. PMID:9749401

  3. The Pseudomonas aeruginosa Flagellum Confers Resistance to Pulmonary Surfactant Protein-A by Impacting the Production of Exoproteases Through Quorum-Sensing

    PubMed Central

    Kuang, Zhizhou; Hao, Yonghua; Hwang, Sunghei; Zhang, Shiping; Kim, Eunice; Akinbi, Henry T; Schurr, Michael J.; Irvin, Randall T.; Hassett, Daniel J; Lau, Gee W.

    2011-01-01

    Surfactant protein-A (SP-A) is an important antimicrobial protein that opsonizes and permeabilizes membranes of microbial pathogens in mammalian lungs. Previously, we have shown that Pseudomonas aeruginosa flagellum-deficient mutants are preferentially cleared in the lungs of wild-type mice by SP-A-mediated membrane permeabilization, and not by opsonization. In this study, we report a flagellum-mediated mechanism of P. aeruginosa resistance to SP-A. We discovered that flagellum-deficient (ΔfliC) bacteria are unable to produce adequate amounts of exoproteases to degrade SP-A in vitro and in vivo, leading to its preferential clearance in the lungs of SP-A+/+ mice. In addition, ΔfliC bacteria failed to degrade another important lung antimicrobial protein lysozyme. Detailed analyses showed that ΔfliC bacteria are unable to upregulate the transcription of lasI and rhlI genes, impairing the production of homoserine lactones necessary for quorum-sensing, an important virulence process that regulates the production of multiple exoproteases. Thus, reduced ability of ΔfliC bacteria to quorum-sense attenuates production of exoproteases and limits degradation of SP-A, thereby conferring susceptibility to this major pulmonary host defense protein. PMID:21205009

  4. Review: Antibiotic discovery in the age of structural biology - a comprehensive overview with special reference to development of drugs for the treatment of Pseudomonas aeruginosa infection.

    PubMed

    Koehnke, Alessa; Friedrich, Reinhard E

    2015-01-01

    Due to the persistence and spread of antibiotic resistance, the discovery and exploitation of new antibiotic targets should be the subject of intensive research. Effective strategies are required to develop antibiotic alternatives. Antibiotics that act on new targets or via novel mechanisms have the greatest likelihood of overcoming resistance. In particular, there is a lack of specific antibiotics for Pseudomonas aeruginosa, one of the leading causes of healthcare-associated infections, exhibiting high resistance levels. Herein we describe how structure-based drug design can be used to achieve new antibiotics for the treatment of Pseudomonas aeruginosa infection, using an essential enzyme of the fatty acid synthesis pathway from P. aeruginosa as an example. PMID:25792642

  5. Irreversible pulmonary hypertension associated with Troglostrongylus brevior infection in a kitten.

    PubMed

    Crisi, Paolo E; Traversa, Donato; Di Cesare, Angela; Luciani, Alessia; Civitella, Carla; Santori, Domenico; Boari, Andrea

    2015-10-01

    A four month-old kitten was referred at the Veterinary Teaching Hospital of Teramo, Italy. Physical examination, echocardiography, thoracic radiography, copromicroscopy and biomolecular assays led to a diagnosis of severe parasitic bronchopneumonia by Troglostrongylus brevior complicated by pulmonary hypertension. A single administration of a spot on solution containing imidacloprid 10%/moxidectin 1% was effective in stopping larval shedding but clinical, radiographic and echocardiographic signs of bronchopneumonia and pulmonary hypertension still persisted after further follow-ups.While cases of pulmonary hypertension are known in infections by Aelurostrongylus abstrusus, this is the first report of irreversible pulmonary hypertension in a kitten with troglostrongylosis. PMID:26412548

  6. Effect of metallo-β-lactamase production and multidrug resistance on clinical outcomes in patients with Pseudomonas aeruginosa bloodstream infection: a retrospective cohort study

    PubMed Central

    2013-01-01

    Background Blood stream infections (BSI) with Pseudomonas aeruginosa lead to poor clinical outcomes. The worldwide emergence and spread of metallo-β-lactamase (MBL) producing, often multidrug-resistant organisms may further aggravate this problem. Our study aimed to investigate the effect of MBL-producing P. aeruginosa (MBL-PA) and various other resistance phenotypes on clinical outcomes. Methods A retrospective cohort study was conducted in three German hospitals. Medical files from 2006 until 2012 were studied, and a number of 113 patients with P. aeruginosa BSI were included. The presence of VIM, IMP and NDM genes was detected using molecular techniques. Genetic relatedness was assessed through multilocus sequence typing (MLST). The effect of resistance patterns or MBL production on clinical outcomes was investigated by using multivariate Cox regression models. Results In-hospital mortality was significantly higher in patients with MBL-PA and multidrug-resistant P. aeruginosa. However, neither BSI with MBL-PA nor BSI with various resistance phenotypes of P. aeruginosa were independently associated with mortality or length of hospital stay. In multivariate models, the SAPS II score (HR 1.046), appropriate definitive treatment (HR range 0.25-0.26), and cardiovascular disease (HR range 0.44-0.46) were independent predictors of mortality. Concomitant infections were associated with an excess length of stay (HR < 1). Conclusions Medication with appropriate antimicrobial agents at any time during the course of infection remains the key for improving clinical outcomes in patients with P. aeruginosa BSI and should be combined with a strict implementation of routine infection control measures. PMID:24176052

  7. [Pulmonary infection caused by Mycobacterium szulgai: a case report].

    PubMed

    Ikeue, Tatsuyoshi; Watanabe, Shigeki; Sugita, Takakazu; Horikawa, Sadao; Suzuki, Yujiro; Nishiyama, Hideki; Maekawa, Nobuo

    2002-05-01

    We reported a case of pulmonary infection caused by Mycobacterium szulgai (M. szulgai) in an immunocompetent, asymptomatic 55-year-old man without underlying disease. A chest radiograph of an annual health examination revealed a right upper lobe infiltrate with thin-walled cavities, which was not present in the previous year. An acid-fast stain of bronchial washing fluid was positive, and antimycobacterial chemotherapy with isoniazid (400 mg/day), rifampin (450 mg/day), and ethambutol (750 mg/day) was initiated on presumptive diagnosis of the case as tuberculosis. DNA-DNA hybridization of sputum and bronchial washing samples identified M. szulgai as the causative organism. Antimicrobial susceptibility testing indicated that the isolate was sensitive to most common antimycobacterial drugs except capreomycin (CPM) and p-aminosalicylic acid (PAS), and was also sensitive to clarithromycin and fluoroquinolones including ofloxacin, levofloxacin, sparfloxacin, and ciprofloxacin. After 12 months of therapy, a repeat chest radiograph demonstrated improvement of the right upper lobe infiltrate. When M. szulgai is isolated, it almost always represents a true pathogen. Therefore, the detection of even a small number of M. szulgai warrants treatment based on susceptibility testing. PMID:12073621

  8. Granulocyte-macrophage colony stimulatory factor enhances the pro-inflammatory response of interferon-γ-treated macrophages to Pseudomonas aeruginosa infection.

    PubMed

    Singh, Sonali; Barr, Helen; Liu, Yi-Chia; Robins, Adrian; Heeb, Stephan; Williams, Paul; Fogarty, Andrew; Cámara, Miguel; Martínez-Pomares, Luisa

    2015-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-γ production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-γ and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN-γ in CF, the effect of IFN-γ alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-γ, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-γ caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-α and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-γ promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-α vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages

  9. Outbreak of infections caused by Pseudomonas aeruginosa producing VIM-1 carbapenemase in Greece.

    PubMed

    Tsakris, A; Pournaras, S; Woodford, N; Palepou, M F; Babini, G S; Douboyas, J; Livermore, D M

    2000-03-01

    Resistance to imipenem and meropenem was observed in 211 (16.5%) isolates of Pseudomonas aeruginosa recovered in a Greek university hospital during 1996 to 1998. In six isolates selected from throughout this period, high-level resistance to both carbapenems (MICs >/= 128 microg/ml) was associated with production of the class B beta-lactamase VIM-1. bla(VIM)-bearing isolates belonged to serotype O:12 and were indistinguishable by pulsed-field gel electrophoresis. PMID:10699045

  10. Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection.

    PubMed

    Tran, Cindy S; Eran, Yoni; Ruch, Travis R; Bryant, David M; Datta, Anirban; Brakeman, Paul; Kierbel, Arlinet; Wittmann, Torsten; Metzger, Ross J; Mostov, Keith E; Engel, Joanne N

    2014-05-14

    The mucosal epithelium consists of polarized cells with distinct apical and basolateral membranes that serve as functional and physical barriers to external pathogens. The apical surface of the epithelium constitutes the first point of contact between mucosal pathogens, such as Pseudomonas aeruginosa, and their host. We observed that binding of P. aeruginosa aggregates to the apical surface of polarized cells led to the striking formation of an actin-rich membrane protrusion with inverted polarity, containing basolateral lipids and membrane components. Such protrusions were associated with a spatially localized host immune response to P. aeruginosa aggregates that required bacterial flagella and a type III secretion system apparatus. Host protrusions formed de novo underneath bacterial aggregates and involved the apical recruitment of a Par3/Par6α/aPKC/Rac1 signaling module for a robust, spatially localized host NF-κB response. Our data reveal a role for spatiotemporal epithelial polarity changes in the activation of innate immune responses. PMID:24832456

  11. Clonal Dissemination, Emergence of Mutator Lineages and Antibiotic Resistance Evolution in Pseudomonas aeruginosa Cystic Fibrosis Chronic Lung Infection

    PubMed Central

    Mulet, Xavier; Cabot, Gabriel; Moyà, Bartolomé; Figuerola, Joan; Togores, Bernat; Pérez, José L.; Oliver, Antonio

    2013-01-01

    Chronic respiratory infection by Pseudomonas aeruginosa is a major cause of mortality in cystic fibrosis (CF). We investigated the interplay between three key microbiological aspects of these infections: the occurrence of transmissible and persistent strains, the emergence of variants with enhanced mutation rates (mutators) and the evolution of antibiotic resistance. For this purpose, 10 sequential isolates, covering up to an 8-year period, from each of 10 CF patients were studied. As anticipated, resistance significantly accumulated overtime, and occurred more frequently among mutator variants detected in 6 of the patients. Nevertheless, highest resistance was documented for the nonmutator CF epidemic strain LES-1 (ST-146) detected for the first time in Spain. A correlation between resistance profiles and resistance mechanisms evaluated [efflux pump (mexB, mexD, mexF, and mexY) and ampC overexpression and OprD production] was not always obvious and hypersusceptibility to certain antibiotics (such as aztreonam or meropenem) was frequently observed. The analysis of whole genome macrorestriction fragments through Pulsed-Field Gel Electrophoresis (PFGE) revealed that a single genotype (clone FQSE-A) produced persistent infections in 4 of the patients. Multilocus Sequence typing (MLST) identified clone FQSE-A as the CF epidemic clone ST-274, but striking discrepancies between PFGE and MLST profiles were evidenced. While PFGE macrorestriction patterns remained stable, a new sequence type (ST-1089) was detected in two of the patients, differing from ST-274 by only two point mutations in two of the genes, each leading to a nonpreviously described allele. Moreover, detailed genetic analyses revealed that the new ST-1089 is a mutS deficient mutator lineage that evolved from the epidemic strain ST-274, acquired specific resistance mechanisms, and underwent further interpatient spread. Thus, presented results provide the first evidence of interpatient dissemination of mutator

  12. Metastatic pulmonary calcification misdiagnosed as a fungal infection: A case report

    PubMed Central

    LIANG, ZHIXIN; QIU, TIAN; ZHAO, ZHIGANG; CHEN, LIANG'AN; SHE, DANYANG

    2016-01-01

    Metastatic pulmonary calcification is a rare lesion, characterized by calcium salt depositing in normal lung tissue. The clinical profile of a case of metastatic pulmonary calcification following renal transplantation was described. A computed tomography scan of the chest revealed ground-glass opacities in bilateral lungs and a node exhibiting a halo in the right upper lobe, which were suspected aspergillus infection. Following examination and therapy, the results of lung biopsy revealed metastatic pulmonary calcification. Although metastatic pulmonary calcification was reported in renal failure patients previously, metastatic pulmonary calcification with cavity lesions has never, to the best of our knowledge, been previously reported. The aim of the present report was to improve the understanding of metastatic pulmonary calcification. PMID:26998293

  13. Infection of human mucosal tissue by Pseudomonas aeruginosa requires sequential and mutually dependent virulence factors and a novel pilus-associated adhesin

    PubMed Central

    Heiniger, Ryan W.; Winther-Larsen, Hanne C.; Pickles, Raymond J.; Koomey, Michael; Wolfgang, Matthew C.

    2010-01-01

    Summary Tissue damage predisposes humans to life-threatening disseminating infection by the opportunistic pathogen Pseudomonas aeruginosa. Bacterial adherence to host tissue is a critical first step in this infection process. It is well established that P. aeruginosa attachment to host cells involves type IV pili (TFP), which are retractile surface fibers. The molecular details of attachment and the identity of the bacterial adhesin and host receptor remain controversial. Using a mucosal epithelium model system derived from primary human tissue, we show that the pilus-associated protein PilY1 is required for bacterial adherence. We establish that P. aeruginosa preferentially binds to exposed basolateral host cell surfaces, providing a mechanistic explanation for opportunistic infection of damaged tissue. Further, we demonstrate that invasion and fulminant infection of intact host tissue requires the coordinated and mutually dependent action of multiple bacterial factors, including pilus fiber retraction and the host cell intoxication system, termed type III secretion. Our findings offer new and important insights into the complex interactions between a pathogen and its human host and provide compelling evidence that PilY1 serves as the principal P. aeruginosa adhesin for human tissue and that it specifically recognizes a host receptor localized or enriched on basolateral epithelial cell surfaces. PMID:20331639

  14. Infection caused by Nocardia farcinica mimicking pulmonary metastasis in an adolescent girl.

    PubMed

    Babayigit, Arzu; Olmez, Duygu; Sozmen, Sule C; Makay, Balahan; Uzuner, Nevin; Karaman, Ozkan; Anal, Ozden; Gulay, Zeynep

    2010-03-01

    Nocardia farcinica infections are rare and potentially life threatening. Herein, we describe a case of pulmonary nocardiosis caused by N. farcinica. This 13-year-old girl admitted with 1-year history of cough, intermittent fever, and recurrent hemoptysis. She was examined for multiple pulmonary nodules mimicking pulmonary metastasis that were detected with chest radiography and computed tomography of the thorax. Eventually, N. farcinica was yielded in culture of sputum and aspiration material of pulmonary nodules. No predisposing factor could be shown for Nocardia infection. Although infections caused by N. farcinica have tendency to disseminate, and are mostly resistant to antibiotics, the patient was successfully treated with prolonged intravenous antibiotic therapy followed with oral amoxicillin-clavulanate. PMID:20216281

  15. Extracellular Adenosine Protects against Streptococcus pneumoniae Lung Infection by Regulating Pulmonary Neutrophil Recruitment.

    PubMed

    Bou Ghanem, Elsa N; Clark, Stacie; Roggensack, Sara E; McIver, Sally R; Alcaide, Pilar; Haydon, Philip G; Leong, John M

    2015-08-01

    An important determinant of disease following Streptococcus pneumoniae (pneumococcus) lung infection is pulmonary inflammation mediated by polymorphonuclear leukocytes (PMNs). We found that upon intratracheal challenge of mice, recruitment of PMNs into the lungs within the first 3 hours coincided with decreased pulmonary pneumococci, whereas large numbers of pulmonary PMNs beyond 12 hours correlated with a greater bacterial burden. Indeed, mice that survived infection largely resolved inflammation by 72 hours, and PMN depletion at peak infiltration, i.e. 18 hours post-infection, lowered bacterial numbers and enhanced survival. We investigated host signaling pathways that influence both pneumococcus clearance and pulmonary inflammation. Pharmacologic inhibition and/or genetic ablation of enzymes that generate extracellular adenosine (EAD) (e.g. the ectoenzyme CD73) or degrade EAD (e.g. adenosine deaminase) revealed that EAD dramatically increases murine resistance to S. pneumoniae lung infection. Moreover, adenosine diminished PMN movement across endothelial monolayers in vitro, and although inhibition or deficiency of CD73 had no discernible impact on PMN recruitment within the first 6 hours after intratracheal inoculation of mice, these measures enhanced PMN numbers in the pulmonary interstitium after 18 hours of infection, culminating in dramatically elevated numbers of pulmonary PMNs at three days post-infection. When assessed at this time point, CD73-/- mice displayed increased levels of cellular factors that promote leukocyte migration, such as CXCL2 chemokine in the murine lung, as well as CXCR2 and β-2 integrin on the surface of pulmonary PMNs. The enhanced pneumococcal susceptibility of CD73-/- mice was significantly reversed by PMN depletion following infection, suggesting that EAD-mediated resistance is largely mediated by its effects on PMNs. Finally, CD73-inhibition diminished the ability of PMNs to kill pneumococci in vitro, suggesting that EAD alters

  16. Pathophysiological Changes Induced by Pseudomonas aeruginosa Infection Are Involved in MMP-12 and MMP-13 Upregulation in Human Carcinoma Epithelial Cells and a Pneumonia Mouse Model

    PubMed Central

    Park, Ji-Won; Shin, In-Sik; Ha, Un-Hwan; Oh, Sei-Ryang

    2015-01-01

    Pseudomonas aeruginosa infections persist in patients with cystic fibrosis (CF) and drive lung disease progression. P. aeruginosa potently activates the innate immune system mostly through the recognition of pathogen-associated molecular patterns, such as flagellin. Matrix metalloproteinases 12 and 13 (MMP-12 and MMP-13, respectively) exacerbate chronic lung infection and inflammation by promoting uncontrolled tissue rearrangements and fibrosis, yet the underlying molecular mechanisms by which this occurs remain largely unknown. In this study, we used quantitative bacteriology, histological examination, and proinflammatory cytokine levels to evaluate the effects of MMP-12 and MMP-13 on P. aeruginosa strain K-induced infection and pneumonia in H292 epithelial cells and mice, respectively. Under inflammatory stimulation, mRNA and protein expression levels of proinflammatory mediators were higher in strain K-infected mice and cells than in uninfected counterparts, in which MMP-12 and MMP-13 expression reached levels similar to those observed in epithelial cells. Moreover, we also found that the NF-κB pathway might be involved in the induction of cytokines in response to strain K infection. Taken together, these data suggest that MMP-12 and MMP-13 alter strain K infection in mice and play a role in inflammatory regulation by modulating cytokine levels. PMID:26438797

  17. Pulmonary infection due to Pseudozyma aphidis in a patient with Burkitt lymphoma: first case report.

    PubMed

    Parahym, Ana Maria Rabelo de Carvalho; da Silva, Carolina Maria; Domingos, Igor de Farias; Gonçalves, Sarah Santos; Rodrigues, Márcia de Melo; de Morais, Vera Lúcia Lins; Neves, Rejane Pereira

    2013-01-01

    Fungal infections are being increasingly reported in patients with malignancies. Pseudozyma aphidis is an opportunistic yeast usually isolated from plants and rarely from human samples. In this study, we report the first case of pulmonary infection due to P. aphidis in a Burkitt lymphoma patient. PMID:23182077

  18. The influence of Imipenem resistant metallo-beta-lactamase positive and negative Pseudomonas aeruginosa nosocomial infections on mortality and morbidity

    PubMed Central

    Babu, Kolhal Veerappa Yogeesha; Visweswaraiah, Divakara Siddanakatte; Kumar, Arun

    2014-01-01

    Background: Metallo-beta-lactamase (MBL) mediated resistance to carbapenems is an emerging threat in Pseudomonas aeruginosa (PA) nosocomial infections. Limited data on role of Imipenem resistant MBL positive PA (IR-MBLP-PA) and IR-MBL negative-PA (IR-MBLN-PA) infections on mortality and morbidity initiated the present study. Objectives: The aim of this study is to determine the role of IR-MBLP-PA and IR-MBLN-PA infections on mortality and morbidity. Materials and Methods: Prospective observational study of 1 year with 110 PA nosocomial infections was conducted with Imipenem + ethylene-diamine-tetra-acetic acid combined disc test for MBL detection. Role of IR-MBLP-PA and IR-MBLN-PA infections on the outcome and morbidity were assessed in terms of crude mortality rate, Charlson's comorbidity score and mean duration of stay in intensive care unit (ICU) until cure and until death, number of episodes of complications and underlying disease. Results were analyzed by z test for proportions and Student t-test. Results: Relatively high crude mortality was observed among IR-MBLP-PA infections than IR-MBLN-PA (42.86% [6/14] vs. 20% [2/10], Z = 0.69, P = 0.49 NS). Ventilator-associated pneumonia was the underlying disease and a confounding factor in all deaths due to IR-MBLP-PA infections. IR-MBLP-PA infections resulted in rapid downhill course to death with short mean duration of stay in ICU until death than IR-MBLN-PA infections (3.167 ± 0.98 days vs. 16 ± 2.82, P < 0.001 highly significant [HS]) with more number of complications (5.85 ± 1.65 vs. 3.7 ± 1.31, P < 0.001 HS). With the exception of previous Imipenem therapy, association of higher Charlson's comorbidity score, severe underlying diseases, multidrug and pandrug resistance and pre-disposing risk factors with IR-MBLP-PA infections was not statistically significant. Conclusions: Higher mortality in IR-MBLP-PA than in IR-MBLN-PA was not significant indicating IR as an important predictor of mortality than MBL

  19. Efficacy of topically delivered moxifloxacin against wound infection by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus.

    PubMed

    Jacobsen, F; Fisahn, C; Sorkin, M; Thiele, I; Hirsch, T; Stricker, I; Klaassen, T; Roemer, A; Fugmann, B; Steinstraesser, L

    2011-05-01

    Wound infection is a common risk for patients with chronic nonhealing wounds, causing high morbidity and mortality. Currently, systemic antibiotic treatment is the therapy of choice, despite often leading to several side effects and the risk of an insufficient tissue penetration due to impaired blood supply. If systemically delivered, moxifloxacin penetrates well into inflammatory blister fluid, muscle, and subcutaneous adipose tissues and might therefore be a possible option for the topical treatment of skin and infected skin wounds. In this study, topical application of moxifloxacin was investigated in comparison to mupirocin, linezolid, and gentamicin using a porcine wound infection and a rat burn infection model. Both animal models were performed either by an inoculation with methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. Wound fluid, tissue, and blood samples were taken, and bacterial counts as well as the moxifloxacin concentration were determined for a 14-day follow-up. A histological comparison of the rat burn wound tissues was performed. Both strains were susceptible to moxifloxacin and gentamicin, whereas mupirocin and linezolid were effective only against MRSA. All antibiotics showed efficient reduction of bacterial counts, and except with MRSA, infected burn wounds reached bacterial counts below 10(5) CFU/g tissue. Additionally, moxifloxacin was observed to promote wound healing as determined by histologic analysis, while no induction of bacterial resistance was observed during the treatment period. The use of topical antibiotics for the treatment of infected wounds confers many benefits. Moxifloxacin is therefore an ideal candidate, due to its broad antibacterial spectrum, its high efficiency, and its potential to promote wound healing. PMID:21343458

  20. Efficacy of Topically Delivered Moxifloxacin against Wound Infection by Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus▿

    PubMed Central

    Jacobsen, F.; Fisahn, C.; Sorkin, M.; Thiele, I.; Hirsch, T.; Stricker, I.; Klaassen, T.; Roemer, A.; Fugmann, B.; Steinstraesser, L.

    2011-01-01

    Wound infection is a common risk for patients with chronic nonhealing wounds, causing high morbidity and mortality. Currently, systemic antibiotic treatment is the therapy of choice, despite often leading to several side effects and the risk of an insufficient tissue penetration due to impaired blood supply. If systemically delivered, moxifloxacin penetrates well into inflammatory blister fluid, muscle, and subcutaneous adipose tissues and might therefore be a possible option for the topical treatment of skin and infected skin wounds. In this study, topical application of moxifloxacin was investigated in comparison to mupirocin, linezolid, and gentamicin using a porcine wound infection and a rat burn infection model. Both animal models were performed either by an inoculation with methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. Wound fluid, tissue, and blood samples were taken, and bacterial counts as well as the moxifloxacin concentration were determined for a 14-day follow-up. A histological comparison of the rat burn wound tissues was performed. Both strains were susceptible to moxifloxacin and gentamicin, whereas mupirocin and linezolid were effective only against MRSA. All antibiotics showed efficient reduction of bacterial counts, and except with MRSA, infected burn wounds reached bacterial counts below 105 CFU/g tissue. Additionally, moxifloxacin was observed to promote wound healing as determined by histologic analysis, while no induction of bacterial resistance was observed during the treatment period. The use of topical antibiotics for the treatment of infected wounds confers many benefits. Moxifloxacin is therefore an ideal candidate, due to its broad antibacterial spectrum, its high efficiency, and its potential to promote wound healing. PMID:21343458

  1. Localized lipidomics in cystic fibrosis: TOF-SIMS imaging of lungs from Pseudomonas aeruginosa-infected mice.

    PubMed

    Desbenoit, Nicolas; Saussereau, Emilie; Bich, Claudia; Bourderioux, Matthieu; Fritsch, Janine; Edelman, Aleksander; Brunelle, Alain; Ollero, Mario

    2014-07-01

    A consistent body of research has linked cystic fibrosis (CF) with variations in the tissue and fluid content in a number of lipid molecules. However, little is known about the spatial localization of those variations. We have recently applied TOF-SIMS mass spectrometry imaging to detect differential lipid signatures at the colon epithelium between normal and cftr-/- mice. In the present work we have used this technology to investigate potential differences in the spatial distribution of lipids due to Pseudomonas aeruginosa (P.a.) infection in mouse lung expressing or not cftr. Wild-type and exon 10 cftr knockout mice were subjected to intranasal infection with a clinical strain of P.a. Lung cryosections from infected and non-infected mice were subjected to cluster TOF-SIMS analysis in the negative ion mode. We observed a highly specific localization of a phosphoinositol fragment ion at m/z 299.1 in bronchial epithelium. Using this ion to delineate a region of interest, we studied the relative abundance of ions below m/z 1500. We found a significant increase in m/z 465.4 (identified as cholesteryl sulfate) in cftr-/- epithelium and in response to bacterial infection, as well as a decrease in most carboxylic ions. In conclusion, the m/z 299.1 ion can be used as a marker of bronchial epithelium, where P.a. infection leads to increased presence of cholesteryl sulfate in this tissue. TOF-SIMS imaging reveals as a valuable tool for the study of respiratory epithelium. PMID:24513532

  2. In Vitro Antibiofilm Efficacies of Different Antibiotic Combinations with Zinc Sulfate against Pseudomonas aeruginosa Recovered from Hospitalized Patients with Urinary Tract Infection

    PubMed Central

    Elkhatib, Walid; Noreddin, Ayman

    2014-01-01

    Urinary tract infections (UTIs) are a serious healthcare dilemma influencing millions of patients every year and represent the second most frequent type of body infection. Pseudomonas aeruginosa is a multidrug-resistant pathogen causing numerous chronic biofilm-associated infections including urinary tract, nosocomial, and medical devices-related infections. In the present study, the biofilm of P. aeruginosa CCIN34519, recovered from inpatients with UTIs, was established on polystyrene substratum and scanning electron microscopy (SEM) and was utilized for visualization of the biofilm. A previously described in vitro system for real-time monitoring of biofilm growth/inhibition was utilized to assess the antimicrobial effects of ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ertapenem, ceftriaxone, gentamicin, and tobramycin as single antibiotics as well as in combinations with zinc sulfate (2.5 mM) against P. aeruginosa CCIN34519 biofilm. Meanwhile, minimum inhibitory concentrations (MICs) at 24 h and mutant prevention concentrations (MPCs) at 96 h were determined for the aforementioned antibiotics. The real-time monitoring data revealed diverse responses of P. aeruginosa CCIN34519 biofilm to the tested antibiotic-zinc sulfate combinations with potential synergisms in cases of fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and norfloxacin) and carbapenem (ertapenem) as demonstrated by reduced MIC and MPC values. Conversely, considerable antagonisms were observed with cephalosporin (ceftriaxone) and aminoglycosides (gentamicin, and tobramycin) as shown by substantially increased MICs and MPCs values. Further deliberate in vivo investigations for the promising synergisms are required to evaluate their therapeutic potentials for treatment of UTIs caused by P. aeruginosa biofilms as well as for developing preventive strategies. PMID:27025734

  3. Integrative model of the immune response to a pulmonary macrophage infection: what determines the infection duration?

    PubMed

    Go, Natacha; Bidot, Caroline; Belloc, Catherine; Touzeau, Suzanne

    2014-01-01

    The immune mechanisms which determine the infection duration induced by pathogens targeting pulmonary macrophages are poorly known. To explore the impact of such pathogens, it is indispensable to integrate the various immune mechanisms and to take into account the variability in pathogen virulence and host susceptibility. In this context, mathematical models complement experimentation and are powerful tools to represent and explore the complex mechanisms involved in the infection and immune dynamics. We developed an original mathematical model in which we detailed the interactions between the macrophages and the pathogen, the orientation of the adaptive response and the cytokine regulations. We applied our model to the Porcine Respiratory and Reproductive Syndrome virus (PRRSv), a major concern for the swine industry. We extracted value ranges for the model parameters from modelling and experimental studies on respiratory pathogens. We identified the most influential parameters through a sensitivity analysis. We defined a parameter set, the reference scenario, resulting in a realistic and representative immune response to PRRSv infection. We then defined scenarios corresponding to graduated levels of strain virulence and host susceptibility around the reference scenario. We observed that high levels of antiviral cytokines and a dominant cellular response were associated with either short, the usual assumption, or long infection durations, depending on the immune mechanisms involved. To identify these mechanisms, we need to combine the levels of antiviral cytokines, including IFNγ, and IL10. The latter is a good indicator of the infected macrophage level, both combined provide the adaptive response orientation. Available PRRSv vaccines lack efficiency. By integrating the main interactions between the complex immune mechanisms, this modelling framework could be used to help designing more efficient vaccination strategies. PMID:25233096

  4. Integrative Model of the Immune Response to a Pulmonary Macrophage Infection: What Determines the Infection Duration?

    PubMed Central

    Go, Natacha; Bidot, Caroline; Belloc, Catherine; Touzeau, Suzanne

    2014-01-01

    The immune mechanisms which determine the infection duration induced by pathogens targeting pulmonary macrophages are poorly known. To explore the impact of such pathogens, it is indispensable to integrate the various immune mechanisms and to take into account the variability in pathogen virulence and host susceptibility. In this context, mathematical models complement experimentation and are powerful tools to represent and explore the complex mechanisms involved in the infection and immune dynamics. We developed an original mathematical model in which we detailed the interactions between the macrophages and the pathogen, the orientation of the adaptive response and the cytokine regulations. We applied our model to the Porcine Respiratory and Reproductive Syndrome virus (PRRSv), a major concern for the swine industry. We extracted value ranges for the model parameters from modelling and experimental studies on respiratory pathogens. We identified the most influential parameters through a sensitivity analysis. We defined a parameter set, the reference scenario, resulting in a realistic and representative immune response to PRRSv infection. We then defined scenarios corresponding to graduated levels of strain virulence and host susceptibility around the reference scenario. We observed that high levels of antiviral cytokines and a dominant cellular response were associated with either short, the usual assumption, or long infection durations, depending on the immune mechanisms involved. To identify these mechanisms, we need to combine the levels of antiviral cytokines, including , and . The latter is a good indicator of the infected macrophage level, both combined provide the adaptive response orientation. Available PRRSv vaccines lack efficiency. By integrating the main interactions between the complex immune mechanisms, this modelling framework could be used to help designing more efficient vaccination strategies. PMID:25233096

  5. Pseudomonas aeruginosa Infective Endocarditis Following Aortic Valve Implantation: A Note of Caution

    PubMed Central

    Dapás, Juan Ignacio; Rivero, Cynthia; Burgos, Pablo; Vila, Andrea

    2016-01-01

    Transcatheter aortic valve implantation (TAVI) is an alternative treatment for severe aortic valve stenosis (AS) in patients with prohibitive risk for surgical aortic valve replacement (SAVR). Prosthetic valve endocarditis (PVE) is a rare complication of this relatively novel procedure and current guidelines do not include specific recommendations for its treatment. We report a case of PVE due to Pseudomonas aeruginosa after TAVI that required SAVR, with successful outcome. PVE usually occurs during the first year after TAVI and entails a high mortality risk because patients eligible for this min-imally invasive procedure are fragile (i.e. advanced age and/or severe comorbidities). Additionally, clinical presentation may be atypical or subtle and transesophageal echocardiogram (TEE) may not be conclusive, which delays diagnosis and treatment worsening the prognosis. This case highlights that open SAVR might be ultimately indicated as part of treatment for TAVI-PVE despite a high-risk surgery score. PMID:27014375

  6. Conception rate, uterine infection and embryo quality after artificial insemination and natural breeding with a stallion carrier of Pseudomonas aeruginosa: a case report

    PubMed Central

    2012-01-01

    Background Pseudomonas aeruginosa may cause venereal disease and infertility in horses. A Pseudomonas aeruginosa - carrier stallion, often unresponsive to artificial vagina collection, was used to naturally breed mares. Semen collected from the same stallion was also used to perform artificial inseminations. Pregnancy rates, embryo quality and incidence of uterine infection were compared between inseminated or naturally-bred mares. Methods P. aeruginosa was isolated from swabbing of the penis, prepuce and distal urethra of the stallion. Before being bred or inseminated, clitoral/vestibular samples were collected from all mares, and cultured for isolation of P. aeruginosa. At the first observed estrus, endometrial swabs were also collected. All mares subjected to natural mating (NS) were re-evaluated for P.aeruginosa by culture of clitoral and endometrial swabs. Artificial inseminations (AI) were performed either with fresh-extended semen (11 AI/7 mares) or frozen semen (10 AI/7 mares). The stallion was also used to breed 3 mares (4 services). For embryo collection, 2 mares were inseminated with fresh-extended semen (1 AI/mare), and 2 additional mares were inseminated with frozen semen (2 AI/mare). Two mares were naturally-bred with a total of 9 services, for embryo collection. All mares were examined after AI or natural service (NS), for uterine pathologies. Embryo recoveries were attempted passing a catheter with inflatable cuff connected to a sterile flexible 2-way flushing catheter, through the cervix. Flushed media was recovered into an Em-Con filter, and embryos searched using a stereoscope. Embryos were graded from 1 (excellent) to 4 (degenerated/dead). Results Pregnancy rates obtained after NS was 50% per cycle. However, more than half of the NS resulted in uterine disease, while uterine pathology was seen only in 22% of the time following AI. Half of the mares bred by NS got positive to P. aeruginosa. Percentage of embryo recovery rates was identical after

  7. Antineutrophil Cytoplasmic Antibody-associated Vasculitis Superimposed on Infection-related Glomerulonephritis Secondary to Pulmonary Mycobacterium avium Complex Infection.

    PubMed

    Asano, Shuichi; Mizuno, Shige; Okachi, Shotaro; Aso, Hiromichi; Wakahara, Keiko; Hashimoto, Naozumi; Ito, Satoru; Kozaki, Yohei; Katsuno, Takayuki; Maruyama, Shoichi; Hasegawa, Yoshinori

    2016-01-01

    A 73-year-old woman was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection and received no treatment. Disease progression was evident one year later with the development of myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA) titers and systemic symptoms of a fever, polyarthritis, purpura, and rapidly progressive glomerulonephritis. Her symptoms did not improve with antibiotic treatment. A renal biopsy revealed crescentic glomerulonephritis with immunodeposition. According to these findings, she was diagnosed with ANCA-associated vasculitis (AAV) superimposed on infection-related glomerulonephritis (IRGN). Although there was a risk of aggravating an underlying infection, the combination therapy of corticosteroid and antibiotics improved AAV, IRGN, and even the lung radiological findings. To the best of our knowledge, this is the first case of AAV and IRGN secondary to pulmonary MAC infection. PMID:27580547

  8. Differentiation of pulmonary bacterial pathogens in cystic fibrosis by volatile metabolites emitted by their in vitro cultures: Pseudomonas aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia and the Burkholderia cepacia complex.

    PubMed

    Dryahina, Kseniya; Sovová, Kristýna; Nemec, Alexandr; Španěl, Patrik

    2016-01-01

    As a contribution to the continuing search for breath biomarkers of lung and airways infection in patients with cystic fibrosis, CF, we have analysed the volatile metabolites released in vitro by Pseudomonas aeruginosa and other bacteria involved in respiratory infections in these patients, i.e. those belonging to the Burkholderia cepacia complex, Staphylococcus aureus or Stenotrophomonas maltophilia. These opportunistic pathogens are generally harmless to healthy people but they may cause serious infections in patients with severe underlying disease or impaired immunity such as CF patients. Volatile organic compounds emitted from the cultures of strains belonging to the above-mentioned four taxa were analysed by selected ion flow tube mass spectrometry. In order to minimize the effect of differences in media composition all strains were cultured in three different liquid media. Multivariate statistical analysis reveals that the four taxa can be well discriminated by the differences in the headspace VOC concentration profiles. The compounds that should be targeted in breath as potential biomarkers of airway infection were identified for each of these taxa of CF pathogens. PMID:27506232

  9. Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy.

    PubMed

    Velásquez, Jorge N; Ledesma, Bibiana A; Nigro, Monica G; Vittar, Natalia; Rueda, Nestor; De Carolis, Luis; Figueiras, Olga; Carnevale, Silvana; Corti, Marcelo

    2016-01-01

    Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART. PMID:26933317

  10. Pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in the era of antiretroviral therapy

    PubMed Central

    Velásquez, Jorge N; Ledesma, Bibiana A; Nigro, Monica G; Vittar, Natalia; Rueda, Nestor; De Carolis, Luis; Figueiras, Olga; Carnevale, Silvana; Corti, Marcelo

    2016-01-01

    Toxoplasmosis is a severe opportunistic infection in patients infected with the human immunodeficiency virus (HIV). The lung is a major site of infection after the central nervous system. In this report we described two cases of pneumonia due to Toxoplasma gondii infection in HIV patients with antiretroviral therapy. Clinical and radiological abnormalities are not specific. Pulmonary toxoplasmosis should be considered in HIV-infected patients with late stage of HIV, CD4 count less than 100 cells/µl and a poor adherence to HAART. PMID:26933317

  11. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis

    PubMed Central

    Mayer-Hamblett, Nicole; Kloster, Margaret; Rosenfeld, Margaret; Gibson, Ronald L.; Retsch-Bogart, George Z.; Emerson, Julia; Thompson, Valeria; Ramsey, Bonnie W.

    2015-01-01

    Background. Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response. Methods. This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed. Results. Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17–.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25–.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline. Conclusions. This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage. Clinical Trials Registration. NCT00097773. PMID:25972024

  12. Haemoptysis in a female with diabetes mellitus: a unique presentation of chronic pulmonary aspergillosis, pulmonary tuberculosis, and Klebsiella peumoniae co-infection.

    PubMed

    Ekwueme, Chinonso; Otu, Akaninyene Asuquo; Chinenye, Sunny; Unachukwu, Chioma; Oputa, Reginald N; Korubo, Ibitrokoemi; Enang, Ofem E

    2016-04-01

    While chronic pulmonary aspergillosis (CPA), pulmonary tuberculosis (PTB), and Klebsiella pneumoniae pneumonia co-infection is rare, we present a 50-year-old woman with uncontrolled diabetes who presented with these three diseases. There is considerable overlap in symptoms of PTB and CPA. Treatment with antifungals, anti-tuberculosis therapy, and antibiotics is beneficial. PMID:27099746

  13. Necrotizing pulmonary aspergillosis and ventricular assist device infection: case report and review of literature.

    PubMed

    Kornberger, A; Walter, V; Jaeger, F; Lehnert, T; Soriano, M; Moritz, A; Stock, U A; Beiras-Fernandez, A

    2015-10-01

    Necrotizing pulmonary aspergillosis and Aspergillus device infection are rare and have potentially fatal complications after left ventricular assist device (LVAD) implantation. To date, few cases of patients surviving Aspergillus device infection have been published, with survival reported only after device removal. We present a patient implanted with an LVAD in whom necrotizing pulmonary aspergillosis with device involvement was successfully treated by segmentectomy and prolonged antifungal treatment without device exchange or removal. Similar cases in the literature were searched for and are discussed in view of the severity of this complication. PMID:26224318

  14. A crucial role of Flagellin in the induction of airway mucus production by Pseudomonas aeruginosa.

    PubMed

    Ben Mohamed, Fatima; Mohamed, Fatima Ben; Garcia-Verdugo, Ignacio; Medina, Mathieu; Balloy, Viviane; Chignard, Michel; Ramphal, Reuben; Touqui, Lhousseine

    2012-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. Flagellin is a P. aeruginosa virulence factor involved in host response to this pathogen. We examined the role of flagellin in P. aeruginosa-induced mucus secretion. Using a mouse model of pulmonary infection we showed that PAK, a wild type strain of P. aeruginosa, induced airway mucus secretion and mucin muc5ac expression at higher levels than its flagellin-deficient mutant (ΔFliC). PAK induced expression of MUC5AC and MUC2 in both human airway epithelial NCI-H292 cell line and in primary epithelial cells. In contrast, ΔFliC infection had lower to no effect on MUC5AC and MUC2 expressions. A purified P. aeruginosa flagellin induced MUC5AC expression in parallel to IL-8 secretion in NCI-H292 cells. Accordingly, ΔFliC mutant stimulated IL-8 secretion at significantly lower levels compared to PAK. Incubation of NCI-H292 cells with exogenous IL-8 induced MUC5AC expression and pre-incubation of these cells with an anti-IL-8 antibody abrogated flagellin-mediated MUC5AC expression. Silencing of TLR5 and Naip, siRNA inhibited both flagellin-induced MUC5AC expression and IL-8 secretion. Finally, inhibition of ERK abolished the expression of both PAK- and flagellin-induced MUC5AC. We conclude that: (i) flagellin is crucial in P. aeruginosa-induced mucus hyper-secretion through TLR5 and Naip pathways; (ii) this process is mediated by ERK and amplified by IL-8. Our findings help understand the mechanisms involved in mucus secretion during pulmonary infectious disease induced by P. aeruginosa, such as in cystic fibrosis. PMID:22768318

  15. Clinical outcomes of multidrug resistant pseudomonas aeruginosa infection and the relationship with type III secretion system in patients with diabetic foot.

    PubMed

    Zhang, Jinghang; Chu, Yuejie; Wang, Penghua; Ji, Xiaoyan; Li, Xiwen; Wang, Chao; Peng, Yue

    2014-09-01

    The objective was to analyze the clinical outcomes of multidrug resistant Pseudomonas aeruginosa (MDRPA) infection and determine the relationship between type III secretion system (TTSS) and MDRPA in diabetic foot (DF) patients. A total of 117 patients infected with P aeruginosa were recruited and grouped into MDRPA and non-MDRPA group according to antimicrobial susceptibility testing. TTSS genes were detected by polymerase chain reaction (PCR). Potential risk factors for MDRPA infection were examined using univariate and multivariate analyses. Clinical outcomes were compared on the basis of MDRPA or TTSS virulence gene. Previous antibiotic therapy, previous hospitalization and osteomyelitis were associated with MDRPA infection. MDRPA group had a higher amputation/toe rate (32.6% vs 16.2%) and lower healing rate (20.9% vs 41.9%) than non-MDRPA group (P = .032). A significantly higher proportion of exoU was present in MDRPA group (75.0% vs 25.0%, P < .05) than non-MDRPA group. Patients infected with exoU isolates had a lower healing rate and higher amputation/toe rate (25.0% vs 65.2%, 33.3% vs 8.7%, P < .05) than infected with exoS isolates. The exoU gene was predominance among MDRPA strains. The poor clinical outcomes of MDRPA infection in patients with DF were attributable to exoU gene. PMID:25106442

  16. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

    PubMed Central

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  17. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens.

    PubMed

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4(+) or CD8(+) T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b(+) myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b(+) myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  18. Do linear logistic model analyses of volatile biomarkers in exhaled breath of cystic fibrosis patients reliably indicate Pseudomonas aeruginosa infection?

    PubMed

    Španěl, Patrik; Sovová, Kristýna; Dryahina, Kseniya; Doušová, Tereza; Dřevínek, Pavel; Smith, David

    2016-01-01

    Non-invasive breath analysis has been used to search for volatile biomarkers of lungs and airways infection by Pseudomonas aeruginosa, PA, in cystic fibrosis patients. The exhaled breath of 20 PA-infected patients and 38 PA-negative patients was analysed using selected ion flow tube mass spectrometry, SIFT-MS. Special attention was given to the positive identification and accurate quantification of 16 volatile compounds (VOCs) as assured by the detailed consideration of their analytical ion chemistry occurring in the SIFT-MS reactor. However, the diagnostic sensitivity and specificity of the concentrations of any of the 16 compounds taken individually were found to be low. But when a linear combination of the concentrations of all 16 VOCs was used to construct an optimised receiver operating characteristics (ROC) curve using a linear logistic model, the diagnostic separation of PA-infected patients relative to the PA-negative patients was apparently good in terms of the derived sensitivity (89%), specificity (86%), and the area under the ROC curve is 0.91. Four compounds were revealed by the linear logistic model as significant, viz. malondialdehyde, isoprene, phenol and acetoin. The implications of these results to PA detection in the airways are assessed. Whilst such a metabolomics approach to optimise the ROC curve is widely used in breath analysis, it can lead to misleading indications. Therefore, we conclude that the results of the linear logistic model analyses are of limited immediate clinical value. The identified compounds should rather be considered as a stimulus for further independent studies involving larger patient cohorts. PMID:27532768

  19. Vaccine-Mediated Immune Responses to Experimental Pulmonary Cryptococcus gattii Infection in Mice

    PubMed Central

    Chaturvedi, Ashok K.; Hameed, Rumanasma S.; Wozniak, Karen L.; Hole, Camaron R.; Leopold Wager, Chrissy M.; Weintraub, Susan T.; Lopez-Ribot, Jose L.; Wormley, Floyd L.

    2014-01-01

    Cryptococcus gattii is a fungal pathogen that can cause life-threatening respiratory and disseminated infections in immune-competent and immune-suppressed individuals. Currently, there are no standardized vaccines against cryptococcosis in humans, underlying an urgent need for effective therapies and/or vaccines. In this study, we evaluated the efficacy of intranasal immunization with C. gattii cell wall associated (CW) and/or cytoplasmic (CP) protein preparations to induce protection against experimental pulmonary C. gattii infection in mice. BALB/c mice immunized with C. gattii CW and/or CP protein preparations exhibited a significant reduction in pulmonary fungal burden and prolonged survival following pulmonary challenge with C. gattii. Protection was associated with significantly increased pro-inflammatory and Th1-type cytokine recall responses, in vitro and increased C. gattii-specific antibody production in immunized mice challenged with C. gattii. A number of immunodominant proteins were identified following immunoblot analysis of C. gattii CW and CP protein preparations using sera from immunized mice. Immunization with a combined CW and CP protein preparation resulted in an early increase in pulmonary T cell infiltrates following challenge with C. gattii. Overall, our studies show that C. gattii CW and CP protein preparations contain antigens that may be included in a subunit vaccine to induce prolonged protection against pulmonary C. gattii infection. PMID:25119981

  20. Concurrent pulmonary Aspergillus fumigatus and mucor infection in a cardiac transplant recipient: a case report.

    PubMed

    Webb, B J; Blair, J E; Kusne, S; Scott, R L; Steidley, D E; Arabia, F A; Vikram, H R

    2013-03-01

    Invasive fungal infections are a significant complication of solid organ transplantation. Here we report the first case of concurrent invasive pulmonary fungal infection caused by Aspergillus fumigatus and Mucor species in a heart transplant recipient. Polymicrobial mold infection is rare but should be considered in solid organ transplant recipients who fail to respond to initial antifungal therapy targeting a single organism. It is also of interest that in addition to potent immunosuppression and prolonged voriconazole therapy, possible airway fungal colonization following hurricane Katrina cleaning efforts might have contributed to this dual invasive mold infection. PMID:23267784

  1. Pseudomonas aeruginosa Biofilm Infections: Community Structure, Antimicrobial Tolerance and Immune Response.

    PubMed

    Rybtke, Morten; Hultqvist, Louise Dahl; Givskov, Michael; Tolker-Nielsen, Tim

    2015-11-20

    Studies of biopsies from infectious sites, explanted tissue and medical devises have provided evidence that biofilms are the underlying cause of a variety of tissue-associated and implant-associated recalcitrant human infections. With a need for novel anti-biofilm treatment strategies, research in biofilm infection microbiology, biofilm formation mechanisms and biofilm-associated antimicrobial tolerance has become an important area in microbiology. Substantial knowledge about biofilm formation mechanisms, biofilm-associated antimicrobial tolerance and immune evasion mechanisms has been obtained through work with biofilms grown in in vitro experimental setups, and the relevance of this information in the context of chronic infections is being investigated by the use of animal models of infection. Because our current in vitro experimental setups and animal models have limitations, new advanced in vitro models developed with knowledge about the chemical landscape at infectious sites are needed. PMID:26319792

  2. Case report of idiopathic pulmonary haemosiderosis in a child with recurrent chest infections.

    PubMed

    Ibrahem, Renan; Arasaretnam, Anita; Ordidge, Katherine; Vedelago, John; Toy, Rosemary

    2011-01-01

    Idiopathic pulmonary haemosiderosis (IPH) is a rare condition that usually presents as a triad of haemoptysis, iron deficiency anaemia and pulmonary infiltrates. We report a case of IPH diagnosed in a 7 year old boy who had recurrent hospital admissions with severe chest infections and haemoptysis from his first few months of life. He was found to have microcytic hypochromic anaemia, diffuse infiltrate shadowing on his chest X-ray (CXR) and ground-glass opacification on his computed tomogram (CT). Perl's Prussian blue staining of his bronchoalveolar lavage fluid revealed haemosiderin-laden macrophage infiltration. After exclusion of infective, cardiac, immunological and glomerular causes, he was diagnosed with idiopathic pulmonary haemosiderosis. He has since been treated intermittently with steroids, which have failed to control his symptoms fully. PMID:22470815

  3. EFFECTS OF ACUTE EXPOSURE TO PHOSGENE ON PULMONARY HOST DEFENSES AND RESISTANCE TO INFECTION

    EPA Science Inventory

    Phosgene is a toxic gas widely used in industrial processes. he most sensitive endpoint for phosgene toxicity in mice is decreased resistance to challenge with bacterial infection or tumor cells. were attributed to impaired alveolar macrophage (AM) and pulmonary natural killer ce...

  4. Possible pulmonary Rhizopus oryzae infection in a previously healthy child after a near-drowning incident.

    PubMed

    Gerlach, Magdalena M; Lippmann, Norman; Kobelt, Louise; Petzold-Quinque, Stefanie; Ritter, Lutz; Kiess, Wieland; Siekmeyer, Manuela

    2016-06-01

    This article reports on a previously healthy 17-month-old boy who developed pulmonary mucormycosis after a near-drowning incident in a goose pond. The patient survived without neurological sequelae and recovered, under treatment with amphotericin B, from the rare and often invasive fungal infection with Rhizopus spp., usually occurring in immunodeficient patients. PMID:26365402

  5. The optimum timing to wean invasive ventilation for patients with AECOPD or COPD with pulmonary infection

    PubMed Central

    Song, Yuanlin; Chen, Rongchang; Zhan, Qingyuan; Chen, Shujing; Luo, Zujin; Ou, Jiaxian; Wang, Chen

    2016-01-01

    COPD is characterized by a progressive decline in lung function and mental and physical comorbidities. It is a significant burden worldwide due to its growing prevalence, comorbidities, and mortality. Complication by bronchial-pulmonary infection causes 50%–90% of acute exacerbations of COPD (AECOPD), which may lead to the aggregation of COPD symptoms and the development of acute respiratory failure. Non-invasive or invasive ventilation (IV) is usually implemented to treat acute respiratory failure. However, ventilatory support (mainly IV) should be discarded as soon as possible to prevent the onset of time-dependent complications. To withdraw IV, an optimum timing has to be selected based on weaning assessment and spontaneous breathing trial or replacement of IV by non-IV at pulmonary infection control window. The former method is more suitable for patients with AECOPD without significant bronchial-pulmonary infection while the latter method is more suitable for patients with AECOPD with acute significant bronchial-pulmonary infection. PMID:27042042

  6. Nosocomial Outbreak of Corynebacterium striatum Infection in Patients with Chronic Obstructive Pulmonary Disease▿

    PubMed Central

    Renom, Feliu; Garau, Margarita; Rubí, Mateu; Ramis, Ferran; Galmés, Antònia; Soriano, Joan B.

    2007-01-01

    We describe an unusual cluster of Corynebacterium striatum infections in 21 patients with chronic obstructive pulmonary disease (COPD) admitted to a medium-size respiratory unit. Eleven isolates from eight patients occurred simultaneously within a month. C. striatum is a potentially pathogenic microorganism with the ability to produce nosocomial infectious outbreaks and respiratory colonization in patients with advanced COPD. PMID:17409213

  7. INTESTINAL AND PULMONARY INFECTION BY Cryptosporidium parvum IN TWO PATIENTS WITH HIV/AIDS

    PubMed Central

    REINA, Fábio Tadeu Rodrigues; RIBEIRO, Camila Aparecida; de ARAÚJO, Ronalda Silva; MATTÉ, Maria Helena; CASTANHO, Roberto Esteves Pires; TANAKA, Ioshie Ibara; VIGGIANI, Ana Maria Ferreira Sornas; MARTINS, Luciamáre Perinetti Alves

    2016-01-01

    We describe two patients with HIV/AIDS who presented pulmonary and intestinal infection caused by Cryptosporidium parvum, with a fatal outcome. The lack of available description of changes in clinical signs and radiographic characteristics of this disease when it is located in the extra-intestinal region causes low prevalence of early diagnosis and a subsequent lack of treatment. PMID:27007564

  8. Surfactant and its role in the pathobiology of pulmonary infection.

    PubMed

    Glasser, Jennifer R; Mallampalli, Rama K

    2012-01-01

    Pulmonary surfactant is a complex surface-active substance comprised of key phospholipids and proteins that has many essential functions. Surfactant's unique composition is integrally related to its surface-active properties, its critical role in host defense, and emerging immunomodulatory activities ascribed to surfactant lipids. Together these effector functions provide for lung stability and protection from a barrage of potentially virulent infectious pathogens. PMID:21945366

  9. Pulmonary Kaposi sarcoma and disseminated Mycobacterium genavense infection in an HIV-infected patient.

    PubMed

    Tribuna, Cindy; Ângela, Cristina; Eira, Isabel; Carvalho, Alexandre

    2015-01-01

    We report a case of Kaposi sarcoma (KS) and disseminated infection by Mycobacterium genavense in a 40-year-old HIV-positive man with CD4+ T-cell count 5/µL. He presented with anorexia, diarrhoea, cachexia and multiple firm violaceous nodules distributed over the face, neck and upper and lower extremities. Biopsy of a skin nodule was performed, confirming KS. Immunoperoxidase staining for human herpesvirus 8 was strongly positive. Endoscopic examination revealed erosive duodenopathy. Multiple biopsy samples showed numerous acid-fast bacilli at direct microscopic examination. Real-time PCR (RT-PCR) identified M. genavense. A CT scan showed diffuse pulmonary infiltrates with a 'tree-in-bud' appearance, striking splenomegaly and abdominal lymphadenopathy. A bronchoscopy was performed, revealing typical Kaposi's lesions in the upper respiratory tract. RT-PCR of bronchial aspirate identified M. genavense and Pneumocystis jirovecii. Despite treatment with highly active antiretroviral therapy, antimycobacterial therapy and trimethoprim/sulfamethoxazole, the outcome was fatal. PMID:26452414

  10. Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aeruginosa Infections.

    PubMed

    Rigatto, Maria Helena; Vieira, Fabiane J; Antochevis, Laura C; Behle, Tainá F; Lopes, Natane T; Zavascki, Alexandre P

    2015-10-01

    There is no clinical evidence supporting the use of polymyxin B in combination with another antimicrobial for infections caused by extensively drug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa isolates. We developed a cohort study of patients in two intensive care units from teaching hospitals to evaluate treatment with intravenous polymyxin B for ≥48 h for severe A. baumannii or P. aeruginosa infections. Covariates potentially associated with 30-day mortality were evaluated in a Cox proportional hazards model. A total of 101 patients were included; 33 (32.7%) were treated with polymyxin B in combination with an antimicrobial lacking in vitro activity and 68 (67.3%) with polymyxin B in monotherapy. The overall 30-day mortality was 59.4% (60 patients), comprising 42.4% (14 of 33) and 67.6% (46 of 68) in combination and monotherapy groups, respectively (P = 0.03). The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in the combination and monotherapy groups, respectively (P = 0.02). Combination therapy was independently associated with lower 30-day mortality (hazard ratio, 0.33; 95% confidence interval, 0.17 to 0.64; P = 0.001). Creatinine clearance of ≥60 ml/min was also a protective factor, while a higher acute physiology and chronic health evaluation (APACHE II) score and polymicrobial infection were associated with increased mortality. The results did not change after adding a propensity score for prescribing combination therapy into the model. The protective effect remained when only combination with β-lactam or carbapenem was considered and in both subgroups of patients: those with A. baumannii infection and those with lower respiratory tract infections. To our knowledge, this is the first clinical study to show a benefit of combination over monotherapy with polymyxin B for severe extensively drug-resistant A. baumannii or P. aeruginosa infections. PMID:26259799

  11. Comparative genomics of isolates of a Pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients.

    PubMed

    Jeukens, Julie; Boyle, Brian; Kukavica-Ibrulj, Irena; Ouellet, Myriam M; Aaron, Shawn D; Charette, Steve J; Fothergill, Joanne L; Tucker, Nicholas P; Winstanley, Craig; Levesque, Roger C

    2014-01-01

    Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung. PMID:24505294

  12. Mannose-modified chitosan microspheres enhance OprF-OprI-mediated protection of mice against Pseudomonas aeruginosa infection via induction of mucosal immunity.

    PubMed

    Cui, Ziyin; Han, Dong; Sun, Xiaoyu; Zhang, Mingliang; Feng, Xin; Sun, Changjiang; Gu, Jingmin; Tong, Chunyu; Lei, Liancheng; Han, Wenyu

    2015-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that localizes to and colonizes mucosal tissue. Thus, vaccines that elicit a strong mucosal response against P. aeruginosa should be superior to other vaccination strategies. In this study, to stimulate rapid and enhanced mucosal immune responses, mannose-modified chitosan microspheres loaded with the recombinant outer membrane protein OprF190-342-OprI21-83 (FI) (FI-MCS-MPs) of P. aeruginosa were developed as a potent subunit vaccine for mucosal delivery. FI-MCS-MPs were successfully obtained via the tripolyphosphate ionic crosslinking method. Confocal and immunohistochemical analyses indicated that FI-MCS-MPs exhibited the ability to bind the macrophage mannose receptor (MMR, CD206) in vitro and in vivo. After intranasal immunization of mice with FI-MCS-MPs, FI-specific humoral immune responses were detected, measured as local IgM antibody titers in lung tissue slurry; IgA antibody titers in nasal washes, bronchoalveolar lavage (BAL), and intestinal lavage; and systemic IgA and IgG antibody titers in serum. FI-MCS-MPs induced early and high mucosal and systemic humoral antibody responses comparable to those in the group vaccinated with unmodified mannose. High levels of IFN-γ and IL-4 in addition to T lymphocyte subsets induced a mixed Th1/Th2 response in mice immunized with FI-MCS-MPs, resulting in the establishment of cellular immunity. Additionally, when immunized mice were challenged with P. aeruginosa via the nasal cavity, FI-MCS-MPs demonstrated 75 % protective efficacy. Together, these data indicate that mannose-modified chitosan microspheres are a promising subunit delivery system for vaccines against P. aeruginosa infection. PMID:25381907

  13. Latent cytomegalovirus infection exacerbates experimental pulmonary fibrosis by activating TGF-β1.

    PubMed

    Li, Yonghuai; Gao, Jian; Wang, Guoliang; Fei, Guanghe

    2016-08-01

    The aim of the present study was to investigate the hypotheses that cytomegalovirus (CMV) may trigger idiopathic pulmonary fibrosis (IPF) in a susceptible host and/or that the presence of CMV may alter IPF in response to a well-defined trigger of pulmonary fibrosis. A mouse model of murine CMV (MCMV) infection was established, and the mice were divided into a control group, bleomycin group and an MCMV+bleomycin group. Changes in the weights of the mice were determined in the three groups. Pulmonary fibrosis was detected using a histopathological method. The activity of transforming growth factor (TGF)‑β1 was measured, and the levels of E‑cadherin, Vimentin and phosphorylated (phospho)‑small mothers against decapentaplegic (SMAD)2 were determined using western blot analysis. MCMV was found to invade the lungs, however, it did not cause pulmonary fibrosis. The progression of fibrosis in the mice treated with MCMV+bleomycin was more rapid, compared with that in the control mice. The protein levels of Vimentin and phospho-SMAD2 were upregulated, whereas the level of E‑cadherin was downregulated in the MCMV+bleomycin group,. The results suggested that latent MCMV infection aggravated pulmonary fibrosis in the mouse model, possibly through the activation of TGF-β1. PMID:27279470

  14. Anti-Pseudomonas aeruginosa IgY Antibodies Induce Specific Bacterial Aggregation and Internalization in Human Polymorphonuclear Neutrophils

    PubMed Central

    Thomsen, K.; Christophersen, L.; Bjarnsholt, T.; Jensen, P. Ø.; Moser, C.

    2015-01-01

    Polymorphonuclear neutrophils (PMNs) are essential cellular constituents in the innate host response, and their recruitment to the lungs and subsequent ubiquitous phagocytosis controls primary respiratory infection. Cystic fibrosis pulmonary disease is characterized by progressive pulmonary decline governed by a persistent, exaggerated inflammatory response dominated by PMNs. The principal contributor is chronic Pseudomonas aeruginosa biofilm infection, which attracts and activates PMNs and thereby is responsible for the continuing inflammation. Strategies to prevent initial airway colonization with P. aeruginosa by augmenting the phagocytic competence of PMNs may postpone the deteriorating chronic biofilm infection. Anti-P. aeruginosa IgY antibodies significantly increase the PMN-mediated respiratory burst and subsequent bacterial killing of P. aeruginosa in vitro. The mode of action is attributed to IgY-facilitated formation of immobilized bacteria in aggregates, as visualized by fluorescence microscopy and the induction of increased bacterial hydrophobicity. Thus, the present study demonstrates that avian egg yolk immunoglobulins (IgY) targeting P. aeruginosa modify bacterial fitness, which enhances bacterial killing by PMN-mediated phagocytosis and thereby may facilitate a rapid bacterial clearance in airways of people with cystic fibrosis. PMID:25895968

  15. Successful treatment with faropenem and clarithromycin of pulmonary Mycobacterium abscessus infection.

    PubMed

    Tanaka, Eisaku; Kimoto, Terumi; Tsuyuguchi, Kazunari; Suzuki, Katsuhiro; Amitani, Ryoichi

    2002-09-01

    Mycobacterium abscessus accounts for 80% of rapidly growing mycobacterial pulmonary infections and can be lethal. Treatment is difficult because of the paucity of effective drugs. We describe a patient with pulmonary M. abscessus infection who was treated with a regimen that included faropenem, a novel oral penem, and clarithromycin. He showed favorable responses to the treatment for more than 12 months. In vitro, faropenem had considerable inhibitory activities against 56 strains of rapidly growing mycobacteria, including M. peregrinum, M. chelonae, M. fortuitum, and M. abscessus (stated in order of increasing minimal inhibitory concentrations). Thus, faropenem has the potential to be used as an adjunctive drug with clarithromycin for the treatment of infection with rapidly growing mycobacteria, including M. abscessus. PMID:12373490

  16. Reversible pulmonary hypertension associated with lungworm infection in a young cat.

    PubMed

    Dirven, Mark; Szatmári, Viktor; van den Ingh, Ted; Nijsse, Rolf

    2012-09-01

    Two ten-week-old kittens presented with dyspnea. Two weeks later dyspnea had worsened and both kittens had developed a heart murmur. One kitten died and necropsy showed severe granulomatous pneumonia and moderate bronchi(oli)tis and peribronchi(oli)tis caused by Aelurostrongylus abstrusus. The results from echocardiography, thoracic radiography and the other kitten's fecal examination were interpreted as severe parasitic pneumonia caused by A. abstrusus infection with pulmonary hypertension. Repeated administration of milbemycine-oxime and praziquantel resulted in cessation of larvae shedding and resolution of clinical, radiographic and echocardiographic signs of bronchopneumonia and pulmonary hypertension. PMID:22877978

  17. Updating our understanding of pulmonary disease associated with HIV infection.

    PubMed

    Estébanez-Muñoz, Miriam; Soto-Abánades, Clara I; Ríos-Blanco, Juan J; Arribas, Jose R

    2012-04-01

    The introduction of highly active antiretroviral therapy (HAART) has resulted in a reduction of opportunistic infections associated with cellular and humoral immunosuppression. However, what is still unclear is the impact of HAART on the development of other diseases not associated with AIDS, such as lung cancer and COPD. The aim of this paper is to review the most innovative and relevant aspects of lung pathology in patients infected with HIV. PMID:22257776

  18. Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

    PubMed Central

    2011-01-01

    Background Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse). Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection. PMID:21943386

  19. Negative Pressure Wound Therapy Decreases Mortality in a Murine Model of Burn-Wound Sepsis Involving Pseudomonas aeruginosa Infection

    PubMed Central

    Dong, Maolong; Wang, Yaojun; Li, Xiao; Hu, Dahai

    2014-01-01

    Background The colonization of burn wounds by Pseudomonas aeruginosa can lead to septic shock, organ injuries, and high mortality rates. We hypothesized that negative pressure wound therapy (NPWT) would decrease invasion and proliferation of P. aeruginosa within the burn wound and reduce mortality. Methods Thermal injuries were induced in anesthetized mice, and P. aeruginosa was applied to the wound surface for 24 h. After removing the burn eschar and debridement, the animals were subjected to either NPWT or wet-to-dry (WTD) treatment protocols. The bacterial loads on the wound surface were assessed during 7 d of treatment, as were the concentrations of inflammatory cytokines in the peripheral blood samples. Survival was monitored daily for 14 d after burn induction. Finally, samples of wounded skin, lung, liver, and kidney were collected and subjected to histopathological examination. Results Applying P. aeruginosa to the burn wound surface led to sepsis. During early stages of treatment, NPWT reduced the mortality of the septic animals and levels of P. aeruginosa within the burn wound compared with WTD-treated animals. Circulating levels of cytokines and cytoarchitectural abnormalities were also significantly reduced via NPWT. Conclusions Our data indicate that NPWT inhibits the invasion and proliferation of P. aeruginosa in burn-wounded tissue and decreases early mortality in a murine model of burn-wound sepsis. These therapeutic benefits likely result from the ability of NPWT to decrease bacterial proliferation on the wound surface, reduce cytokine serum concentrations, and prevent damage to internal organs. PMID:24587379

  20. Effect of hypochlorous acid solution on the eradication and prevention of Pseudomonas aeruginosa infection, serum biochemical variables, and cecum microbiota in rats.

    PubMed

    Goto, Kazuo; Kuwayama, Eri; Nozu, Ryoko; Ueno, Masami; Hayashimoto, Nobuhito

    2015-01-01

    In this study, hypochlorous acid solution, a weak acid, provided as drinking water to rats, was evaluated for its ability to eradicate and prevent Pseudomonas aeruginosa infection, while monitoring its simultaneous effect on serum biochemical variables and microbiota in the rat cecum. The results suggest that the solution could not eliminate the bacteria in the experimentally infected rats; however, the administration of a 10-parts-per-million (ppm) hypochlorous acid solution as drinking water was effective in inhibiting horizontal spread of P. aeruginosa infection among cage mates. Additionally, exposure to hypochlorous solution did not have any effect on serum biochemical variables of the rat including levels of total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, total bilirubin, lipase, amylase, urea nitrogen, total protein, calcium (Ca), phosphorus (P), sodium (Na), chlorine (Cl), except for potassium (K) levels. The most frequently isolated bacteria in the rat cecum included species belonging to Bacteroidales, Lactobacillus, Clostridiales, Erysipelotrichaceae, Akkermansia, Coriobacteriales, and Firmicutes. The ratio of the terminal restriction fragment length polymorphism (T-RFLP) peaks did not differ across rats administered with 5 and 10 ppm weak acid solution as compared to the control group for any of the bacteria, except for Erysipelotrichaceae and Firmicutes, where the ratio of T-RFLP peaks was higher in the 5 ppm group for Erysipelotrichaceae and in the 10 ppm group for Firmicutes than that in the control group (P<0.01). The results suggest that the weak acid hypochlorous solution could not eradicate P. aeruginosa completely from rats. The solution was effective in preventing infection without affecting serum biochemical variables; however, some of bacterial microbiota may have changed due to administration of the solution. PMID:25736708

  1. Effect of hypochlorous acid solution on the eradication and prevention of Pseudomonas aeruginosa infection, serum biochemical variables, and cecum microbiota in rats

    PubMed Central

    GOTO, Kazuo; KUWAYAMA, Eri; NOZU, Ryoko; UENO, Masami; HAYASHIMOTO, Nobuhito

    2015-01-01

    In this study, hypochlorous acid solution, a weak acid, provided as drinking water to rats, was evaluated for its ability to eradicate and prevent Pseudomonas aeruginosa infection, while monitoring its simultaneous effect on serum biochemical variables and microbiota in the rat cecum. The results suggest that the solution could not eliminate the bacteria in the experimentally infected rats; however, the administration of a 10-parts-per-million (ppm) hypochlorous acid solution as drinking water was effective in inhibiting horizontal spread of P. aeruginosa infection among cage mates. Additionally, exposure to hypochlorous solution did not have any effect on serum biochemical variables of the rat including levels of total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, total bilirubin, lipase, amylase, urea nitrogen, total protein, calcium (Ca), phosphorus (P), sodium (Na), chlorine (Cl), except for potassium (K) levels. The most frequently isolated bacteria in the rat cecum included species belonging to Bacteroidales, Lactobacillus, Clostridiales, Erysipelotrichaceae, Akkermansia, Coriobacteriales, and Firmicutes. The ratio of the terminal restriction fragment length polymorphism (T-RFLP) peaks did not differ across rats administered with 5 and 10 ppm weak acid solution as compared to the control group for any of the bacteria, except for Erysipelotrichaceae and Firmicutes, where the ratio of T-RFLP peaks was higher in the 5 ppm group for Erysipelotrichaceae and in the 10 ppm group for Firmicutes than that in the control group (P<0.01). The results suggest that the weak acid hypochlorous solution could not eradicate P. aeruginosa completely from rats. The solution was effective in preventing infection without affecting serum biochemical variables; however, some of bacterial microbiota may have changed due to administration of the solution. PMID:25736708

  2. Immunization with 3-oxododecanoyl-L-homoserine lactone-r-PcrV conjugate enhances survival of mice against lethal burn infections caused by Pseudomonas aeruginosa.

    PubMed

    Golpasha, Isar Dejban; Mousavi, Seyed Fazlollah; Owlia, Parviz; Siadat, Seyed Davar; Irani, Shiva

    2015-01-01

    Quorum Sensing and type III secretion system play an important role in the virulence of Pseudomonas (P.) aeruginosa in burn wound infections. We aimed to explore the feasibility of using 3-oxo-C₁₂-HSL-r-PcrV conjugate as a candidate vaccine against P. aeruginosa caused infections. 3-oxo-C₁₂-HSL-r-PcrV conjugate was prepared and used for immunization of mice (10 μg, subcutaneous, three times, at 2-week intervals). Mice were divided into five groups: I: PcrV; II: 3-oxo-C₁₂-HSL-r-PcrV (10 μg); III: 3-oxo-C₁₂-HSL-r-PcrV (20 μg); IV: 3-oxo-C₁₂-HSL; and V: PBS receiving groups. After each shot of immunization, total and isotype antibody responses against corresponding antigen were measured to determine the immunization efficacy. One month after the last immunization, all groups were burned and challenged subeschar with P. aeruginosa PAO1. Survival rate and bacterial quantity in the skin and internal organs (liver and spleen) were evaluated 25-hr after burn infection. Immunization with 3-oxo-C₁₂-HSL-r-PcrV significantly increased total IgG and specific subclass antibodies (IgG₁, IgG₂a, IgG₂b, and IgM) in the serum of the groups II and III compared to the control group (p<0.001). While all the control mice (PBS injected group) died within 2 days after bacterial challenge, 64% of the group I, 78% of group II, and 86% of group III, survived within 14 days after challenge. Interestingly, bacterial burden in the liver and spleen of 3-oxo-C₁₂-HSL-r-PcrV injected group (III) was significantly lower than the control group (p<0.001). The present study proposed two-component vaccine to inhibit Pseudomonas infections in burned mouse. PMID:26042508

  3. Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection

    PubMed Central

    Scherzer, Rebecca; Heringer, Amanda S.; Macgregor, John S.; Martin, Jeffrey N.; Deeks, Steven G.; Ganz, Peter

    2016-01-01

    Background HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described. Methods We measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH. Results Among 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses. Conclusions Higher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH. PMID:26752193

  4. Rapid detection of Pseudomonas aeruginosa biomarkers in biological fluids using surface-enhanced Raman scattering

    NASA Astrophysics Data System (ADS)

    Wu, Xiaomeng; Chen, Jing; Zhao, Yiping; Zughaier, Susu M.

    2014-05-01

    Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes major infection not only in Cystic Fibrosis patients but also in chronic obstructive pulmonary disease and in critically ill patients in intensive care units. Successful antibiotic treatment of the infection relies on accurate and rapid identification of the infectious agents. Conventional microbiological detection methods usually take more than 3 days to obtain accurate results. We have developed a rapid diagnostic technique based on surface-enhanced Raman scattering to directly identify PA from biological fluids. P. aeruginosa strains, PAO1 and PA14, are cultured in lysogeny broth, and the SERS spectra of the broth show the signature Raman peaks from pyocyanin and pyoverdine, two major biomarkers that P. aeruginosa secretes during its growth, as well as lipopolysaccharides. This provides the evidence that the presence of these biomarkers can be used to indicate P. aeruginosa infection. A total of 22 clinical exhaled breath condensates (EBC) samples were obtained from subjects with CF disease and from non-CF healthy donors. SERS spectra of these EBC samples were obtained and further analyzed by both principle component analysis and partial least square-discriminant analysis (PLS-DA). PLS-DA can discriminate the samples with P. aeruginosa infection and the ones without P. aeruginosa infection at 99.3% sensitivity and 99.6% specificity. In addition, this technique can also discriminate samples from subject with CF disease and healthy donor with 97.5% sensitivity and 100% specificity. These results demonstrate the potential of using SERS of EBC samples as a rapid diagnostic tool to detect PA infection.

  5. A Rare Case of Pulmonary Artery Dissection Associated With Infective Endocarditis

    PubMed Central

    Shi, Xiaoqing; Wang, Xiaoqin; Wang, Chuan; Zhou, Kaiyu; Li, Yifei; Hua, Yimin

    2016-01-01

    Abstract Pulmonary artery dissection (PAD) is a rare condition with high mortality and has not been reported in patient with infective endocarditis (IE). Here, we report the first case of such patient who experienced PDA and survived after surgical intervention. A 10-year-old female child was diagnosed as IE with a patent ductus arteriosis (PDA) and a vegetation on the left side of pulmonary artery trunk (10 × 5 mm2). Following 3-week antibacterial treatment, the body temperature of patient returned to normal, and the size of vegetation reduced (7 × 3 mm2). However, the patient had a sudden attack of sustained and crushing right chest pain, orthopnea with increasing respiratory rate (> 60/min), and acute high fever. Echocardiography revealed the detachment of vegetation on the first day and dissection of pulmonary artery on the next day. The patient received immediate surgical intervention. It was found that aneurysm had a size of 28 × 20 mm2 and its orifice (the dissecting site) located on the opposite side of the PDA opening (right side of the pulmonary artery trunk). The dissected left wall of pulmonary artery trunk was reconstructed followed by the closure of PDA with suture. The patient recovered uneventfully. From this case, we learned that the surgical intervention should be considered at an early time for IE patients who have a vegetation in pulmonary artery and PDA. After the infection is under control, the earlier surgery may prevent severe complications. PMID:27175632

  6. A Rare Case of Pulmonary Artery Dissection Associated With Infective Endocarditis.

    PubMed

    Shi, Xiaoqing; Wang, Xiaoqin; Wang, Chuan; Zhou, Kaiyu; Li, Yifei; Hua, Yimin

    2016-05-01

    Pulmonary artery dissection (PAD) is a rare condition with high mortality and has not been reported in patient with infective endocarditis (IE). Here, we report the first case of such patient who experienced PDA and survived after surgical intervention.A 10-year-old female child was diagnosed as IE with a patent ductus arteriosis (PDA) and a vegetation on the left side of pulmonary artery trunk (10 × 5 mm). Following 3-week antibacterial treatment, the body temperature of patient returned to normal, and the size of vegetation reduced (7 × 3 mm). However, the patient had a sudden attack of sustained and crushing right chest pain, orthopnea with increasing respiratory rate (> 60/min), and acute high fever. Echocardiography revealed the detachment of vegetation on the first day and dissection of pulmonary artery on the next day. The patient received immediate surgical intervention. It was found that aneurysm had a size of 28 × 20 mm and its orifice (the dissecting site) located on the opposite side of the PDA opening (right side of the pulmonary artery trunk). The dissected left wall of pulmonary artery trunk was reconstructed followed by the closure of PDA with suture. The patient recovered uneventfully.From this case, we learned that the surgical intervention should be considered at an early time for IE patients who have a vegetation in pulmonary artery and PDA. After the infection is under control, the earlier surgery may prevent severe complications. PMID:27175632

  7. O3-ENHANCED PULMONARY INFECTION WITH STREPTOCOCCUS ZOOEPIDEMICUS IN MICE: THE ROLE OF ALVEOLAR MACROPHAGE FUNCTION AND CAPSULAR VIRULENCE FACTORS

    EPA Science Inventory

    Ozone exposure has been shown to increase the susceptibility of mice to pulmonary bacterial infection. n this paper we report differences in susceptibility of two strains of mice (C3H/HeJ and C57BI/6) to pulmonary challenge with Streptococcus zooepidemicus, and demonstrate an ass...

  8. Hypertonic saline infusion in traumatic brain injury increases the incidence of pulmonary infection.

    PubMed

    Coritsidis, George; Diamond, Nechama; Rahman, Aleef; Solodnik, Paul; Lawrence, Kayode; Rhazouani, Salwa; Phalakornkul, Suganda

    2015-08-01

    We aimed to investigate the incidence of electrolyte abnormalities, acute kidney injury (AKI), deep venous thrombosis (DVT) and infections in patients with traumatic brain injury (TBI) treated with hypertonic saline (HTS) as osmolar therapy. We retrospectively studied 205 TBI patients, 96 with HTS and 109 without, admitted to the surgical/trauma intensive care unit between 2006 and 2012. Hemodynamics, electrolytes, length of stay (LOS), acute physiological assessment and chronic health evaluation II (APACHE II), injury severity scores (ISS) and mortality were tabulated. Infection, mechanical ventilation, DVT and AKI incidence were reviewed. HTS was associated with increased LOS and all infections (p=0.0001). After correction for the Glasgow coma scale (GCS) and ventilator need, pulmonary infections (p=0.001) and LOS remained higher with HTS (p=0.0048). HTS did not result in increased blood pressure, DVT, AKI or neurological benefits. HTS significantly increased the odds for all infections, most specifically pulmonary infections, in patients with GCS<8. Due to these findings, HTS in TBI should be administered with caution regardless of acuity. PMID:26055957

  9. Co-Carriage of blaKPC-2 and blaNDM-1 in Clinical Isolates of Pseudomonas aeruginosa Associated with Hospital Infections from India

    PubMed Central

    Paul, Deepjyoti; Dhar Chanda, Debadatta; Maurya, Anand Prakash; Mishra, Shweta; Chakravarty, Atanu; Sharma, Gauri Dutt; Bhattacharjee, Amitabha

    2015-01-01

    Global spread of KPC poses to be a serious threat complicating treatment options in hospital settings. The present study investigates the genetic environment of blaKPC-2 among clinical isolates of Pseudomonas aeruginosa from a tertiary referral hospital of India. The study isolates were collected from different wards and clinics of Silchar Medical College and Hospital, India, from 2012–2013. The presence of blaKPC was confirmed by genotypic characterization followed by sequencing. Cloning of the blaKPC-2 gene was performed and the genetic environment of this gene was characterized as well. Transferability of the resistance gene was determined by transformation assay and Southern hybridization. Additionally, restriction mapping was also carried out. Two isolates of P. aeruginosa were found to harbor blaKPC-2, were resistant towards aminoglycosides, quinolone and β-lactam-β-lactamase inhibitor combination. In both the isolates, the resistance determinant was associated with class 1 integron and horizontally transferable. Both the isolates were co-harboring blaNDM-1. The first detection of this integron mediated blaKPC-2 coexisting with blaNDM-1 in P. aeruginosa from India is worrisome, and further investigation is required to track the gene cassette mediated blaKPC-2 in terms of infection control and to prevent the spread of this gene in hospitals as well as in the community. PMID:26714034

  10. Ibuprofen modifies the inflammatory response of the murine lung to Pseudomonas aeruginosa.

    PubMed

    Sordelli, D O; Cerquetti, M C; el-Tawil, G; Ramwell, P W; Hooke, A M; Bellanti, J A

    1985-08-01

    In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs. PMID:3863757

  11. Altered serum microRNAs as biomarkers for the early diagnosis of pulmonary tuberculosis infection

    PubMed Central

    2012-01-01

    Background Pulmonary tuberculosis (TB) is a highly lethal infectious disease and early diagnosis of TB is critical for the control of disease progression. The objective of this study was to profile a panel of serum microRNAs (miRNAs) as potential biomarkers for the early diagnosis of pulmonary TB infection. Methods Using TaqMan Low-Density Array (TLDA) analysis followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) validation, expression levels of miRNAs in serum samples from 30 patients with active tuberculosis and 60 patients with Bordetella pertussis (BP), varicella-zoster virus (VZV) and enterovirus (EV) were analyzed. Results The Low-Density Array data showed that 97 miRNAs were differentially expressed in pulmonary TB patient sera compared with healthy controls (90 up-regulated and 7 down-regulated). Following qRT-PCR confirmation and receiver operational curve (ROC) analysis, three miRNAs (miR-361-5p, miR-889 and miR-576-3p) were shown to distinguish TB infected patients from healthy controls and other microbial infections with moderate sensitivity and specificity (area under curve (AUC) value range, 0.711-0.848). Multiple logistic regression analysis of a combination of these three miRNAs showed an enhanced ability to discriminate between these two groups with an AUC value of 0.863. Conclusions Our study suggests that altered levels of serum miRNAs have great potential to serve as non-invasive biomarkers for early detection of pulmonary TB infection. PMID:23272999

  12. Probiotics: a new way to fight bacterial pulmonary infections?

    PubMed

    Alexandre, Y; Le Blay, G; Boisramé-Gastrin, S; Le Gall, F; Héry-Arnaud, G; Gouriou, S; Vallet, S; Le Berre, R

    2014-01-01

    Antibiotics, of which Fleming has identified the first representative, penicillin, in 1928, allowed dramatical improvement of the treatment of patients presenting with infectious diseases. However, once an antibiotic is used, resistance may develop more or less rapidly in some bacteria. It is thus necessary to develop therapeutic alternatives, such as the use of probiotics, defined by the World Health Organization (WHO) as "micro-organisms which, administered live and in adequate amounts, confer a benefit to the health of the host". The scope of these micro-organisms is broad, concerning many areas including that of infectious diseases, especially respiratory infections. We describe the rational use of probiotics in respiratory tract infections and detail the results of various clinical studies describing the use of probiotics in the management of respiratory infections such as nosocomial or community acquired pneumonia, or on specific grounds such as cystic fibrosis. The results are sometimes contradictory, but the therapeutic potential of probiotics seems promising. Implementing research to understand their mechanisms of action is critical to conduct therapeutic tests based on a specific rational for the strains to be used, the dose, as well as the chosen mode and rhythm of administration. PMID:23820129

  13. Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis

    PubMed Central

    Emond, Mary J.; Louie, Tin; Emerson, Julia; Chong, Jessica X.; Mathias, Rasika A.; Knowles, Michael R.; Rieder, Mark J.; Tabor, Holly K.; Nickerson, Debbie A.; Barnes, Kathleen C.; GO, Lung; Gibson, Ronald L.; Bamshad, Michael J.

    2015-01-01

    Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were

  14. Mycobacterium sherrisii Lung Infection in a Brazilian Patient with Silicosis and a History of Pulmonary Tuberculosis

    PubMed Central

    de Oliveira Abrão, Carolina; de Araújo Filho, João Alves

    2015-01-01

    Nontuberculous mycobacteria (NTM) diseases became relevant with the emergence and spread of HIV and are also related to lung infection in non-HIV individuals with structural lung diseases. Mycobacterium sherrisii is a NTM first characterized in 2004. Only a few cases have been reported. The aim of this case report is to describe the first detailed case of infection with M. sherrisii in a patient with silicosis and history of pulmonary tuberculosis. A 50-year-old HIV-negative white male, previous smoker, with silicosis and a history of treated pulmonary tuberculosis developed a worsening of cough and expectoration pattern, and two sputum samples were positive for acid-fast bacilli. Presumptive treatment for pulmonary tuberculosis was initiated with rifampin, isoniazid, pyrazinamide, and ethambutol, but, at month 5 of treatment, despite correct medication intake and slight improvement of symptoms, sputum bacilloscopy remained positive. Sputum cultures were positive Mycobacterium sherrisii. Treatment regimen was altered to streptomycin (for 2 months), ethambutol, clarithromycin, rifabutin, and trimethoprim-sulfamethoxazole. M. sherrisii should be considered a possible etiological agent of lung infections in patients with pneumoconiosis and history of tuberculosis. PMID:26557395

  15. Intranasal Immunization Strategy To Impede Pilin-Mediated Binding of Pseudomonas aeruginosa to Airway Epithelial Cells

    PubMed Central

    Hsieh, Jennifer C.; Tham, Doris M.; Feng, Weijun; Huang, Fan; Embaie, Selamawit; Liu, Keyi; Dean, Deborah; Hertle, Ralf; FitzGerald, David J.; Mrsny, Randall J.

    2005-01-01

    Prevention of pulmonary Pseudomonas aeruginosa infections represents a critical unmet medical need for cystic fibrosis (CF) patients. We have examined the tenet that a mucosal immunization approach can reduce interactions of a piliated form of this opportunistic pathogen with respiratory epithelial cells. Vaccinations were performed using ntPEpilinPAK, a protein chimera composed of a nontoxic form of P. aeruginosa exotoxin A (ntPE), where the C-terminal loop amino acid sequence of the PAK strain pilin protein was inserted in place of the ntPE Ib domain. Intranasal (i.n.) immunization of BALB/c mice with ntPEpilinPAK generated both serum and saliva immune responses. A series of in vitro studies showed that diluted samples of saliva obtained from immunized mice reduced pilin-dependent P. aeruginosa binding to polarized human tracheal epithelial cells, protected human pulmonary epithelial cells from cytotoxic actions associated with bacterial challenge, and reduced exotoxin A toxicity. Overall, i.n. administration of ntPEpilinPAK induced mucosal and systemic immune responses that may be beneficial for blocking early stage adhesion and/or infection events of epithelial cell-P. aeruginosa interactions at oropharyngeal surfaces. PMID:16239575

  16. Pulmonary infection with rapidly growing mycobacteria in a singer with achalasia: a case report.

    PubMed

    Cramer, J P; Sudeck, H; Burchard, G D

    2007-04-01

    We report the case of a 37-year-old male patient with prolonged pneumonia and achalasia. Culture and molecular genetic typing identified Mycobacterium abscessus as causative agent. Treatment with clarithromycin and minocycline over 8 months gradually resolved the infection. Rapidly growing, non-obligate pathogenic mycobacteria are widespread in the environment. Several cases of pulmonary infections with these mycobacteria in patients with achalasia have been reported, suggesting a causative association. This is the first report of a case with isolation of M. abscessus in this context. PMID:17316814

  17. Hamster-adapted Sin Nombre virus causes disseminated infection and efficiently replicates in pulmonary endothelial cells without signs of disease.

    PubMed

    Safronetz, David; Prescott, Joseph; Haddock, Elaine; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki

    2013-04-01

    To date, a laboratory animal model for the study of Sin Nombre virus (SNV) infection or associated disease has not been described. Unlike infection with Andes virus, which causes lethal hantavirus pulmonary syndrome (HPS)-like disease in hamsters, SNV infection is short-lived, with no viremia and little dissemination. Here we investigated the effect of passaging SNV in hamsters. We found that a host-adapted SNV achieves prolonged and disseminated infection in hamsters, including efficient replication in pulmonary endothelial cells, albeit without signs of disease. PMID:23388711

  18. Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus

    PubMed Central

    Behar, Samuel M.; Carpenter, Stephen M.; Booty, Matthew G.; Barber, Daniel L.; Jayaraman, Pushpa

    2014-01-01

    Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage. PMID:25311810

  19. Laguna Negra Virus Infection Causes Hantavirus Pulmonary Syndrome in Turkish Hamsters (Mesocricetus brandti).

    PubMed

    Hardcastle, K; Scott, D; Safronetz, D; Brining, D L; Ebihara, H; Feldmann, H; LaCasse, R A

    2016-01-01

    Laguna Negra virus (LNV) is a New World hantavirus associated with severe and often fatal cardiopulmonary disease in humans, known as hantavirus pulmonary syndrome (HPS). Five hamster species were evaluated for clinical and serologic responses following inoculation with 4 hantaviruses. Of the 5 hamster species, only Turkish hamsters infected with LNV demonstrated signs consistent with HPS and a fatality rate of 43%. Clinical manifestations in infected animals that succumbed to disease included severe and rapid onset of dyspnea, weight loss, leukopenia, and reduced thrombocyte numbers as compared to uninfected controls. Histopathologic examination revealed lung lesions that resemble the hallmarks of HPS in humans, including interstitial pneumonia and pulmonary edema, as well as generalized infection of endothelial cells and macrophages in major organ tissues. Histologic lesions corresponded to the presence of viral antigen in affected tissues. To date, there have been no small animal models available to study LNV infection and pathogenesis. The Turkish hamster model of LNV infection may be important in the study of LNV-induced HPS pathogenesis and development of disease treatment and prevention strategies. PMID:25722219

  20. Insights into the respiratory tract microbiota of patients with cystic fibrosis during early Pseudomonas aeruginosa colonization

    SciTech Connect

    Keravec, Marlène; Mounier, Jérôme; Prestat, Emmanuel; Vallet, Sophie; Jansson, Janet K.; Burgaud, Gaëtan; Rosec, Sylvain; Gouriou, Stéphanie; Rault, Gilles; Coton, Emmanuel; Barbier, Georges; Héry-Arnaud, Geneviève

    2015-08-09

    Pseudomonas aeruginosa plays a major role in cystic fibrosis (CF) progression. Therefore, it is important to understand the initial steps of P. aeruginosa infection. The structure and dynamics of CF respiratory tract microbial communities during the early stages of P. aeruginosa colonization were characterized by pyrosequencing and cloning-sequencing. The respiratory microbiota showed high diversity, related to the young age of the CF cohort (mean age 10 years). Wide inter- and intra-individual variations were revealed. A common core microbiota of 5 phyla and 13 predominant genera was found, the majority of which were obligate anaerobes. A few genera were significantly more prevalent in patients never infected by P. aeruginosa. Persistence of an anaerobic core microbiota regardless of P. aeruginosa status suggests a major role of certain anaerobes in the pathophysiology of lung infections in CF. Some genera may be potential biomarkers of pulmonary infection state.

  1. Prevalence and characterization of opportunistic candidal infections among patients with pulmonary tuberculosis

    PubMed Central

    Astekar, Madhusudan; Bhatiya, Priyanka Sharma; Sowmya, GV

    2016-01-01

    Background: Although Candida albicans remains the most common cause of human candidiasis, the frequency of infection attributed to other members of the genus is also increasing. Hence, the present study was carried out to know the prevalence of opportunistic candidal infection in tuberculosis, and if positive, the species of Candida that is most commonly associated. Materials and Methods: The present study comprised sixty pulmonary tuberculosis patients who were divided into (1) fresh or untreated group, (2A) chronic or treated group having no complications and (2B) having complications, comprising twenty patients each, respectively. The collected sputum samples were initially stained with Ziehl–Neelsen stain for confirmation of presence of tubercle Bacilli. Primary isolation was done on Sabouraud Dextrose Agar (SDA). The candidal colonies were confirmed microscopically for the presence of pseudohyphae. Further speciation of the positive candidal samples was carried out using ChromAgar. Result: The total fungal prevalence among 60 patients with pulmonary tuberculosis on SDA was 33 (55%) Candida and 3 (5%) Aspergillus. The prevalence of different candidal species on ChromAgar showed C. albicans as the predominant one, followed by Candida tropicalis and Candida krusei. Freshly diagnosed or untreated group was less commonly associated with pulmonary mycoses than chronic or treated group. The prevalence of Candida had increased with treatment, duration and age, and it was more in males than females. Conclusion: The present study confirms the phenomenon of opportunistic candidal infections in pulmonary tuberculosis patients. Rapid and reliable identification of Candida species is essential as they differ in their virulence and sensitivity to antifungal drugs. PMID:27601806

  2. Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

    PubMed Central

    George, Parakkal Jovvian; Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. PMID:25375117

  3. cIAP-1 Controls Innate Immunity to C. pneumoniae Pulmonary Infection

    PubMed Central

    Prakash, Hridayesh; Becker, Daniel; Böhme, Linda; Albert, Lori; Witzenrath, Martin; Rosseau, Simone; Meyer, Thomas F.; Rudel, Thomas

    2009-01-01

    The resistance of epithelial cells infected with Chlamydophila pneumoniae for apoptosis has been attributed to the induced expression and increased stability of anti-apoptotic proteins called inhibitor of apoptosis proteins (IAPs). The significance of cellular inhibitor of apoptosis protein-1 (cIAP-1) in C. pneumoniae pulmonary infection and innate immune response was investigated in cIAP-1 knockout (KO) mice using a novel non-invasive intra-tracheal infection method. In contrast to wildtype, cIAP-1 knockout mice failed to clear the infection from their lungs. Wildtype mice responded to infection with a strong inflammatory response in the lung. In contrast, the recruitment of macrophages was reduced in cIAP-1 KO mice compared to wildtype mice. The concentration of Interferon gamma (IFN-γ) was increased whereas that of Tumor Necrosis Factor (TNF-α) was reduced in the lungs of infected cIAP-1 KO mice compared to infected wildtype mice. Ex vivo experiments on mouse peritoneal macrophages and splenocytes revealed that cIAP-1 is required for innate immune responses of these cells. Our findings thus suggest a new immunoregulatory role of cIAP-1 in the course of bacterial infection. PMID:19657383

  4. Inhaled formulations and pulmonary drug delivery systems for respiratory infections.

    PubMed

    Zhou, Qi Tony; Leung, Sharon Shui Yee; Tang, Patricia; Parumasivam, Thaigarajan; Loh, Zhi Hui; Chan, Hak-Kim

    2015-05-01

    Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'. PMID:25451137

  5. Cystic fibrosis–adapted Pseudomonas aeruginosa quorum sensing lasR mutants cause hyperinflammatory responses

    PubMed Central

    LaFayette, Shantelle L.; Houle, Daniel; Beaudoin, Trevor; Wojewodka, Gabriella; Radzioch, Danuta; Hoffman, Lucas R.; Burns, Jane L.; Dandekar, Ajai A.; Smalley, Nicole E.; Chandler, Josephine R.; Zlosnik, James E.; Speert, David P.; Bernier, Joanie; Matouk, Elias; Brochiero, Emmanuelle; Rousseau, Simon; Nguyen, Dao

    2015-01-01

    Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogen Pseudomonas aeruginosa and severe neutrophilic pulmonary inflammation. P. aeruginosa undergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator gene lasR commonly arise. We sought to define how mutations in lasR alter host-pathogen relationships. We demonstrate that lasR mutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease–dependent cytokine degradation. In subacute pulmonary infections, lasR mutant–infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected with lasR mutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients. PMID:26457326

  6. Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses

    PubMed Central

    McConnell, Kevin W.; McDunn, Jonathan E.; Clark, Andrew T.; Dunne, W. Michael; Dixon, David J.; Turnbull, Isaiah R.; DiPasco, Peter J.; Osberghaus, William F.; Sherman, Benjamin; Martin, James R.; Walter, Michael J.; Cobb, J. Perren; Buchman, Timothy G.; Hotchkiss, Richard S.; Coopersmith, Craig M.

    2009-01-01

    Objective Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, treatment involves only non-specific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar following disparate infections with similar mortalities. Design Prospective, randomized controlled study. Setting Animal laboratory in a university medical center. Interventions Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple timepoints. Measurements and Main Results The host response was dependent upon the causative organism as well as kinetics of mortality, but the pro- and anti- inflammatory response was independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of 5 distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary MIP-2 and IL-10 with progression of infection while elevated plasma TNFsr2 and MCP-1 were indicative of fulminant disease with >90% mortality within 48 hours. Conclusions Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a potential therapeutic

  7. Correlation between cytotoxicity induced by Pseudomonas aeruginosa clinical isolates from acute infections and IL-1β secretion in a model of human THP-1 monocytes.

    PubMed

    Anantharajah, Ahalieyah; Buyck, Julien M; Faure, Emmanuel; Glupczynski, Youri; Rodriguez-Villalobos, Hector; De Vos, Daniel; Pirnay, Jean-Paul; Bilocq, Florence; Guery, Benoît; Tulkens, Paul M; Mingeot-Leclercq, Marie-Paule; Van Bambeke, Françoise

    2015-10-01

    Type III secretion system (T3SS) in Pseudomonas aeruginosa is associated with poor clinical outcome in acute infections. T3SS allows for injection of bacterial exotoxins (e.g. ExoU or ExoS) into the host cell, causing cytotoxicity. It also activates the cytosolic NLRC4 inflammasome, activating caspase-1, inducing cytotoxicity and release of mature IL-1β, which impairs bacterial clearance. In addition, flagellum-mediated motility has been suggested to also modulate inflammasome response and IL-1β release. Yet the capacity of clinical isolates to induce IL-1β release and its relation with cytotoxicity have never been investigated. Using 20 clinical isolates from acute infections with variable T3SS expression levels and human monocytes, our aim was to correlate IL-1β release with toxin expression, flagellar motility and cytotoxicity. ExoU-producing isolates caused massive cell death but minimal release of IL-1β, while those expressing T3SS but not ExoU (i.e. expressing ExoS or no toxins) induced caspase-1 activation and IL-1β release, the level of which was correlated with cytotoxicity. Both effects were prevented by a specific caspase-1 inhibitor. Flagellar motility was not correlated with cytotoxicity or IL-1β release. No apoptosis was detected. Thus, T3SS cytotoxicity is accompanied by a modification in cytokine balance for P. aeruginosa clinical isolates that do not express ExoU. PMID:26203053

  8. Dynamics of Clarithromycin and Azithromycin Efficacies against Experimental Haemophilus influenzae Pulmonary Infection

    PubMed Central

    Alder, J. D.; Ewing, P. J.; Nilius, A. M.; Mitten, M.; Tovcimak, A.; Oleksijew, A.; Jarvis, K.; Paige, L.; Tanaka, S. K. T.

    1998-01-01

    The dynamics of clarithromycin and azithromycin efficacy against pulmonary Haemophilus influenzae infection in rats were evaluated. Efficacy was measured by reduction in pulmonary H. influenzae burden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains of H. influenzae tested, including four strains for which MICs were above the susceptible breakpoint (8 μg/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats, H. influenzae was found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs for H. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy. PMID:9736568

  9. Prevalence of and risk factors for pulmonary tuberculosis among newly diagnosed HIV-1 infected Nigerian children

    PubMed Central

    Ebonyi, Augustine O.; Oguche, Stephen; Ejeliogu, Emeka U.; Agbaji, Oche O.; Shehu, Nathan Y.; Abah, Isaac O.; Sagay, Atiene S.; Ugoagwu, Placid O.; Okonkwo, Prosper I.; Idoko, John A.; Kanki, Phyllis J.

    2016-01-01

    Introduction Studies on the prevalence of and risk factors for tuberculosis (TB) among newly diagnosed human immunodeficiency virus (HIV)-infected children in sub-Saharan Africa are scarce and in Nigeria there is paucity of reported data. We determined the prevalence of and risk factors for pulmonary TB (PTB) in newly diagnosed (treatment-naïve) HIV-1 infected children at the pediatric HIV clinic of the Jos University Teaching Hospital (JUTH) in Nigeria. Methods We performed a retrospective analysis of 876 children, aged 2 months – 13 years, diagnosed with HIV-1 infection between July 2005 and December 2012, of which 286 were diagnosed with PTB at presentation after TB screening. The study site was the AIDS Prevention Initiative in Nigeria (APIN)-supported Pediatric HIV clinic at JUTH, Jos. A multivariate forward logistic regression modelling was used to identify risk factors for PTB-HIV co-infection. Results The prevalence of PTB-HIV co-infection was 32% (286/876). Severe immunosuppression (SI) and World Health Organization (WHO) HIV clinical stage 3/4 were identified as independent risk factors for PTB-HIV co-infection in HIV infected children. The odds of PTB-HIV co-infection was increased two-fold in HIV-infected children with WHO clinical stage 3/4 compared to those with stage 1/2 (adjusted odds ratio (AOR) 1.76 [1.31-2.37], p<0.001) and 1.5-fold in children with SI compared to those without SI (AOR 1.52 [1.12-2.06], p=0.007). Conclusion In our setting, the burden of PTB was high among newly diagnosed HIV-infected children, and late WHO HIV clinical stage and severe immunosuppression were associated with PTB-HIV co-infection. Therefore there is a clear need to improve strategies for early diagnosis of both HIV and PTB to optimize clinical outcomes. PMID:27019829

  10. The Pseudomonas aeruginosa Lipid A Deacylase: Selection for Expression and Loss within the Cystic Fibrosis Airway

    PubMed Central

    Ernst, Robert K.; Adams, Kristin N.; Moskowitz, Samuel M.; Kraig, Gretchen M.; Kawasaki, Kiyoshi; Stead, Christopher M.; Trent, M. Stephen; Miller, Samuel I.

    2006-01-01

    Lipopolysaccharide (LPS) is the major surface component of gram-negative bacteria, and a component of LPS, lipid A, is recognized by the innate immune system through the Toll-like receptor 4/MD-2 complex. Pseudomonas aeruginosa, an environmental gram-negative bacterium that opportunistically infects the respiratory tracts of patients with cystic fibrosis (CF), can synthesize various structures of lipid A. Lipid A from P. aeruginosa strains isolated from infants with CF has a specific structure that includes the removal of the 3 position 3-OH C10 fatty acid. Here we demonstrate increased expression of the P. aeruginosa lipid A 3-O-deacylase (PagL) in isolates from CF infants compared to that in environmental isolates. PagL activity was increased in environmental isolates by growth in medium limited for magnesium and decreased by growth at low temperature in laboratory-adapted strains of P. aeruginosa. P. aeruginosa PagL was shown to be an outer membrane protein by isopycnic density gradient centrifugation. Heterologous expression of P. aeruginosa pagL in Salmonella enterica serovar Typhimurium and Escherichia coli resulted in removal of the 3-OH C14 fatty acid from lipid A, indicating that P. aeruginosa PagL recognizes either 3-OH C10 or 3-OH C14. Finally, deacylated lipid A species were not observed in some clinical P. aeruginosa isolates from patients with severe pulmonary disease, suggesting that loss of PagL function can occur during long-term adaptation to the CF airway. PMID:16352835

  11. Next-Generation “-omics” Approaches Reveal a Massive Alteration of Host RNA Metabolism during Bacteriophage Infection of Pseudomonas aeruginosa

    PubMed Central

    Monot, Marc; Kogadeeva, Maria; Sauer, Uwe; Jorth, Peter; Whiteley, Marvin; Debarbieux, Laurent; Lavigne, Rob

    2016-01-01

    As interest in the therapeutic and biotechnological potentials of bacteriophages has grown, so has value in understanding their basic biology. However, detailed knowledge of infection cycles has been limited to a small number of model bacteriophages, mostly infecting Escherichia coli. We present here the first analysis coupling data obtained from global next-generation approaches, RNA-Sequencing and metabolomics, to characterize interactions between the virulent bacteriophage PAK_P3 and its host Pseudomonas aeruginosa. We detected a dramatic global depletion of bacterial transcripts coupled with their replacement by viral RNAs over the course of infection, eventually leading to drastic changes in pyrimidine metabolism. This process relies on host machinery hijacking as suggested by the strong up-regulation of one bacterial operon involved in RNA processing. Moreover, we found that RNA-based regulation plays a central role in PAK_P3 lifecycle as antisense transcripts are produced mainly during the early stage of infection and viral small non coding RNAs are massively expressed at the end of infection. This work highlights the prominent role of RNA metabolism in the infection strategy of a bacteriophage belonging to a new characterized sub-family of viruses with promising therapeutic potential. PMID:27380413

  12. Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

    PubMed Central

    Qiu, Yafeng; Dayrit, Jeremy K.; Davis, Michael J.; Carolan, Jacob F.; Osterholzer, John J.; Curtis, Jeffrey L.; Olszewski, Michal A.

    2014-01-01

    Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA+/+ mice and SRA−/− mice were infected intratracheally with C. neoformans. Results show that infection of SRA−/− mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA+/+ mice. Improved fungal clearance in SRA−/− mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4+ T cells and CD11b+ dendritic cells. Additional parameters were consistent with enhanced anti-cryptococcal immunity in the infected SRA−/− mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs. PMID:23733871

  13. Overexpression of RORγt Enhances Pulmonary Inflammation after Infection with Mycobacterium Avium.

    PubMed

    Matsuyama, Masashi; Ishii, Yukio; Sakurai, Hirofumi; Ano, Satoshi; Morishima, Yuko; Yoh, Keigyou; Takahashi, Satoru; Ogawa, Kenji; Hizawa, Nobuyuki

    2016-01-01

    Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial disease in humans. The role of Th17 immunity in the pathogenesis of intracellular bacteria, such as MAC, is not currently understood. Transcription factor RAR-related orphan receptor gamma t (RORγt) is known as the master regulator for Th17 cell development. Here, we investigated the role of RORγt in host responses against MAC infection. Wild-type (WT) mice and RORγt-overexpressing mice were infected with MAC via intratracheal inoculation. Systemic MAC growth was not different between WT mice and RORγt-overexpressing mice. However, neutrophilic pulmonary inflammation following MAC infection was enhanced in RORγt-overexpressing mice compared with that in WT mice. The cytokine expression shifted toward a Th17 phenotype in the lungs of RORγt-overexpressing mice following MAC infection; the levels of IL-6 and IL-17 were significantly higher in the lung of these mice than in WT mice. In addition to the increase in IL-17 single-positive T cells, T cells producing both IL-17 and interferon-γ were elevated in the lung of RORγt-overexpressing mice following MAC infection. These findings suggest that RORγt overexpression-mediated Th17 bias contributes to local inflammation rather than systemic responses, by regulating neutrophil recruitment into the sites of infection during MAC infection. PMID:26784959

  14. Prolonged survival of scavenger receptor class A-deficient mice from pulmonary Mycobacterium tuberculosis infection

    PubMed Central

    Sever-Chroneos, Zvjezdana; Tvinnereim, Amy; Hunter, Robert L.; Chroneos, Zissis C.

    2016-01-01

    SUMMARY The present study tested the hypothesis that the scavenger receptor SR-A modulates granuloma formation in response to pulmonary infection with Mycobacterium tuberculosis (MTB). To test this hypothesis, we monitored survival and histopathology in WT and SR-A-deficient mice following aerosol infection with MTB Rv. SR-A-deficient (SR-A−/−) mice infected with MTB survived significantly longer than WT mice; the mean survival of SR-A−/− mice exceeded 430 days compared to 230 days for WT mice. Early granuloma formation was not impaired in SR-A−/− mice. The extended survival of SR-A−/− mice was associated with 13- and 3-fold higher number of CD4+ lymphocytes and antigen presenting cells in SR-A−/− lungs compared to WT mice 280 after infection. The histopathology of chronically infected SR-A−/− lungs, however, was marked by abundant cholesterol clefts in parenchymal lesions containing infection in multinucleated giant cells. The present study indicates SR-A as a candidate gene of the innate immune system influencing the chronic phase of M. tuberculosis infection. PMID:22088322

  15. [Intestinal disorder of anaerobic bacteria aggravates pulmonary immune pathological injury of mice infected with influenza virus].

    PubMed

    Wu, Sha; Yan, Yuqi; Zhang, Mengyuan; Shi, Shanshan; Jiang, Zhenyou

    2016-04-01

    Objective To investigate the relationship between the intestinal disorder of anaerobic bacteria and influenza virus infection, and the effect on pulmonary inflammatory cytokines in mice. Methods Totally 36 mice were randomly divided into normal control group, virus-infected group and metronidazole treatment group (12 mice in each group). Mice in the metronidazole group were administrated orally with metronidazole sulfate for 8 days causing anaerobic bacteria flora imbalance; then all groups except the normal control group were treated transnasally with influenza virus (50 μL/d FM1) for 4 days to establish the influenza virus-infected models. Their mental state and lung index were observed, and the pathological morphological changes of lung tissues, caecum and intestinal mucosa were examined by HE staining. The levels of interleukin 4 (IL-4), interferon γ (IFN-γ), IL-10 and IL-17 in the lung homogenates were determined by ELISA. Results Compared with the virus control group, the metronidazole group showed obviously increased lung index and more serious pathological changes of the lung tissue and appendix inflammation performance. After infected by the FM1 influenza virus, IFN-γ and IL-17 of the metronidazole group decreased significantly and IL-4 and IL-10 levels were raised, but there was no statistically difference between the metronidazole and virus control groups. Conclusion Intestinal anaerobic bacteria may inhibit the adaptive immune response in the lungs of mice infected with FM1 influenza virus through adjusting the lung inflammatory factors, affect the replication and clean-up time of the FM1 influenza virus, thus further aggravating pulmonary immune pathological injury caused by the influenza virus infection. PMID:27053604

  16. Isolation of Mycobacterium kumamotonense from a patient with pulmonary infection and latent tuberculosis.

    PubMed

    Kontos, Fanourios; Mavromanolakis, Dimitrios Nikitas; Zande, Marina Chari; Gitti, Zoe Georgios

    2016-01-01

    Mycobacterium kumamotonense is a novel, slow-growing non-chromogenic nontuberculous mycobacterium, which belongs to Mycobacterium terrae complex. We report, for the first time in Greece, the isolation of M. kumamotonense from an immunocompetent patient with pulmonary infection and latent tuberculosis. M. kumamotonense was identified by sequencing analysis of 16S rDNA and 65-kDa heat shock protein genes while by commercial molecular assays it was misidentified as Mycobacterium celatum. Antibiotic susceptibility testing was performed by the reference broth microdilution method. The strain was susceptible to amikacin, clarithromycin, rifampin, ciprofloxacin, moxifloxacin, rifabutin, ethambutol and linezolid. PMID:27080783

  17. Role of the platelet-activating factor (PAF) receptor during pulmonary infection with gram negative bacteria

    PubMed Central

    Soares, A C; Pinho, V S; Souza, D G; Shimizu, T; Ishii, S; Nicoli, J R; Teixeira, M M

    2002-01-01

    The lipid mediator PAF plays an important role in the phagocytosis of particles, including bacteria, and consequent production of pro-inflammatory cytokines, such as TNF-α and IL-8. Using a PAF receptor antagonist (UK-74,505) and PAF receptor knock-out mice, we have investigated the relevance of PAF for the inflammatory changes and lethality after pulmonary infection with the gram-negative bacteria Klebsiella pneumoniae in mice. At an inoculum of 3×106 bacteria, there was marked pulmonary (bronchoalveolar lavage and lung) neutrophilia that started early (2.5 h after infection) and peaked at 48 h. All animals were dead by day 4 of infection. The chemokine KC and the pro-inflammatory cytokine TNF-α increased rapidly and persisted for 48 h in the lungs. Pretreatment with UK-74,505 (30 mg kg−1 per day, p.o.) had no significant effects on the number of infiltrating neutrophils in BAL fluid or lung tissue, as assessed by histology and measuring myeloperoxidase, or on the concentrations of KC. In contrast, concentrations of TNF-α and the number of bacteria inside neutrophils were significantly diminished. In order to support a role for the PAF during K. pneumoniae infection, experiments were also carried out in PAFR-deficient mice. In the latter animals, lethality occurred earlier than in wild-type controls. This was associated with greater number of bacteria in lung tissue and diminished percentage of neutrophils containing bacteria in their cytoplasm. Our results suggest that PAF, acting on its receptor, plays a protective role during infection with K. pneumoniae in mice. PMID:12381675

  18. Intestinal Parasite Co-infection among Pulmonary Tuberculosis Cases without Human Immunodeficiency Virus Infection in a Rural County in China

    PubMed Central

    Li, Xin-Xu; Chen, Jia-Xu; Wang, Li-Xia; Tian, Li-Guang; Zhang, Yu-Ping; Dong, Shuang-Pin; Hu, Xue-Guang; Liu, Jian; Wang, Feng-Feng; Wang, Yue; Yin, Xiao-Mei; He, Li-Jun; Yan, Qiu-Ye; Zhang, Hong-Wei; Xu, Bian-Li; Zhou, Xiao-Nong

    2014-01-01

    Epidemiologic studies of co-infection with tuberculosis (TB) and intestinal parasites in humans have not been extensively investigated in China. A cross-section study was conducted in a rural county of Henan Province, China. Pulmonary TB (PTB) case-patients receiving treatment for infection with Mycobacterium tuberculosis and healthy controls matched for geographic area, age, and sex were surveyed by using questionnaires. Fecal and blood specimens were collected for detection of intestinal parasites, routine blood examination, and infection with human immunodeficiency virus. The chi-square test was used for univariate analysis and multivariate logistic regression models were used to adjust for potential confounding factors. A total of 369 persons with PTB and 366 healthy controls were included; all participants were negative for human immunodeficiency virus. The overall prevalence of intestinal parasites in persons with PTB was 14.9%, including intestinal protozoa (7.9%) and helminthes (7.6%). The infection spectrum of intestinal parasites was Entamoeba spp. (1.4%), Blastocystis hominis (6.2%), Trichomonas hominis (0.3%), Clonorchis sinensis (0.3%), Ascaris lumbricoides (0.5%), Trichuris trichiura (2.2%), and hookworm (4.6%). The prevalence of intestinal parasites showed no significant difference between persons with PTB and healthy controls after adjusting for potential confounding factors. There was no factor that affected infection rates for intestinal parasites between the two groups. Infection with intestinal parasites of persons with PTB was associated with female sex (adjusted odds ratio [AOR] = 2.05, 95% confidence interval [CI] = 1.01–4.17), body mass index ≤ 19 (AOR = 3.02, 95% CI = 1.47–6.20), and anemia (AOR = 2.43, 95% CI = 1.17–5.03). Infection of healthy controls was only associated with an annual labor time in farmlands > 2 months (AOR = 4.50, 95% CI = 2.03–10.00). In addition, there was no significant trend between rates of infection with

  19. Inhibition of Quorum Sensing-Controlled Virulence Factors and Biofilm Formation in Pseudomonas aeruginosa by Culture Extract from Novel Bacterial Species of Paenibacillus Using a Rat Model of Chronic Lung Infection.

    PubMed

    Alasil, Saad Musbah; Omar, Rahmat; Ismail, Salmah; Yusof, Mohd Yasim

    2015-01-01

    Quorum sensing (QS) is a key regulator of virulence factors and biofilm formation in Gram-negative bacteria such as Pseudomonas aeruginosa. Microorganisms that inhabit soil are of strategic importance in the discovery of compounds with anti-QS properties. The objective of the study was to test the culture extract of a taxonomically novel species of Paenibacillus strain 139SI for its inhibitory effects on the QS-controlled virulence factors and biofilm formation of Pseudomonas aeruginosa both in vitro and in vivo. The Paenibacillus sp. culture extract was used to test its anti-QS effects on the LasA protease, LasB elastase, pyoverdin production, and biofilm formation of P. aeruginosa as well as evaluate its therapeutic effects on lung bacteriology, pathology, hematological profile, and serum antibody responses of experimental animals in a rat model of chronic lung infection. Results showed significant decrease in the activities of QS-controlled LasA protease, LasB elastase pyoverdin, and biofilm formation of P. aeruginosa caused by the culture extract. Moreover, the extract significantly prolonged the survival times of rats and facilitated the clearance of biofilm infections from infected lungs. In conclusion, the antiquorum sensing effects of culture extract from a novel species of Paenibacillus provide new insights to combat biofilm-associated infections. PMID:26904749

  20. Inhibition of Quorum Sensing-Controlled Virulence Factors and Biofilm Formation in Pseudomonas aeruginosa by Culture Extract from Novel Bacterial Species of Paenibacillus Using a Rat Model of Chronic Lung Infection

    PubMed Central

    Alasil, Saad Musbah; Omar, Rahmat; Yusof, Mohd Yasim

    2015-01-01

    Quorum sensing (QS) is a key regulator of virulence factors and biofilm formation in Gram-negative bacteria such as Pseudomonas aeruginosa. Microorganisms that inhabit soil are of strategic importance in the discovery of compounds with anti-QS properties. The objective of the study was to test the culture extract of a taxonomically novel species of Paenibacillus strain 139SI for its inhibitory effects on the QS-controlled virulence factors and biofilm formation of Pseudomonas aeruginosa both in vitro and in vivo. The Paenibacillus sp. culture extract was used to test its anti-QS effects on the LasA protease, LasB elastase, pyoverdin production, and biofilm formation of P. aeruginosa as well as evaluate its therapeutic effects on lung bacteriology, pathology, hematological profile, and serum antibody responses of experimental animals in a rat model of chronic lung infection. Results showed significant decrease in the activities of QS-controlled LasA protease, LasB elastase pyoverdin, and biofilm formation of P. aeruginosa caused by the culture extract. Moreover, the extract significantly prolonged the survival times of rats and facilitated the clearance of biofilm infections from infected lungs. In conclusion, the antiquorum sensing effects of culture extract from a novel species of Paenibacillus provide new insights to combat biofilm-associated infections. PMID:26904749

  1. Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets.

    PubMed

    Hassett, Daniel J; Cuppoletti, John; Trapnell, Bruce; Lymar, Sergei V; Rowe, John J; Yoon, Sang Sun; Hilliard, George M; Parvatiyar, Kislay; Kamani, Moneesha C; Wozniak, Daniel J; Hwang, Sung Hei; McDermott, Timothy R; Ochsner, Urs A

    2002-12-01

    Recent evidence indicates that Pseudomonas aeruginosa residing as biofilms in airway mucus of cystic fibrosis (CF) patients is undergoing anaerobic metabolism, a form of growth requiring gene products that are not utilized during aerobic growth. The outer membrane protein, OprF, and the rhl quorum sensing circuit are two previously unrecognized cellular factors that are required for optimal anaerobic biofilm viability. Without OprF, bacteria grow extremely poorly because they lack nitrite reductase activity while lacking rhlR or rhlI forces bacteria to undergo metabolic suicide by overproduction of nitric oxide. Furthermore, anaerobic growth favors maintenance of the mucoid, alginate-overproducing phenotype. Thus, with increasing age of CF patients, mucoid populations predominate, indicating that anaerobic bacteria reside in the inspissated airway mucus. Because many frontline antibiotics used in the treatment of CF airway disease are either ineffective or show reduced efficacy during anaerobic conditions, we propose development of new drugs to combat anaerobic metabolism by P. aeruginosa for more effective treatment of chronic CF lung infections. PMID:12458153

  2. Pouring salt on a wound: Pseudomonas aeruginosa virulence factors alter Na+ and Cl- flux in the lung.

    PubMed

    Ballok, Alicia E; O'Toole, George A

    2013-09-01

    Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen with multiple niches in the human body, including the lung. P. aeruginosa infections are particularly damaging or fatal for patients with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and cystic fibrosis (CF). To establish an infection, P. aeruginosa relies on a suite of virulence factors, including lipopolysaccharide, phospholipases, exoproteases, phenazines, outer membrane vesicles, type III secreted effectors, flagella, and pili. These factors not only damage the epithelial cell lining but also induce changes in cell physiology and function such as cell shape, membrane permeability, and protein synthesis. While such virulence factors are important in initial infection, many become dysregulated or nonfunctional during the course of chronic infection. Recent work on the virulence factors alkaline protease (AprA) and CF transmembrane conductance regulator inhibitory factor (Cif) show that P. aeruginosa also perturbs epithelial ion transport and osmosis, which may be important for the long-term survival of this microbe in the lung. Here we discuss the literature regarding host physiology-altering virulence factors with a focus on Cif and AprA and their potential roles in chronic infection and immune evasion. PMID:23836869

  3. Validating a Scoring System for the Diagnosis of Smear-Negative Pulmonary Tuberculosis in HIV-Infected Adults

    PubMed Central

    Coimbra, Isabella; Maruza, Magda; Albuquerque, Maria de Fátima Pessoa Militão; Batista, Joanna D’Arc Lyra; Braga, Maria Cynthia; Moura, Líbia Vilela; Miranda-Filho, Demócrito Barros; Montarroyos, Ulisses Ramos; Lacerda, Heloísa Ramos; Rodrigues, Laura Cunha; de Alencar Ximenes, Ricardo Arraes

    2014-01-01

    Background The challenge of diagnosing smear-negative pulmonary TB (tuberculosis) in people living with HIV justifies the use of instruments other than the smear test for diagnosing the disease. Considering the clinical-radiological similarities of TB amongst HIV-infected adults and children, the proposal of this study was to assess the accuracy of a scoring system used to diagnose smear-negative pulmonary TB in children and adolescents, in HIV-infected adults suspected of having smear-negative pulmonary TB. Methods A Phase III validation study aiming to assess the diagnostic accuracy of a scoring system for diagnosing smear-negative pulmonary TB in HIV-infected adults. The study assessed sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values of the scoring system. Three versions of the scoring system were tested. Results From a cohort of 2,382 (HIV-infected adults), 1276 were investigated and 128 were diagnosed with pulmonary TB. Variables associated with the diagnosis of TB were: coughing, weight loss, fever, malnutrition, chest X-ray, and positive tuberculin test. The best diagnostic performance occurred with the scoring system with new scores, with sensitivity = 81.2% (95%-CI 74.5% –88%), specificity = 78% (75.6% –80.4%), PPV = 29.2% (24.5% –33.9%) and NPV = 97.4% (96.4% –98.4%), LR+ = 3.7 (3.4–4.0) and LR− = 0.24 (0.2–0.4). Conclusion The proposed scoring system (with new scores) presented a good capacity for discriminating patients who did not have pulmonary TB, in the studied population. Further studies are necessary in order to validate it, thus permitting the assessment of its use in diagnosing smear-negative pulmonary TB in HIV-infected adults. PMID:24755628

  4. [Analysis on the effective dosage regimens for meropenem, biapenem and doripenem against P. aeruginosa infection based on pharmacokinetics and pharmacodynamics theory].

    PubMed

    Sumitani, Yuko; Kobayashi, Yoshio

    2007-12-01

    Recently, PK/PD (pharmacokinetics/pharmacodynamics) analysis for the antimicrobial dosage method became one of the popular categories in chemotherapy and infectious disease societies world wide. Carbapenems are often used for empiric therapy because of its broad-spectrum and activities against microorganisms. PK/PD analysis is well studied in some antibiotics including carbapenems and it is necessary also from the point of view of prevention for emergence of resistant strains. We report the result of the analysis for the effective dosage regimens of meropenem, biapenem and doripenem against Pseudomonas aeruginosa infection based on PK/PD theory with the MIC distributions against the strains isolated from the patients blood at Keio University in 2004 and 2006. The highest target attainment rate for the free drug 40% time above the MIC (40%T > or = MIC) in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 90.89% in 500 mg every 6 hours regimen for meropenem, 83.25% in 300 mg every 6 hours regimen for biapenem, 81.73% in 250 mg every 6 hours regimen for doripenem in the approved maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 100% in 500 mg every 6 hours regimen for meropenem, 83.97% in 300 mg every 8 hours regimen for biapenem, 99.98% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agents. The highest target attainment rate for the free drug 40%T > or = MIC in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 80.57% in 500 mg dose in every 6 hours regimen for meropenem, 56.70% in 300 mg every 6 hours regimen for biapenem

  5. Invasive Microascus trigonosporus Species Complex Pulmonary Infection in a Lung Transplant Recipient

    PubMed Central

    Schoeppler, Kelly E.; Zamora, Martin R.; Northcutt, Noelle M.; Barber, Gerard R.; O'Malley-Schroeder, Gayle; Lyu, Dennis M.

    2015-01-01

    Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient's fungal burden. Despite this apparent improvement, the patient's pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death. PMID:26075134

  6. Pulmonary responses to pathogen-specific antigens in latent Mycobacterium tuberculosis infection.

    PubMed

    Jarvela, Jessica R; Tuscano, Lori; Lee, Hung; Silver, Richard F

    2016-01-01

    In this study, we used ELISPOT to quantify frequencies of bronchoalveolar lavage (BAL) and peripheral blood T cells capable of producing IFNγ in response to PPD, antigen 85B, and Mtb-specific antigens CFP-10 and ESAT-6 in individuals with latent tuberculosis infection (LTBI) and Mtb-naïve controls. Compared to peripheral blood, BAL cells of LTBI subjects displayed significant enrichment for T cells responding to PPD, antigen 85B, and CFP-10, but not to ESAT-6. Baseline BAL cells of LTBI subjects displayed significant production of Mig (CXCL9) in response to PPD, antigen 85B, and CFP-10 as well. These findings suggest that enrichment for Mtb-specific T cells within BAL is not unique to active pulmonary tuberculosis and may, to the contrary, contribute to protection from re-infection in Mtb immune individuals. PMID:26732045

  7. Viral infection and aging as cofactors for the development of pulmonary fibrosis

    PubMed Central

    Naik, Payal K; Moore, Bethany B

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a disease of unknown origin and progression that primarily affects older adults. Accumulating clinical and experimental evidence suggests that viral infections may play a role, either as agents that predispose the lung to fibrosis or exacerbate existing fibrosis. In particular, herpesviruses have been linked with IPF. This article summarizes the evidence for and against viral cofactors in IPF pathogenesis. In addition, we review mechanistic studies in animal models that highlight the fibrotic potential of viral infection, and explore the different mechanisms that might be responsible. We also review early evidence to suggest that the aged lung may be particularly susceptible to viral-induced fibrosis and make recommendations for future research directions. PMID:21128751

  8. Rates of pulmonary infection by pentastomids in lizards species from a restinga habitat in northeastern Brazil.

    PubMed

    Almeida, W O; Santana, G G; Vieira, W L S; Wanderley, I C; Ribeiro, S C

    2009-02-01

    Pulmonary parasitism by pentastomids was examined in two lizard species inhabiting an area of restinga vegetation (coastal sand dunes) situated in the municipality of Mataraca (6 degrees 29' S and 34 degrees 56' W), on the extreme northern coast of Paraíba State, Brazil. A total of 123 lizards were collected, being 75 specimens of Micrablepharus maximiliani (Gymnophtalmidae) and 48 specimens of Cnemidophorus ocellifer (Teiidae). Only a single species of Pentastomida (Raillietiella mottae) was found parasitizing three females M. maximiliani, with a prevalence of 4% and an average infection intensity of 2.3 +/- 1.3 (range 1-5). The infection rate by pentastomids encountered in the present study was similar to that seen with other species of restinga lizards. Raillietiella mottae is a generalist parasite species that is probably transmitted by common and widely distributed insects making up part of the diet of many insectivorous lizard species from northeastern Brazil. PMID:19347165

  9. Invasive Microascus trigonosporus Species Complex Pulmonary Infection in a Lung Transplant Recipient.

    PubMed

    Schoeppler, Kelly E; Zamora, Martin R; Northcutt, Noelle M; Barber, Gerard R; O'Malley-Schroeder, Gayle; Lyu, Dennis M

    2015-01-01

    Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused by Microascus trigonosporus species complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient's fungal burden. Despite this apparent improvement, the patient's pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death. PMID:26075134

  10. Prevalence of latent tuberculosis infection among health care workers in a hospital for pulmonary diseases

    PubMed Central

    Schablon, Anja; Beckmann, Gudrun; Harling, Melanie; Diel, Roland; Nienhaus, Albert

    2009-01-01

    Background Little is known about the prevalence of latent tuberculosis infections (LTBI) in health care workers (HCW) in low-incidence countries especially in hospitals for pulmonary diseases. With Interferon-gamma release assays (IGRA), a new method for diagnosis of LTBI is available which is more specific than the tuberculin skin test (TST). Objectives The study was designed to estimate prevalence of LTBI among 270 HCW in a Hospital of Pulmonary Diseases routinely screened for TB. Methods LTBI was assessed by the QuantiFERON-Gold In Tube (QFT-IT). Information on gender, age, workplace, job title, BCG vaccination and history of both TB and TST were collected using a standardised questionnaire. Adjusted odds ratios for potential risk factors for LTBI were calculated. Results The prevalence of LTBI was 7.2%. In HCW younger than 30 years LTBI prevalence was 3.5% and in those older than 50 years 22%. Physicians and nurses showed a higher prevalence rate than other professions (10.8% to 4.5%). The putative risk factors for LTBI were age (>50 year OR 9.3, 95%CI 2.5–33.7), working as physicians/nurses (OR 3. 95%CI 1.2–10.4) and no previous TST in medical history (OR 4.4, 95%CI 1.01–18.9) when compared to those with a negative TST. Conclusion Prevalence of LTBI assessed by QFT-IT is low, this indicates a low infection risk even in hospitals for pulmonary diseases. No statement can be made regarding the occupational risk as compared to the general population because there are no LTBI prevalence data from Germany available. The higher LTBI prevalence rate in older HCWs might be due to the cohort effect or the longer time at risk. PMID:19134168

  11. Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr−/− Mice

    PubMed Central

    Sajjan, Uma; Thanassoulis, George; Cherapanov, Vera; Lu, Annie; Sjolin, Carola; Steer, Brent; Wu, Yi Jun; Rotstein, Ori D.; Kent, Geraldine; McKerlie, Colin; Forstner, Janet; Downey, Gregory P.

    2001-01-01

    Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia cepacia (genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs of Cftr m1unc−/− (Cftr−/−) and congenic Cftr+/+ controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptible Cftr−/− mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from the Cftr−/− mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages from Cftr−/− mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF. PMID:11447196

  12. Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia.

    PubMed

    Marion, Chad R; Wang, Jianmiao; Sharma, Lokesh; Losier, Ashley; Lui, Wei; Andrews, Nathaniel; Elias, Jack A; Kazmierczak, Barbara I; Roy, Craig R; Dela Cruz, Charles S

    2016-07-01

    Pseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1β (IL-1β) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor α2 (IL-13Rα2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-α) and IL-1β compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1β production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1β production but only partially rescues stimulated BMDMs from IL-13Rα2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses. PMID:27141083

  13. Impact of pre-transplant pulmonary infection developed in horizontal laminar flow unit on the outcome of subsequent allogeneic hematopoietic stem cell transplantation

    PubMed Central

    He, Gan-Lin; Chang, Ying-Jun; Xu, Lan-Ping; Zhang, Xiao-Hui; Wang, Yu; Liu, Kai-Yan

    2016-01-01

    Background So far, there is very little literature on how pre-transplant pulmonary infection developed in horizontal laminar flow unit (HLFU) affects outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A retrospective analysis was performed on allo-HSCT recipients who were diagnosed with pre-transplant pulmonary infection developed in HLFU between January 2012 and December 2012. Various tests were analyzed to evaluate the overall survival (OS) and pulmonary infection rate after allo-HSCT. Results Among 317 patients who received allo-HSCT from related donors, 7 cases of human leukocyte antigen (HLA)-haploidentical transplantation reported a fever, cough, and other symptoms before transplantation. Chest radiography findings showed pulmonary infection, and the C-reactive protein (CRP) level was higher than normal, which confirmed pulmonary infection (incidence rate 2.21%). The Breslow test suggested that the early survival rate was lower in the group with pre-transplant pulmonary infection than in the group without pre-transplant pulmonary infection (OS: 28.4 vs. 42.4 months; P=0.023); the early survival rate was lower in patients with a pulmonary infection accompanied by bilateral pleural effusion than in patients without pleural effusion (OS: 1.5 vs. 36.3 months; P=0.010). In the first month after transplantation, the difference in the CD4CD45RO+CD45RA- and CD4CD45RO-CD45RA+ between the groups with and without pre-transplant pulmonary infection was statistically significant (P<0.05). Patients with pre-transplant pulmonary infection who survived >3 years had a higher rate of pulmonary infection in the first 2 months after allo-HSCT than those without pre-transplant pulmonary infection [100% (5/5 patients) vs. 38.1% (118/310); χ2=5.542, P=0.019]. Conclusions Development of pre-transplant pulmonary infection in the HLFU in patients with hematological malignancies who receive HLA-haploidentical HSCT is associated with an increased risk

  14. [Microbiological results of bronchoalveolar lavage that was performed for opportunistic pulmonary infections].

    PubMed

    Gülcü, Aylin; Sevinç, Can; Esen, Nuran; Kilinç, Oğuz; Uçan, Eyüp Sabri; Itil, Oya; Cimrin, Arif Hikmet; Kömüs, Nuray; Sener, Gülper; Akkoçlu, Atila; Gülay, Zeynep; Yücesoy, Mine

    2006-01-01

    Between 2001-2002; in 62 cases, 33 (53%) male, 29 (47%) female, mean age 51.4 +/- 18.1 years) bronchoalveolar lavage (BAL) was performed for diagnosis of opportunistic pulmonary infection and specimens were evaluated for results of microbiological examinations. There was hematological malignancy in 18 (29%) and solid organ malignancy in 13 (21%) cases. Thirty-one (50%) cases were immunocompromised for reasons other than malignancy. By endoscopic evaluation endobronchial lesion was seen in 2 (3%) cases, indirect tumor signs were seen in 2 (3%) cases and signs of infection were seen in 11 (18%) cases. Forty-even (76%) cases were endoscopically normal. Acid-fast bacilli (AFB) direct examination was positive in 3 (5%) cases. In 4 (6%) cases mycobacterial culture was positive, Mycobacterium tuberculosis-polymerase chain reaction (PCR) was also positive in these four cases. Examination of gram-stained smears for bacteria was associated with infection in 14 (23%) cases. Bacteriologic cultures were positive for single potential pathogen in 10 (16%) cases, and for mixed pathogens in 7 (11%) cases for a total number of 17 (27%). Fungal cultures were positive in 3 (5%) cases all of which had hematological malignancy. As a result in 24 (39%) cases microbiological agent of infection is determined: in four mycobacteria, in 17 bacteria other than mycobacteria and in three fungi. PMID:17001542

  15. Detection of blaSPM-1, blaKPC, blaTEM and blaCTX-M genes in isolates of Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella spp. from cancer patients with healthcare-associated infections.

    PubMed

    Jácome, Paula Regina Luna de Araújo; Alves, Lílian Rodrigues; Jácome-Júnior, Agenor Tavares; Silva, Maria Jesuíta Bezerra da; Lima, Jailton Lobo da Costa; Araújo, Paulo Sérgio Ramos; Lopes, Ana Catarina S; Maciel, Maria Amélia Vieira

    2016-07-01

    Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella spp. are three of the pathogens most frequently involved in infections of cancer patients, and the production of β -lactamases is a major mechanism of resistance due to its wide diversity of existing enzymes. Therefore, the aim of the present study was to investigate the microbiological profile and data related to patients and infections, and to search for β -lactamase genes in bacterial isolates from hospitalized cancer patients in a hospital in Recife, Pernambuco, Brazil. A total of 169 isolates were recovered between 2012 and 2014, of which 58 were P. aeruginosa, 36 were Acinetobacter spp. and 75 were Klebsiella spp. A high percentage of carbapenem resistance was observed in P. aeruginosa and Acinetobacter spp. Among the carbapenem-resistant bacteria, the blaSPM-1 gene was detected in P. aeruginosa (35.5 %) and Acinetobacter spp. (3.8 %), while blaKPC was detected in P. aeruginosa (25.8 %) only. Among the third- and fourth-generation cephalosporin-resistant strains, in Klebsiella spp. we detected the genes blaTEM (30.6 %), blaCTX-M (58.3 %) and blaKPC (5.6 %), and in Acinetobacter spp. only blaTEM (25.9 %). This the first report of an Acinetobacter baumannii blaSPM-1 gene carrier that has been isolated in Brazil. The most frequent cancer types were bowel tumour [14.8 %; 95 % confidence interval (CI95 %) 9.8-21.1 %], breast cancer (13.6 %; CI95 % 8.8-19.7 %) and prostate cancer (11.2%; CI95 % 6.9-17.0 %). These results therefore provide knowledge of susceptibility profile and resistance mechanisms and thus can contribute to the strategic formulation of hospital infection control plans and the rational use of antimicrobials, reducing mortality from infection levels in cancer patients. PMID:27217349

  16. Pulmonary tuberculosis in severely-malnourished or HIV-infected children with pneumonia: a review.

    PubMed

    Chisti, Mohammod Jobayer; Ahmed, Tahmeed; Pietroni, Mark A C; Faruque, Abu S G; Ashraf, Hasan; Bardhan, Pradip K; Hossain, Iqbal; Das, Sumon Kumar; Salam, Mohammed Abdus

    2013-09-01

    Presentation of pulmonary tuberculosis (PTB) as acute pneumonia in severely-malnourished and HIV-positive children has received very little attention, although this is very important in the management of pneumonia in children living in communities where TB is highly endemic. Our aim was to identify confirmed TB in children with acute pneumonia and HIV infection and/or severe acute malnutrition (SAM) (weight-for-length/height or weight-for-age z score <-3 of the WHO median, or presence of nutritional oedema). We conducted a literature search, using PubMed and Web of Science in April 2013 for the period from January 1974 through April 2013. We included only those studies that reported confirmed TB identified by acid fast bacilli (AFB) through smear microscopy, or by culture-positive specimens from children with acute pneumonia and SAM and/or HIV infection. The specimens were collected either from induced sputum (IS), or gastric lavage (GL), or broncho-alveolar lavage (BAL), or percutaneous lung aspirates (LA). Pneumonia was defined as the radiological evidence of lobar or patchy consolidation and/or clinical evidence of severe/ very severe pneumonia according to the WHO criteria of acute respiratory infection. A total of 17 studies met our search criteria but 6 were relevant for our review. Eleven studies were excluded as those did not assess the HIV status of the children or specify the nutritional status of the children with acute pneumonia and TB. We identified only 747 under-five children from the six relevant studies that determined a tubercular aetiology of acute pneumonia in children with SAM and/or positive HIV status. Three studies were reported from South Africa and one each from the Gambia, Ethiopia, and Thailand where 610, 90, 35, and 12 children were enrolled and 64 (10%), 23 (26%), 5 (14%), and 1 (8%) children were identified with active TB respectively, with a total of 93 (12%) children with active TB. Among 610 HIV-infected children in three studies

  17. Enterovirus 71 Infection Causes Severe Pulmonary Lesions in Gerbils, Meriones unguiculatus, Which Can Be Prevented by Passive Immunization with Specific Antisera

    PubMed Central

    Xia, Yong; Qian, Lei; Yang, Zhang-Nv; Xie, Rong-Hui; Sun, Yi-Sheng; Lu, Hang-Jing; Miao, Zi-Ping; Li, Chan; Li, Xiao; Liang, Wei-Feng; Huang, Xiao-Xiao; Xia, Shi-Chang; Chen, Zhi-Ping; Jiang, Jian-Min; Zhang, Yan-Jun; Mei, Ling-Ling; Liu, She-Lan; Gu, Hua; Xu, Zhi-Yao; Fu, Xiao-Fei; Zhu, Zhi-Yong; Zhu, Han-Ping

    2015-01-01

    Neurogenic pulmonary edema caused by severe brainstem encephalitis is the leading cause of death in young children infected by Enterovirus 71 (EV71). However, no pulmonary lesions have been found in EV71-infected transgenic or non-transgenic mouse models. Development of a suitable animal model is important for studying EV71 pathogenesis and assessing effect of therapeutic approaches. We had found neurological disorders in EV71-induced young gerbils previously. Here, we report severe pulmonary lesions characterized with pulmonary congestion and hemorrhage in a gerbil model for EV71 infection. In the EV71-infected gerbils, six 21-day-old or younger gerbils presented with a sudden onset of symptoms and rapid illness progression after inoculation with 1×105.5 TCID50 of EV71 via intraperitoneal (IP) or intramuscular (IM) route. Respiratory symptoms were observed along with interstitial pneumonia, pulmonary congestion and extensive lung hemorrhage could be detected in the lung tissues by histopathological examination. EV71 viral titer was found to be peak at late stages of infection. EV71-induced pulmonary lesions, together with severe neurological disorders were also observed in gerbils, accurately mimicking the disease process in EV71-infected patients. Passive transfer with immune sera from EV71 infected adult gerbils with a neutralizing antibody (GMT=89) prevented severe pulmonary lesion formation after lethal EV71 challenge. These results establish this gerbil model as a useful platform for studying the pathogenesis of EV71-induced pulmonary lesions, immunotherapy and antiviral drugs. PMID:25767882

  18. Pulmonary ultrasonographic abnormalities associated with naturally occurring equine influenza virus infection in standardbred racehorses.

    PubMed

    Gross, Diane K; Morley, Paul S; Hinchcliff, Kenneth W; Reichle, Jean K; Slemons, Richard D

    2004-01-01

    The purpose of this investigation was to determine if naturally occurring acute infectious upper respiratory disease (IRD) caused by equine influenza virus is associated with ultrasonographically detectable pleural and pulmonary abnormalities in horses. Standardbred racehorses were evaluated for signs of IRD, defined as acute coughing or mucopurulent nasal discharge. For every horse with IRD (n = 16), 1 or 2 horses with no signs of IRD and the same owner or trainer (n = 30) were included. Thoracic ultrasonography was performed within 5-10 days of the onset of clinical disease in horses with IRD. Horses without IRD were examined at the same time as the horses with IRD with which they were enrolled. The rank of the ultrasound scores of horses with IRD was compared to that of horses without IRD. Equine influenza virus was identified as the primary etiologic agent associated with IRD in this study. Mild lung consolidation and peripheral pulmonary irregularities were found in 11 (69%) of 16 of the horses with IRD and 11 (37%) of 30 of control horses. Lung consolidation (median score = 1) and peripheral irregularities scores (median score = 1) were greater in horses with IRD compared to horses without IRD (median score = 0; P < .05). Pleural effusion was not observed. Equine influenza virus infection can result in abnormalities of the equine lower respiratory tract. Despite the mild nature of IRD observed in this study, lung consolidation and peripheral pulmonary irregularities were more commonly observed in horses with clinical signs of IRD. Further work is needed to determine the clinical significance of these ultrasonographic abnormalities. PMID:15515590

  19. Liposomal antibiotic formulations for targeting the lungs in the treatment of Pseudomonas aeruginosa.

    PubMed

    Alipour, Misagh; Suntres, Zacharias E

    2014-04-01

    Pseudomonas aeruginosa is a Gram-negative bacterium that causes serious lung infections in cystic fibrosis, non-cystic fibrosis bronchiectasis, immunocompromised, and mechanically ventilated patients. The arsenal of conventional antipseudomonal antibiotic drugs include the extended-spectrum penicillins, cephalosporins, carbapenems, monobactams, polymyxins, fluoroquinolones, and aminoglycosides but their toxicity and/or increasing antibiotic resistance are of particular concern. Improvement of existing therapies against Pseudomonas aeruginosa infections involves the use of liposomes - artificial phospholipid vesicles that are biocompatible, biodegradable, and nontoxic and able to entrap and carry hydrophilic, hydrophobic, and amphiphilic molecules to the site of action. The goal of developing liposomal antibiotic formulations is to improve their therapeutic efficacy by reducing drug toxicity and/or by enhancing the delivery and retention of antibiotics at the site of infection. The focus of this review is to appraise the current progress of the development and application of liposomal antibiotic delivery systems for the treatment pulmonary infections caused by P. aeruginosa. PMID:24856168

  20. Wheeze in Preschool Age Is Associated with Pulmonary Bacterial Infection and Resolves after Antibiotic Therapy

    PubMed Central

    2011-01-01

    Background Neonates with airways colonized by Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis are at increased risk for recurrent wheeze which may resemble asthma early in life. It is not clear whether chronic colonization by these pathogens is causative for severe persistent wheeze in some preschool children and whether these children might benefit from antibiotic treatment. We assessed the relevance of bacterial colonization and chronic airway infection in preschool children with severe persistent wheezing and evaluated the outcome of long-time antibiotic treatment on the clinical course in such children. Methodology/Principal Findings Preschool children (n = 42) with severe persistent wheeze but no symptoms of acute pulmonary infection were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Differential cell counts and microbiological and virological analyses were performed on BAL samples. Patients diagnosed with bacterial infection were treated with antibiotics for 2–16 weeks (n = 29). A modified ISAAC questionnaire was used for follow-up assessment of children at least 6 months after bronchoscopy. Of the 42 children with severe wheezing, 34 (81%) showed a neutrophilic inflammation and 20 (59%) of this subgroup had elevated bacterial counts (≥104 colony forming units per milliliter) suggesting infection. Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis were the most frequently isolated species. After treatment with appropriate antibiotics 92% of patients showed a marked improvement of symptoms upon follow-up examination. Conclusions/Significance Chronic bacterial infections are relevant in a subgroup of preschool children with persistent wheezing and such children benefit significantly from antibiotic therapy. PMID:22140482

  1. Case Report Serious pulmonary infection in a splenectomized patient with adult type 1 Gaucher disease.

    PubMed

    Zhang, Y; Mao, Y F; Du, J M

    2015-01-01

    A 49-year-old man with a history of Gaucher disease type 1, resulting in serious splenomegaly and eating disorder, was referred to our department and underwent a splenectomy under general anesthesia. Gaucher disease is very rare, and its first signs are unexplained splenomegaly and hypersplenism. On preoperative examination, the patient's platelet count was slightly low, and his other test results were normal. Surprisingly, on the first postoperative day, the patient developed a lung infection. This gradually progressed to acute respiratory distress syndrome with respiratory failure, requiring intubation and mechanical ventilation. The patient eventually recovered, and he was discharged after receiving antibiotics and other treatments to enhance immunity. However, his postoperative lung infection led to a significantly prolonged and expensive hospital stay. This case suggests that we must pay close attention to the immune dysfunction of patients with Gaucher disease type 1. Anesthesia and surgery with accompanying post-traumatic stress can weaken patients' immunity and cause susceptibility to severe lung infections. Pulmonary signs and functions should be monitored closely during the perioperative period, and, if necessary, gamma globulin and thymosin should be administered early in the preoperative or postoperative period to enhance immunity. PMID:25966100

  2. IL-22 Defect During Streptococcus pneumoniae Infection Triggers Exacerbation of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Pichavant, Muriel; Sharan, Riti; Le Rouzic, Olivier; Olivier, Cécile; Hennegrave, Florence; Rémy, Gaëlle; Pérez-Cruz, Magdiel; Koné, Bachirou; Gosset, Pierre; Just, Nicolas; Gosset, Philippe

    2015-01-01

    Progression of chronic obstructive pulmonary disease (COPD) is linked to episodes of exacerbations caused by bacterial infections due to Streptococcus pneumoniae. Our objective was to identify during COPD, factors of susceptibility to bacterial infections among cytokine network and their role in COPD exacerbations. S. pneumoniae was used to sub-lethally challenge mice chronically exposed to air or cigarette smoke (CS) and to stimulate peripheral blood mononuclear cells (PBMC) from non-smokers, smokers and COPD patients. The immune response and the cytokine production were evaluated. Delayed clearance of the bacteria and stronger lung inflammation observed in infected CS-exposed mice were associated with an altered production of IL-17 and IL-22 by innate immune cells. This defect was related to a reduced production of IL-1β and IL-23 by antigen presenting cells. Importantly, supplementation with recombinant IL-22 restored bacterial clearance in CS-exposed mice and limited lung alteration. In contrast with non-smokers, blood NK and NKT cells from COPD patients failed to increase IL-17 and IL-22 levels in response to S. pneumoniae, in association with a defect in IL-1β and IL-23 secretion. This study identified IL-17 and IL-22 as susceptibility factors in COPD exacerbation. Therefore targeting such cytokines could represent a potent strategy to control COPD exacerbation. PMID:26870795

  3. Pulmonary surfactant as vehicle for intratracheally instilled tobramycin in mice infected with Klebsiella pneumoniae.

    PubMed Central

    van't Veen, A.; Mouton, J. W.; Gommers, D.; Lachmann, B.

    1996-01-01

    1. The use of pulmonary surfactant has been proposed as a vehicle for antibiotic delivery to the alveolar compartment of the lung. This study investigated survival rates of mice with a respiratory Klebsiella pneumoniae infection treated intratracheally with tobramycin using a natural exogenous surfactant preparation as vehicle. 2. At day 1 after infection, animals were injected intratracheally with 20 microliters of the following solutions: (1) a mixture of surfactant (500 micrograms) and tobramycin (250 micrograms); (2) tobramycin (250 micrograms) alone; (3) surfactant (500 micrograms) alone; and (4) NaHCO3 buffer (control, sham-treatment). A fifth group received no treatment (control). Deaths were registered every 12 h for 8 consecutive days. 3. The results show an increased survival in the group receiving the surfactant-tobramycin mixture compared to the group receiving tobramycin alone (P < 0.05), the group receiving surfactant alone (P < 0.01) and the control groups (P < 0.01). It is concluded that intratracheal instillation of surfactant-tobramycin is superior to tobramycin alone in protecting animals from death due to a respiratory Klebsiella pneumoniae infection. PMID:8937717

  4. Bacterial Infection in Chronic Obstructive Pulmonary Disease in 2000: a State-of-the-Art Review

    PubMed Central

    Sethi, Sanjay; Murphy, Timothy F.

    2001-01-01

    Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. The precise role of bacterial infection in the course and pathogenesis of COPD has been a source of controversy for decades. Chronic bacterial colonization of the lower airways contributes to airway inflammation; more research is needed to test the hypothesis that this bacterial colonization accelerates the progressive decline in lung function seen in COPD (the vicious circle hypothesis). The course of COPD is characterized by intermittent exacerbations of the disease. Studies of samples obtained by bronchoscopy with the protected specimen brush, analysis of the human immune response with appropriate immunoassays, and antibiotic trials reveal that approximately half of exacerbations are caused by bacteria. Nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the most common causes of exacerbations, while Chlamydia pneumoniae causes a small proportion. The role of Haemophilus parainfluenzae and gram-negative bacilli remains to be established. Recent progress in studies of the molecular mechanisms of pathogenesis of infection in the human respiratory tract and in vaccine development guided by such studies promises to lead to novel ways to treat and prevent bacterial infections in COPD. PMID:11292642

  5. RX-P873, a Novel Protein Synthesis Inhibitor, Accumulates in Human THP-1 Monocytes and Is Active against Intracellular Infections by Gram-Positive (Staphylococcus aureus) and Gram-Negative (Pseudomonas aeruginosa) Bacteria

    PubMed Central

    Buyck, Julien M.; Peyrusson, Frédéric; Tulkens, Paul M.

    2015-01-01

    The pyrrolocytosine RX-P873, a new broad-spectrum antibiotic in preclinical development, inhibits protein synthesis at the translation step. The aims of this work were to study RX-P873's ability to accumulate in eukaryotic cells, together with its activity against extracellular and intracellular forms of infection by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies (Emax values) and bacteriostatic concentrations (Cs values) on the basis of Hill equations of the concentration-response curves. RX-P873's apparent concentration in human THP-1 monocytes was about 6-fold higher than the extracellular one. In broth, MICs ranged from 0.125 to 0.5 mg/liter (S. aureus) and 2 to 8 mg/liter (P. aeruginosa), with no significant shift in these values against strains resistant to currently used antibiotics being noted. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as the decrease in the number of CFU from that in the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log units and 5 log units in broth, respectively, and 0.7 log unit and 2.7 log units in infected THP-1 cells, respectively, after 24 h. Cs values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, and daptomycin for S. aureus; ciprofloxacin and ceftazidime for P. aeruginosa). Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus. Taken together, these data suggest that RX-P873 may constitute a useful alternative for infections involving intracellular bacteria, especially Gram-negative species. PMID:26014952

  6. Massive pulmonary hemorrhage in enterovirus 71-infected hand, foot, and mouth disease

    PubMed Central

    Lee, Dong Seong; Lee, Young Il; Ahn, Jeong Bae; Kim, Mi Jin; Kim, Jae Hyun; Kim, Nam Hee; Hwang, Jong Hee; Kim, Dong Wook; Lee, Chong Guk

    2015-01-01

    Hand, foot, and mouth disease (HFMD) is an acute, mostly self-limiting infection. Patients usually recover without any sequelae. However, a few cases are life threatening, especially those caused by enterovirus 71 (EV71). A 12-month-old boy was admitted to a primary hospital with high fever and vesicular lesions of the mouth, hands, and feet. After 3 days, he experienced 3 seizure episodes and was referred to our hospital. On admission, he was conscious and his chest radiograph was normal. However, 6 hours later, he suddenly lost consciousness and had developed a massive pulmonary hemorrhage that continued until his death. He experienced several more intermittent seizures, and diffuse infiltration of both lung fields was observed on chest radiography. Intravenous immunoglobulin, dexamethasone, cefotaxime, leukocyte-depleted red blood cells, fresh frozen plasma, inotropics, vitamin K, and endotracheal epinephrine were administered. The patient died 9 hours after intubation, within 3 days from fever onset. EV71 subgenotype C4a was isolated retrospectively from serum and nasopharyngeal swab by real-time reverse transcription-polymerase chain reaction. Here, we report a fatal case of EV71-associated HFMD with sudden-onset massive pulmonary hemorrhage and suspected encephalitis. PMID:25861335

  7. Tuberculosis and pulmonary candidiasis co-infection present in a previously healthy patient

    PubMed Central

    Jiménez Borré, Gustavo; Gómez Camargo, Doris; Chalavé Jiménez, Neylor; Bellido Rodríguez, Javier; Cuadrado Cano, Bernarda; Navarro Gómez, Shirley

    2016-01-01

    Background: The coexistance among fungal pathogens and tuberculosis pulmonary is a clinical condition that generally occurs in immunosuppressive patients, however, immunocompetent patients may have this condition less frequently. Objective: We report the case of an immunocompetent patient diagnosed with coinfection Mycobacterium tuberculosis and Candida albicans. Case Description: A female patient, who is a 22-years old, with fever and a new onset of hemoptysis. Clinical findings and diagnosis: Diminished vesicular breath sounds in the apical region and basal crackling rales in the left lung base were found in the physical examination. Microbiological tests include: chest radiography and CAT scan pictograms in high resolution, Ziehl-Neelsen stain, growth medium for fungus and mycobacteria through Sabouraudís agar method with D-glucose. Medical examinations showed Candida albicans fungus and Mycobacterium tuberculosis present in the patient. Treatment and Outcome: Patient was treated with anti-tuberculosis and anti-fungal medications, which produced good responses. Clinical relevance: Pulmonary tuberculosis and fungal co-infection are not common in immunocompetent patients. However, we can suspect that there is a presence of these diseases by detecting new onset of hemoptysis in patients. PMID:27546933

  8. Massive pulmonary hemorrhage in enterovirus 71-infected hand, foot, and mouth disease.

    PubMed

    Lee, Dong Seong; Lee, Young Il; Ahn, Jeong Bae; Kim, Mi Jin; Kim, Jae Hyun; Kim, Nam Hee; Hwang, Jong Hee; Kim, Dong Wook; Lee, Chong Guk; Song, Tae Won

    2015-03-01

    Hand, foot, and mouth disease (HFMD) is an acute, mostly self-limiting infection. Patients usually recover without any sequelae. However, a few cases are life threatening, especially those caused by enterovirus 71 (EV71). A 12-month-old boy was admitted to a primary hospital with high fever and vesicular lesions of the mouth, hands, and feet. After 3 days, he experienced 3 seizure episodes and was referred to our hospital. On admission, he was conscious and his chest radiograph was normal. However, 6 hours later, he suddenly lost consciousness and had developed a massive pulmonary hemorrhage that continued until his death. He experienced several more intermittent seizures, and diffuse infiltration of both lung fields was observed on chest radiography. Intravenous immunoglobulin, dexamethasone, cefotaxime, leukocyte-depleted red blood cells, fresh frozen plasma, inotropics, vitamin K, and endotracheal epinephrine were administered. The patient died 9 hours after intubation, within 3 days from fever onset. EV71 subgenotype C4a was isolated retrospectively from serum and nasopharyngeal swab by real-time reverse transcription-polymerase chain reaction. Here, we report a fatal case of EV71-associated HFMD with sudden-onset massive pulmonary hemorrhage and suspected encephalitis. PMID:25861335

  9. Diagnosis and prevalence of ovine pulmonary adenocarcinoma in lung tissues of naturally infected farm sheep

    PubMed Central

    Sonawane, Ganesh G.; Tripathi, Bhupendra Nath; Kumar, Rajiv; Kumar, Jyoti

    2016-01-01

    Aim: This study was aimed to detect ovine pulmonary adenocarcinoma (OPA) in sheep flocks affected with pulmonary disorders at organized farm. Materials and Methods: A total of 75 sheep died naturally were thoroughly examined for the lesions of OPA during necropsy. Tissue sections from affected portion of the lungs from each animal were collected aseptically and divided into two parts; one each for polymerase chain reaction (PCR) and another for histopathology. Results: On PCR examination of lung tissues, six sheep (8%) were found to be positive for JSRV. Two of them were 3-6 months of age and did not show clinical signs/gross lesions of OPA. Four adult sheep positive on PCR revealed characteristic lesions of OPA on gross and histopathological examination. Conclusion: In the absence of known specific antibody response to the infection with JSRV, there is no diagnostic serological test available. The PCR assay employed in this study on lung tissues, using primers based on the U3 region of the viral long terminal repeat for JSRV would be helpful in the screening of preclinical and clinical cases of OPA in sheep. PMID:27182131

  10. Pulmonary migratory infiltrates due to mycoplasma infection: case report and review of the literature

    PubMed Central

    You, Wenjie; Chen, Bi; Li, Jing; Shou, Juan; Xue, Shan; Liu, Xueqing

    2016-01-01

    Pulmonary migratory infiltrates (PMI) are observed in a few diseases. We report here a case of PMI attributed to Mycoplasma pneumonia (Mp) infection. The patient’s past medical history was characterized by fleeting and/or relapses of patchy opacification or infiltrates of parenchyma throughout the whole lung field except for left lower lobe radiographically. Serological assays revealed an elevation of IgG antibody specific to Mp and its fourfold increase in convalescent serum. Histopathological findings showed polypoid plugs of fibroblastic tissue filling and obliterating small air ways and interstitial infiltrates of mononuclear inflammatory cells in the vicinal alveolar septa. The patient was treated with azithromycin which resulted in a dramatic improvement clinically and imageologically. In spite of the increasing incidence of Mp, the possible unusual imaging manifestation and underlying mechanism haven’t attracted enough attention. To our knowledge, there are rare reports of such cases. PMID:27293865

  11. Pulmonary migratory infiltrates due to mycoplasma infection: case report and review of the literature.

    PubMed

    You, Wenjie; Chen, Bi; Li, Jing; Shou, Juan; Xue, Shan; Liu, Xueqing; Jiang, Handong

    2016-06-01

    Pulmonary migratory infiltrates (PMI) are observed in a few diseases. We report here a case of PMI attributed to Mycoplasma pneumonia (Mp) infection. The patient's past medical history was characterized by fleeting and/or relapses of patchy opacification or infiltrates of parenchyma throughout the whole lung field except for left lower lobe radiographically. Serological assays revealed an elevation of IgG antibody specific to Mp and its fourfold increase in convalescent serum. Histopathological findings showed polypoid plugs of fibroblastic tissue filling and obliterating small air ways and interstitial infiltrates of mononuclear inflammatory cells in the vicinal alveolar septa. The patient was treated with azithromycin which resulted in a dramatic improvement clinically and imageologically. In spite of the increasing incidence of Mp, the possible unusual imaging manifestation and underlying mechanism haven't attracted enough attention. To our knowledge, there are rare reports of such cases. PMID:27293865

  12. Links between Anr and Quorum Sensing in Pseudomonas aeruginosa Biofilms

    PubMed Central

    Hammond, John H.; Dolben, Emily F.; Smith, T. Jarrod; Bhuju, Sabin

    2015-01-01

    ABSTRACT In Pseudomonas aeruginosa, the transcription factor Anr controls the cellular response to low oxygen or anoxia. Anr activity is high in oxygen-limited environments, including biofilms and populations associated with chronic infections, and Anr is necessary for persistence in a model of pulmonary infection. In this study, we characterized the Anr regulon in biofilm-grown cells at 1% oxygen in the laboratory strain PAO1 and in a quorum sensing (QS)-deficient clinical isolate, J215. As expected, transcripts related to denitrification, arginine fermentation, high-affinity cytochrome oxidases, and CupA fimbriae were lower in the Δanr derivatives. In addition, we observed that transcripts associated with quorum sensing regulation, iron acquisition and storage, type VI secretion, and the catabolism of aromatic compounds were also differentially expressed in the Δanr strains. Prior reports have shown that quorum sensing-defective mutants have higher levels of denitrification, and we found that multiple Anr-regulated processes, including denitrification, were strongly inversely proportional to quorum sensing in both transcriptional and protein-based assays. We also found that in LasR-defective strains but not their LasR-intact counterparts, Anr regulated the production of the 4-hydroxy-2-alkylquinolines, which play roles in quorum sensing and interspecies interactions. These data show that Anr was required for the expression of important metabolic pathways in low-oxygen biofilms, and they reveal an expanded and compensatory role for Anr in the regulation of virulence-related genes in quorum sensing mutants, such as those commonly isolated from infections. IMPORTANCE Pseudomonas aeruginosa causes acute ocular, soft tissue, and pulmonary infections, as well as chronic infections in the airways of cystic fibrosis patients. P. aeruginosa uses quorum sensing (QS) to regulate virulence, but mutations in the gene encoding the master regulator of QS, lasR, are frequently

  13. IgA and/or IgG subclass deficiency in children with recurrent respiratory infections and its relationship with chronic pulmonary damage.

    PubMed

    Ozkan, H; Atlihan, F; Genel, F; Targan, S; Gunvar, T

    2005-01-01

    Most patients with IgA and/or IgG subclass deficiency are asymptomatic but some may suffer from frequent mainly respiratory infections. The aim of our study was to determine the frequency of IgA and/or IgG subclass deficiencies and the rate of chronic pulmonary damage secondary to recurrent pulmonary infections in these children. Serum IgA and IgG subclass levels were measured in 225 children aged 6 months to 6 years with recurrent sinopulmonary infections (44 with recurrent upper respiratory tract infections, 100 with recurrent pulmonary infections and 81 with recurrent bronchiolitis). In order to determine chronic pulmonary damage due to recurrent infections in patients with recurrent pulmonary infections CT scans of thorax were also obtained. The overall frequency of antibody defects was found to be 19.1%. IgA deficiency was observed in 9.3%, IgG subclass deficiency in 8.4% and IgA + IgG subclass deficiency in 1.4%. The prevalance of IgA and/or IgG subclass deficiency was 25% in patients with recurrent upper respiratory tract infections, 22% in patients with recurrent pulmonary infections and 12.3% in patients with recurrent bronchiolitis (p>0.05). Chronic pulmonary damage in lungs was determined radiologically in 17 of 100 cases with recurrent pulmonary infection. In IgG subclass deficiencies sequel changes, although not statistically significant, were observed five times more frequently than that of IgA deficiencies. CT scans revealed pulmonary sequels in 5 of the 22 (22.7%) patients with recurrent pulmonary infections and immunodeficiency (bronchiectasis in 2 patients with IgG3 deficiency, fibrotic changes in one with IgA deficiency and in one with IgG3 deficiency, bronchiolitis obliterans in one with IgG2 + IgG3 deficiency). On the other hand, pulmonary sequels were observed in 12 patients (15.4%) with normal immunoglobulin levels. Eight of them were bronchiolitis obliterans, 2 of them were atelectasia and 1 of them was bronchiectasia. We therefore suggest

  14. D-enantiomeric peptides that eradicate wild-type and multi-drug resistant biofilms and protect against lethal Pseudomonas aeruginosa infections

    PubMed Central

    de la Fuente-Núñez, César; Reffuveille, Fany; Mansour, Sarah C.; Reckseidler-Zenteno, Shauna L.; Hernández, Diego; Brackman, Gilles; Coenye, Tom; Hancock, Robert E.W.

    2015-01-01

    SUMMARY In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active anti-biofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating pre-formed biofilms of seven species of wild-type and multiply antibiotic resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal P. aeruginosa infections, and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease resistant peptides produced here were more effective both in vitro and in vivo. PMID:25699603

  15. Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells

    PubMed Central

    Kwok, Hoi-Hin; Poon, Po-Ying; Fok, Siu-Ping; Ying-Kit Yue, Patrick; Mak, Nai-Ki; Chan, Michael Chi-Wai; Peiris, Joseph Sriyal Malik; Wong, Ricky Ngok-Shun

    2016-01-01

    Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3′-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3′-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-β and IFN-γ1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection. PMID:26732368

  16. IL-10 Restrains IL-17 to Limit Lung Pathology Characteristics following Pulmonary Infection with Francisella tularensis Live Vaccine Strain

    PubMed Central

    Slight, Samantha R.; Monin, Leticia; Gopal, Radha; Avery, Lyndsay; Davis, Marci; Cleveland, Hillary; Oury, Tim D.; Rangel-Moreno, Javier; Khader, Shabaana A.

    2014-01-01

    IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10–deficient mice (Il10−/−), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10−/−-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain. PMID:24007881

  17. Oral colonization and susceptibility testing of Pseudomonas aeruginosa oral isolates from cystic fibrosis patients.

    PubMed

    Lindemann, R A; Newman, M G; Kaufman, A K; Le, T V

    1985-01-01

    Microbial samples from the oral cavities of cystic fibrosis (C.F.) patients and 20 age-matched normal control subjects were characterized. Mucoid variant Pseudomonas aeruginosa was isolated from the tongue, buccal mucosa, and saliva of C.F. patients only. Analysis of the data suggests that the oral cavity is a potential reservoir for this organism. Aspiration and cross-contamination from this reservoir may be important in perpetuating chronic pulmonary infection in C.F. patients. Susceptibility testing was performed on 20 mucoid variant P. aeruginosa oral isolates obtained from the patients according to standardized broth dilution procedures. The in vitro antimicrobial effects of sodium fluoride, stannous fluoride, and chlorhexidine were measured. Analysis of the data suggests that clinically safe and achievable levels of chlorhexidine and stannous fluoride may be antimicrobial. PMID:3918088

  18. Flow Cytometric Analysis of Protective T-Cell Response Against Pulmonary Coccidioides Infection.

    PubMed

    Hung, Chiung-Yu; Wozniak, Karen L; Cole, Garry T

    2016-01-01

    The incidence of systemic fungal infections has increased throughout the world, spurring much interest in developing effective vaccines. Coccidioidomycosis, also known as San Joaquin Valley fever, is a potentially life-threatening respiratory mycosis. A vaccine against Coccidioides infection would contribute significantly to the well-being of the approx. 30 million residents in the Southwestern USA as well as the multitude of travelers who annually visit the endemic regions. We have applied a live, attenuated vaccine (∆T) to explore the nature of vaccine immunity in mice after intranasal challenge with a potentially lethal dose of Coccidioides spores. Coccidioides spores are airborne and highly infectious for mammalian hosts and classified as a biosafety level 3 agent. T cells are critical in the development of protective immunity against a variety of microorganisms as well as the development of autoimmune disease and allergic responses. Profiles of cytokines detected in lung homogenates of ∆T-vaccinated mice were indicative of a mixed Th1, Th2, and Th17 immune response. We have developed an intracellular cytokine staining and flow cytometric (ICS) technique to measure activated CD4(+) and CD8(+) T cells and IFN-γ-, IL-4-, IL-5-, and IL-17A-producing T cells in the lungs of mice that are challenged with a potentially lethal dose of Coccidioides spores. The numbers of pulmonary Th1 and Th17 cells during the first 2 weeks post-challenge showed a progressive increase in vaccinated mice and corresponded with reduction of fungal burden. In this protocol, we describe the methodology for culture and isolation of the live, attenuated ΔT spores of Coccidioides used to vaccinate mice, preparation of pulmonary cells, and staining protocol for cell surface markers and intracellular cytokines. This is the most reliable and robust procedure to measure frequencies and numbers of each selected T-cell subsets in lungs of vaccinated versus control mice and can be readily

  19. Oral administration of specific yolk antibodies (IgY) may prevent Pseudomonas aeruginosa infections in patients with cystic fibrosis: a phase I feasibility study.

    PubMed

    Kollberg, Hans; Carlander, David; Olesen, Hanne; Wejåker, Per-Erik; Johannesson, Marie; Larsson, Anders

    2003-06-01

    Respiratory infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Chronic Pseudomonas aeruginosa (PA) infections ultimately occur in virtually all patients. It is impossible to eradicate PA when a patient has been chronically colonized. Immunotherapy with specific egg-yolk antibodies (IgY) may be an alternative to antibiotics for the prevention of PA infections. We wanted to determine if treatment with specific IgY can prolong the period between the first and the second PA colonization? And long-term, can the treatment diminish the number of positive PA cultures and postpone the onset of chronic colonization? CF patients gargled daily with an IgY-antibody preparation, purified from eggs of hens immunized with PA bacteria. They were compared to a group of patients who did not gargle with the preparation. Both groups had their first colonization with PA eradicated by antibiotics. The basic treatment was essentially the same in both groups. In the initial study, the period between the first and second colonization with PA was significantly prolonged for the treated vs. the control group (Kaplan-Meier P = 0.015, Breslow test). In the prolonged study, the treated group had only 2.5 sputum cultures positive for PA per 100 months of observation, and none of these patients became chronically colonized with PA. No adverse events were reported. In the control group, 13.7 cultures per 100 months of observation were positive for PA, and 5 (24%) patients became chronically colonized with PA. This feasibility study shows that antipseudomonal IgY has the potential to effectively prevent PA colonization without any severe adverse effects. A phase III study should be initiated. PMID:12746939

  20. Novel Inhaled Combination Powder Containing Amorphous Colistin and Crystalline Rifapentine with Enhanced Antimicrobial Activities against Planktonic Cells and Biofilm of Pseudomonas aeruginosa for Respiratory Infections.

    PubMed

    Zhou, Qi Tony; Sun, Si-Ping; Chan, John Gar Yan; Wang, Ping; Barraud, Nicolas; Rice, Scott A; Wang, Jiping; Li, Jian; Chan, Hak-Kim

    2015-08-01

    Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment of respiratory infections. The combination formulation was produced by spray-drying rifapentine particles suspended in an aqueous colistin solution. The combination dry powder had enhanced antimicrobial activities against planktonic cells and biofilm cultures of Pseudomonas aeruginosa, with both minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) values (2 and 4 mg/L, respectively) being half that of pure colistin (MIC 4 mg/L and MBIC 8 mg/L) and 1/16th that of pure rifapentine (MIC 32 mg/L and MBIC 64 mg/L). High aerosol performance, as measured via an Aerolizer device, was observed with emitted doses>89% and fine particle fraction (FPF) total>76%. The proportion of submicron particles of rifapentine particles was minimized by the attachment of colistin, which increased the overall particle mass and aerodynamic size distribution. Using the spray-drying method described here, stable particles of amorphous colistin and crystalline rifapentine were distributed homogeneously in each stage of the impinger. Unlike the colistin alone formulation, no deterioration in aerosol performance was found for the combination powder when exposed to a high relative humidity of 75%. In our previous study, surface coating by rifampicin contributed to the moisture protection of colistin. Here, a novel approach with a new mechanism was proposed whereby moisture protection was attributed to the carrier effect of elongated crystalline rifapentine particles, which minimized contact between hygroscopic colistin particles. This inhaled combination antibiotic formulation with enhanced aerosol dispersion efficiency and in vitro efficacy

  1. Ndk, a novel host-responsive regulator, negatively regulates bacterial virulence through quorum sensing in Pseudomonas aeruginosa.

    PubMed

    Yu, Hua; Xiong, Junzhi; Zhang, Rong; Hu, Xiaomei; Qiu, Jing; Zhang, Di; Xu, Xiaohui; Xin, Rong; He, Xiaomei; Xie, Wei; Sheng, Halei; Chen, Qian; Zhang, Le; Rao, Xiancai; Zhang, Kebin

    2016-01-01

    Pathogenic bacteria could adjust gene expression to enable their survival in the distinct host environment. However, the mechanism by which bacteria adapt to the host environment is not well described. In this study, we demonstrated that nucleoside diphosphate kinase (Ndk) of Pseudomonas aeruginosa is critical for adjusting the bacterial virulence determinants during infection. Ndk expression was down-regulated in the pulmonary alveoli of a mouse model of acute pneumonia. Knockout of ndk up-regulated transcription factor ExsA-mediated T3S regulon expression and decreased exoproduct-related gene expression through the inhibition of the quorum sensing hierarchy. Moreover, in vitro and in vivo studies demonstrated that the ndk mutant exhibits enhanced cytotoxicity and host pathogenicity by increasing T3SS proteins. Taken together, our data reveal that ndk is a critical novel host-responsive gene required for coordinating P. aeruginosa virulence upon acute infection. PMID:27345215

  2. Ndk, a novel host-responsive regulator, negatively regulates bacterial virulence through quorum sensing in Pseudomonas aeruginosa

    PubMed Central

    Yu, Hua; Xiong, Junzhi; Zhang, Rong; Hu, Xiaomei; Qiu, Jing; Zhang, Di; Xu, Xiaohui; Xin, Rong; He, Xiaomei; Xie, Wei; Sheng, Halei; Chen, Qian; Zhang, Le; Rao, Xiancai; Zhang, Kebin

    2016-01-01

    Pathogenic bacteria could adjust gene expression to enable their survival in the distinct host environment. However, the mechanism by which bacteria adapt to the host environment is not well described. In this study, we demonstrated that nucleoside diphosphate kinase (Ndk) of Pseudomonas aeruginosa is critical for adjusting the bacterial virulence determinants during infection. Ndk expression was down-regulated in the pulmonary alveoli of a mouse model of acute pneumonia. Knockout of ndk up-regulated transcription factor ExsA-mediated T3S regulon expression and decreased exoproduct-related gene expression through the inhibition of the quorum sensing hierarchy. Moreover, in vitro and in vivo studies demonstrated that the ndk mutant exhibits enhanced cytotoxicity and host pathogenicity by increasing T3SS proteins. Taken together, our data reveal that ndk is a critical novel host-responsive gene required for coordinating P. aeruginosa virulence upon acute infection. PMID:27345215

  3. GBA2-Encoded β-Glucosidase Activity Is Involved in the Inflammatory Response to Pseudomonas aeruginosa

    PubMed Central

    Lampronti, Ilaria; Marchetti, Nicola; Aureli, Massimo; Bassi, Rosaria; Giri, Maria Grazia; Bezzerri, Valentino; Lovato, Valentina; Cantù, Cinzia; Munari, Silvia; Cheng, Seng H.; Cavazzini, Alberto; Gambari, Roberto; Sonnino, Sandro; Cabrini, Giulio; Dechecchi, Maria Cristina

    2014-01-01

    Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF) are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs) in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (Genz-529648). In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2. PMID:25141135

  4. Pulmonary Tuberculosis in Severely-malnourished or HIV-infected Children with Pneumonia: A Review

    PubMed Central

    Ahmed, Tahmeed; Pietroni, Mark A.C.; Faruque, Abu S.G.; Ashraf, Hasan; Bardhan, Pradip K.; Hossain, Md. Iqbal; Das, Sumon Kumar; Salam, Mohammed Abdus

    2013-01-01

    Presentation of pulmonary tuberculosis (PTB) as acute pneumonia in severely-malnourished and HIV-positive children has received very little attention, although this is very important in the management of pneumonia in children living in communities where TB is highly endemic. Our aim was to identify confirmed TB in children with acute pneumonia and HIV infection and/or severe acute malnutrition (SAM) (weight-for-length/height or weight-for-age z score <-3 of the WHO median, or presence of nutritional oedema). We conducted a literature search, using PubMed and Web of Science in April 2013 for the period from January 1974 through April 2013. We included only those studies that reported confirmed TB identified by acid fast bacilli (AFB) through smear microscopy, or by culture-positive specimens from children with acute pneumonia and SAM and/or HIV infection. The specimens were collected either from induced sputum (IS), or gastric lavage (GL), or broncho-alveolar lavage (BAL), or percutaneous lung aspirates (LA). Pneumonia was defined as the radiological evidence of lobar or patchy consolidation and/or clinical evidence of severe/very severe pneumonia according to the WHO criteria of acute respiratory infection. A total of 17 studies met our search criteria but 6 were relevant for our review. Eleven studies were excluded as those did not assess the HIV status of the children or specify the nutritional status of the children with acute pneumonia and TB. We identified only 747 under-five children from the six relevant studies that determined a tubercular aetiology of acute pneumonia in children with SAM and/or positive HIV status. Three studies were reported from South Africa and one each from the Gambia, Ethiopia, and Thailand where 610, 90, 35, and 12 children were enrolled and 64 (10%), 23 (26%), 5 (14%), and 1 (8%) children were identified with active TB respectively, with a total of 93 (12%) children with active TB. Among 610 HIV-infected children in three studies

  5. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors

    PubMed Central

    Hentzer, Morten; Wu, Hong; Andersen, Jens Bo; Riedel, Kathrin; Rasmussen, Thomas B.; Bagge, Niels; Kumar, Naresh; Schembri, Mark A.; Song, Zhijun; Kristoffersen, Peter; Manefield, Mike; Costerton, John W.; Molin, Søren; Eberl, Leo; Steinberg, Peter; Kjelleberg, Staffan; Høiby, Niels; Givskov, Michael

    2003-01-01

    Traditional treatment of infectious diseases is based on compounds that kill or inhibit growth of bacteria. A major concern with this approach is the frequent development of resistance to antibiotics. The discovery of communication systems (quorum sensing systems) regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with growth. Compounds that can override communication signals have been found in the marine environment. Using Pseudomonas aeruginosa PAO1 as an example of an opportunistic human pathogen, we show that a synthetic derivate of natural furanone compounds can act as a potent antagonist of bacterial quorum sensing. We employed GeneChip® microarray technology to identify furanone target genes and to map the quorum sensing regulon. The transcriptome analysis showed that the furanone drug specifically targeted quorum sensing systems and inhibited virulence factor expression. Application of the drug to P.aeruginosa biofilms increased bacterial susceptibility to tobramycin and SDS. In a mouse pulmonary infection model, the drug inhibited quorum sensing of the infecting bacteria and promoted their clearance by the mouse immune response. PMID:12881415

  6. Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

    PubMed Central

    Ueno, Keigo; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-01-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  7. Dendritic cell-based immunization ameliorates pulmonary infection with highly virulent Cryptococcus gattii.

    PubMed

    Ueno, Keigo; Kinjo, Yuki; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-04-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  8. Pulmonary Arterial Lesions in New World Camelids in Association With Dicrocoelium dendriticum and Fasciola hepatica Infection.

    PubMed

    Hilbe, M; Robert, N; Pospischil, A; Gerspach, C

    2015-11-01

    In Switzerland, dicrocoeliasis is regarded as the most significant parasitic infection of llamas and alpacas. Fasciola hepatica infestation is also a problem but less common. The aim of the present retrospective study was to evaluate the lungs of New World camelids (NWCs) for evidence of arterial hypertension in association with liver changes due to liver fluke infestation. The lungs of 20 llamas and 20 alpacas with liver fluke infestation were histologically evaluated. The hematoxylin and eosin and van Gieson (VG)-elastica stains as well as immunohistology for the expression of α-smooth muscle actin (α-SMA) were used to visualize the structures of arterial walls. Parasitology of fecal matter (11 llamas and 17 alpacas) confirmed that most of these animals were infested with both Dicrocoelium dendriticum and other gastrointestinal parasites. In most cases (10/12 llamas, 4/6 alpacas), liver enzyme activity in serum was elevated. Histologically, arteries in the lungs of 9 of 20 llamas (45%) and 3 of 20 alpacas (15%) showed severe intimal and adventitial and slight to moderate medial thickening, which was confirmed with α-SMA and VG-elastica staining. All animals exhibited typical liver changes, such as fibrosis and biliary hyperplasia, in association with the presence of liver flukes. This study shows that liver flukes can induce proliferative changes in lung arteries in NWCs that resemble those seen with pulmonary arterial hypertension due to liver parasites in humans. However, the degree of liver fluke infestation was not correlated with the extent of liver damage, or with the amount of thoracic or abdominal effusion or pulmonary arterial changes. PMID:25637085

  9. The Accessory Genome of Pseudomonas aeruginosa

    PubMed Central

    Kung, Vanderlene L.; Ozer, Egon A.; Hauser, Alan R.

    2010-01-01

    Summary: Pseudomonas aeruginosa strains exhibit significant variability in pathogenicity and ecological flexibility. Such interstrain differences reflect the dynamic nature of the P. aeruginosa genome, which is composed of a relatively invariable “core genome” and a highly variable “accessory genome.” Here we review the major classes of genetic elements comprising the P. aeruginosa accessory genome and highlight emerging themes in the acquisition and functional importance of these elements. Although the precise phenotypes endowed by the majority of the P. aeruginosa accessory genome have yet to be determined, rapid progress is being made, and a clearer understanding of the role of the P. aeruginosa accessory genome in ecology and infection is emerging. PMID:21119020

  10. Capsule production by Pseudomonas aeruginosa

    SciTech Connect

    Lynn, A.R.

    1984-01-01

    Mucoid strains of Pseudomonas aeruginosa, associated almost exclusively with chronic respiratory infections in patients with cystic fibrosis, possess a capsule composed of alginic acid similar to one produced by Azotobacter vinelandii. Recent reports have provided evidence that the biosynthetic pathway for alginate in P. aeruginosa may differ from the pathway proposed for A. vinelandii in that synthesis in P. aeruginosa may occur by way of the Entner-Doudoroff pathway. Incorporation of isotope from (6-/sup 14/C)glucose into alginate by both P. aueroginosa and A. vinelandii was 10-fold greater than that from either (1-/sup 14/C)/sup -/ or (2-/sup 14/C)glucose, indicating preferential utilization of the bottom half of the glucose molecule for alginate biosynthesis. These data strongly suggest that the Entner-Doudoroff pathway plays a major role in alginate synthesis in both P. aeruginosa and A. vinelandii. The enzymes of carbohydrate metabolism in mucoid strains of P. aeruginosa appear to be unchanged whether alignate is actively produced or not and activities do not differ significantly from nonmucoid strain PAO.

  11. Sequential Treatment of Biofilms with Aztreonam and Tobramycin Is a Novel Strategy for Combating Pseudomonas aeruginosa Chronic Respiratory Infections.

    PubMed

    Rojo-Molinero, Estrella; Macià, María D; Rubio, Rosa; Moyà, Bartolomé; Cabot, Gabriel; López-Causapé, Carla; Pérez, José L; Cantón, Rafael; Oliver, Antonio

    2016-05-01

    Traditional therapeutic strategies to control chronic colonization in cystic fibrosis (CF) patients are based on the use of a single nebulized antibiotic. In this study, we evaluated the therapeutic efficacy and dynamics of antibiotic resistance in Pseudomonas aeruginosa biofilms under sequential therapy with inhaled aztreonam (ATM) and tobramycin (TOB). Laboratory strains PAO1, PAOMS (hypermutable), PAOMA (mucoid), and PAOMSA (mucoid and hypermutable) and two hypermutable CF strains, 146-HSE (Liverpool epidemic strain [LES-1]) and 1089-HSE (ST1089), were used. Biofilms were developed using the flow cell system. Mature biofilms were challenged with peak and 1/10-peak concentrations of ATM (700 mg/liter and 70 mg/liter), TOB (1,000 mg/liter and 100 mg/liter), and their alternations (ATM/TOB/ATM and TOB/ATM/TOB) for 2 (t = 2), 4 (t = 4), and 6 days (t = 6). The numbers of viable cells (CFU) and resistant mutants were determined. Biofilm structural dynamics were monitored by confocal laser scanning microscopy and processed with COMSTAT and IMARIS software programs. TOB monotherapy produced an intense decrease in CFU that was not always correlated with a reduction in biomass and/or a bactericidal effect on biofilms, particularly for the CF strains. The ATM monotherapy bactericidal effect was lower, but effects on biofilm biomass and/or structure, including intense filamentation, were documented. The alternation of TOB and ATM led to an enhancement of the antibiofilm activity against laboratory and CF strains compared to that with the individual regimens, potentiating the bactericidal effect and/or the reduction in biomass, particularly at peak concentrations. Resistant mutants were not documented in any of the regimens at the peak concentrations and only anecdotally at the 1/10-peak concentrations. These results support the clinical evaluation of sequential regimens with inhaled antibiotics in CF, as opposed to the current maintenance treatments with just one

  12. Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1β response to Pseudomonas aeruginosa.

    PubMed

    Patankar, Yash R; Mabaera, Rodwell; Berwin, Brent

    2015-10-15

    The NLRC4 inflammasome is responsible for IL-1β processing by macrophages in response to Pseudomonas aeruginosa infection. We therefore hypothesized that mice that lack ASC, an NLRC4 inflammasome adaptor protein necessary for in vitro IL-1β production by macrophages, would be preferentially protected from a hyperinflammatory lethal challenge that is dependent on bacterial type three secretion system (T3SS) activity. We report herein that lack of ASC does not confer preferential protection in response to P. aeruginosa acute infection and that ASC(-/-) mice are capable of producing robust amounts of IL-1β comparable with C57BL/6 mice. We now identify that neutrophils represent the ASC-independent source of IL-1β production during the acute phases of infection both in models of acute pneumonia and peritonitis. Consequently, depletion of neutrophils in ASC(-/-) mice leads to a marked deficit in IL-1β production in vivo. The pulmonary neutrophil IL-1β response is predominantly dependent on caspase-1, which contrasts with data derived from ocular infection. These studies therefore identify a noncanonical mechanism of IL-1β production by neutrophils independent of ASC and demonstrate the first physiological contribution of neutrophils as an important source of IL-1β in response to acute P. aeruginosa infection during acute pneumonia and peritonitis. PMID:26472815

  13. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2)

    ClinicalTrials.gov

    2016-04-13

    Acquired Immunodeficiency Syndrome; Lung Diseases; Cardiovascular Diseases; Heart Diseases; Heart Failure; HIV Infections; Cytomegalovirus Infections; Pneumocystis Carinii Infections; Ebstein-Barr Virus Infections

  14. Protection of immunocompromised mice against lethal infection with Pseudomonas aeruginosa by active or passive immunization with recombinant P. aeruginosa outer membrane protein F and outer membrane protein I fusion proteins.

    PubMed Central

    von Specht, B U; Knapp, B; Muth, G; Bröker, M; Hungerer, K D; Diehl, K D; Massarrat, K; Seemann, A; Domdey, H

    1995-01-01

    Recombinant outer membrane proteins (Oprs) of Pseudomonas aeruginosa were expressed in Escherichia coli as glutathione S-transferase (GST)-linked fusion proteins. GST-linked Oprs F and I (GST-OprF190-350 [GST linked to OprF spanning amino acids 190 to 350] and GST-OprI21-83, respectively) and recombinant hybrid Oprs (GST-OprF190-342-OprI21-83 and GST-OprI21-83-OprF190-350) were isolated and tested for their efficacy as vaccines in immunodeficient mice. GST-OprF-OprI protected the mice against a 975-fold 50% lethal dose of P. aeruginosa. Expression of GST-unfused OprF-OprI failed in E. coli, although this hybrid protein has been expressed without a fusion part in Saccharomyces cerevisiae and used for immunizing rabbits. The immune rabbit sera protected severe combined deficient (SCID) mice against a 1,000-fold 50% lethal dose of P. aeruginosa. Evidence is provided to show that the most C-terminal part of OprF (i.e., amino acids 332 to 350) carries an important protective epitope. Opr-based hybrid proteins may have implications for a clinical vaccine against P. aeruginosa. PMID:7729895

  15. Detection of Host-Derived Sphingosine by Pseudomonas aeruginosa Is Important for Survival in the Murine Lung

    PubMed Central

    LaBauve, Annette E.; Wargo, Matthew J.

    2014-01-01

    Pseudomonas aeruginosa is a common environmental bacterium that is also a significant opportunistic pathogen, particularly of the human lung. We must understand how P. aeruginosa responds to the lung environment in order to identify the regulatory changes that bacteria use to establish and maintain infections. The P. aeruginosa response to pulmonary surfactant was used as a model to identify transcripts likely induced during lung infection. The most highly induced transcript in pulmonary surfactant, PA5325 (sphA), is regulated by an AraC-family transcription factor, PA5324 (SphR). We found that sphA was specifically induced by sphingosine in an SphR-dependent manner, and also via metabolism of sphingomyelin, ceramide, or sphingoshine-1-phosphate to sphingosine. These sphingolipids not only play a structural role in lipid membranes, but some are also intracellular and intercellular signaling molecules important in normal eukaryotic cell functions as well as orchestrating immune responses. The members of the SphR transcriptome were identified by microarray analyses, and DNA binding assays showed specific interaction of these promoters with SphR, which enabled us to determine the consensus SphR binding site. SphR binding to DNA was modified by sphingosine and we used labeled sphingosine to demonstrate direct binding of sphingosine by SphR. Deletion of sphR resulted in reduced bacterial survival during mouse lung infection. In vitro experiments show that deletion of sphR increases sensitivity to the antimicrobial effects of sphingosine which could, in part, explain the in vivo phenotype. This is the first identification of a sphingosine-responsive transcription factor in bacteria. We predict that SphR transcriptional regulation may be important in response to many sites of infection in eukaryotes and the presence of homologous transcription factors in other pathogens suggests that sphingosine detection is not limited to P. aeruginosa. PMID:24465209

  16. Influenza A (H1N1) Virus Infection Triggers Severe Pulmonary Inflammation in Lupus-Prone Mice following Viral Clearance

    PubMed Central

    Slight-Webb, Samantha R.; Bagavant, Harini; Crowe, Sherry R.; James, Judith A.

    2015-01-01

    Each year, up to one fifth of the United States population is infected with influenza virus. Although mortality rates are low, hundreds of thousands are hospitalized each year in the United States. Specific high risk groups, such as those with suppressed or dysregulated immune systems, are at greater danger for influenza complications. Respiratory infections are a common cause of hospitalizations and early mortality in patients with systemic lupus erythematosus (SLE); however, whether this increased infection risk is a consequence of the underlying dysregulated immune background and/or immunosuppressing drugs is unknown. To evaluate the influenza immune response in the context of lupus, as well as assess the effect of infection on autoimmune disease in a controlled setting, we infected lupus-prone MRL/MpJ-Faslpr mice with influenza virus A PR/8/34 H1N1. Interestingly, we found that Faslpr mice generated more influenza A virus specific T cells with less neutrophil accumulation in the lung during acute infection. Moreover, Faslpr mice produced fewer flu-specific IgG and IgM antibodies, but effectively cleared the virus. Further, increased extrinsic apoptosis during influenza infection led to a delay in autoimmune disease pathology with decreased severity of splenomegaly and kidney disease. Following primary influenza A infection, Faslpr mice had severe complications during the contraction and resolution phase with widespread severe pulmonary inflammation. Our findings suggest that influenza infection may not exacerbate autoimmune pathology in mice during acute infection as a direct result of virus induced apoptosis. Additionally, autoimmunity drives an enhanced antigen-specific T cell response to clear the virus, but persisting pulmonary inflammation following viral clearance may cause complications in this lupus animal model. PMID:25563403

  17. Human immunodeficiency virus (HIV)-related pulmonary complications in pregnancy.

    PubMed

    Saade, G R

    1997-08-01

    With changes in the demographics of human immunodeficiency virus (HIV) infection, women and children are becoming the fastest growing group of newly infected patients. With longer survival after HIV infection, more women infected with HIV are becoming pregnant. Pulmonary disease is one of the most common presenting conditions in an AIDS-defining illness. Pneumocystis carini pneumonia and tuberculosis are the most common disorders that herald the onset of AIDS. They are also the most frequently encountered HIV-related pulmonary complications during pregnancy. Others have been rarely reported during pregnancy and include fungal infections (Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitus), bacterial infections (Haemophilus influenzae and Streptococcus pneumoniae along with Pseudomona aeruginosa), viral infections (CMV), opportunistic neoplasms (Kaposi's sarcoma, lymphoma) and miscellaneous conditions peculiar to HIV-infected individuals (nonspecific interstitial pneumonitis, lymphoid interstitial pneumonitis, isolated pulmonary hypertension, and pulmonary edema secondary to cardiac disease or drug abuse). Most of the data regarding the pulmonary complications of HIV infection come from studies in nonpregnant patients. The extent to which pregnancy affects the course of respiratory disease in HIV infection and vice versa is not well documented. Clinical presentation is usually not altered by pregnancy. Except for minor modifications mainly related to potential fetal effects, the diagnostic work-up and management are similar to those in the nonpregnant patient. The most important effect of pregnancy on these conditions remains the delay in diagnosis and treatment. A high index of suspicion should, therefore, be maintained. In addition, most prophylactic measures recommended in nonpregnant HIV-infected individuals also apply to pregnant women. PMID:9298723

  18. Determination of the Minimal Clinically Important Difference Scores for the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale in Two Populations of Patients With Cystic Fibrosis and Chronic Pseudomonas aeruginosa Airway Infection

    PubMed Central

    Quittner, Alexandra L.; Modi, Avani C.; Wainwright, Claire; Otto, Kelly; Kirihara, Jean; Montgomery, A. Bruce

    2009-01-01

    Background: The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated patient-reported outcome (PRO) containing both generic scales and scales specific to cystic fibrosis (CF). The minimal clinically important difference (MCID) score for a PRO corresponds to the smallest clinically relevant change a patient can detect. MCID scores for the CFQ-R respiratory symptom (CFQ-R-Respiratory) scale were determined using data from two 28 day, open-label, tobramycin inhalation solution (TIS) studies in patients with CF and chronic Pseudomonas aeruginosa airway infection. At study enrollment, patients in the study 1-exacerbation had symptoms indicative of pulmonary exacerbation (n = 84; < 14 years of age, 31 patients; ≥ 14 years of age, 53 patients); patients in study 2-stable had stable respiratory symptoms (n = 140; < 14 years of age, 14 patients; ≥ 14 years, 126 patients). Methods: The anchor-based method utilized a global rating-of-change questionnaire (GRCQ) that assessed patients' perceptions of change in their respiratory symptoms after TIS treatment. The mean change from baseline CFQ-R-Respiratory scores were mapped onto the GRCQ to estimate the MCID. The two distribution-based methods were as follows: (1) 0.5 SD of mean change in CFQ-R-Respiratory scores (baseline to end of TIS treatment); and (2) 1 SEM for baseline CFQ-R-Respiratory scores. Triangulation of these three estimates defined the MCIDs. Results: MCID scores were larger for patients in study 1-exacerbation (8.5 points) than for those in study 2-stable (4.0 points), likely reflecting differences in patient disease status (exacerbation/stable) between these studies. Conclusions: Patient benefit from new and current CF therapies can be evaluated using changes in CFQ-R-Respiratory scores. Using the MCID provides a systematic way to interpret these changes, and facilitates the identification of CF treatments that improve both symptoms and physiologic variables, potentially leading to better treatment

  19. Comparison of susceptibility of cystic-fibrosis-related and non-cystic-fibrosis-related Pseudomonas aeruginosa to chlorine-based disinfecting solutions: implications for infection prevention and ward disinfection.

    PubMed

    Moore, John E; Rendall, Jacqueline C

    2014-09-01

    Multidrug-resistant (MDR) Pseudomonas aeruginosa isolated from cystic fibrosis (CF) sputum was shown to be more tolerant to the most commonly used chlorine-based disinfecting agent in the UK, with approximately 7 out of 10 isolates surviving a residual free chlorine (RFC) concentration of 500 p.p.m., when compared with antibiotic-sensitive invasive P. aeruginosa from a non-CF blood culture source, where 8 out of 10 isolates were killed at a RFC concentration of 100 p.p.m. All CF isolates were killed at 1000 p.p.m. chlorine. Additional studies were performed to examine factors that influenced the concentration of RFC from chlorine-based (sodium dichloroisocyanurate) disinfecting agents in contact with CF sputum and their components (bacterial cells, glycocalyx) to assess the reduction of the bactericidal activity of such disinfecting agents. Pseudomonas glycocalyx had a greater inhibitory effect of chlorine deactivation than bacterial cells. Calibration curves demonstrated the relative deactivating capacity on RFC from clinical soils, in the order pus>CF sputum>wound discharge fluid/synovial fluid>ascites fluid>bile, where quantitatively each 1 % (w/v) CF sputum reduced the RFC by 43 p.p.m. Sublethal stressing of P. aeruginosa with chlorine resulted in lowered susceptibility to colistin (P = 0.0326) but not to meropenem, tobramycin or ciprofloxacin. In conclusion, heavy contamination of healthcare fomites with CF sputum containing MDR P. aeruginosa may result in exhaustion of RFC, and this, combined with an increased resistance to chlorine with such strains, may lead to their survival and increased antibiotic resistance in such environments. CF infection prevention strategies in such scenarios should therefore target interventions with increased concentrations of chlorine to ensure the eradication of MDR P. aeruginosa from the CF healthcare environment. PMID:24925907

  20. Trappin-2 promotes early clearance of Pseudomonas aeruginosa through CD14-dependent macrophage activation and neutrophil recruitment.

    PubMed

    Wilkinson, Thomas S; Dhaliwal, Kevin; Hamilton, Thomas W; Lipka, Alexander F; Farrell, Lesley; Davidson, Donald J; Duffin, Rodger; Morris, Andrew Conway; Haslett, Chris; Govan, John R W; Gregory, Christopher D; Sallenave, Jean-Michel; Simpson, A John

    2009-04-01

    Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection. PMID:19264904

  1. Trappin-2 Promotes Early Clearance of Pseudomonas aeruginosa through CD14-Dependent Macrophage Activation and Neutrophil Recruitment

    PubMed Central

    Wilkinson, Thomas S.; Dhaliwal, Kevin; Hamilton, Thomas W.; Lipka, Alexander F.; Farrell, Lesley; Davidson, Donald J.; Duffin, Rodger; Morris, Andrew Conway; Haslett, Chris; Govan, John R.W.; Gregory, Christopher D.; Sallenave, Jean-Michel; Simpson, A. John

    2009-01-01

    Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection. PMID:19264904

  2. Ozone-enhanced pulmonary infection with Streptococcus zooepidemicus in mice. The role of alveolar macrophage function and capsular virulence factors

    SciTech Connect

    Gilmour, M.I.; Park, P.; Selgrade, M.K. )

    1993-03-01

    Ozone exposure has been shown to increase the susceptibility of mice to pulmonary bacterial infection. We report here the differences in susceptibility of two strains of mice (C3H/HeJ and C57Bl/6) to pulmonary challenge with Streptococcus zooepidemicus, and demonstrate an association between O3 exposure, reduced alveolar macrophage (AM) function, and increased mortality to infection. After a 3-h exposure to air or to 0.4 or 0.8 ppm O3, mice received an infection of bacteria by aerosol. Subsequent mortality observed over a 20-day period for any given exposure concentration was greater in the C3H/HeJ mice than in the C57Bl/6 mice. Phagocytosis assays identified the AM from O3-exposed lungs as having an impaired ability to engulf the bacteria. Baseline phagocytic activity in C3H/HeJ mice was lower than that in C57Bl/6 mice. Microbiologic assessment of the lungs at various times after infection revealed that the streptococci proliferated rapidly in the lungs of O3-exposed mice, grew more quickly upon isolation, and displayed a mucoid colony appearance indicative of increased encapsulation. In vitro assays confirmed that the encapsulated isolates prevented binding of the bacteria to AM, and reinfection of nonexposed mice with the encapsulated isolate resulted in increased mortality compared with infection with similar numbers of the original unencapsulated bacteria. We have demonstrated that O3 inhalation impairs AM activity in the lung. The streptococci are then able to proliferate and more fully express virulence factors, in particular, the antiphagocytic capsule, which prohibits the ingestion of bacteria by pulmonary phagocytes and leads to increased severity of infection.

  3. Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis

    PubMed Central

    Ribeiro, Laura R. R.; Loures, Flávio V.; de Araújo, Eliseu F.; Feriotti, Cláudia; Costa, Tânia A.; Serezani, Carlos Henrique; Jancar, Sonia; Calich, Vera L. G.

    2015-01-01

    Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages. PMID:26635449

  4. Septic Pulmonary Embolism Caused by Infected Pacemaker Leads After Replacement of a Cardiac Resynchronization Therapy Device

    PubMed Central

    Said, Salah A.M.; Nijhuis, Rogier; Derks, Anita; Droste, Herman

    2016-01-01

    Patient: Male, 70 Final Diagnosis: Pacemaker leads endocarditis Symptoms: Bacterial lead endocarditis • congestive heart failure • fever • pacemaker dysfunction Medication: — Clinical Procedure: Pacemaker box replacement due to end-of-service Specialty: Cardiology Objective: Unusual clinical course Background: Cardiac resynchronization therapy (CRT) has been demonstrated to reduce morbidity and mortality in patients with advanced, drug-refractory heart failure. Procedure-related mortality is less than 1% in larger studies. Approximately10% of CRT patients have to undergo surgical revision because of infections, dislocations, or unacceptable electrical behavior manifested as high threshold, unstable sensing, or unwanted phrenic nerve stimulation. Case Report: A 70-year-old man with symptomatic congestive heart failure underwent implantation of a biventricular pacemaker on the left anterior chest wall in 2003 and pulse generator exchange in August 2009. The patient responded well to CRT. At follow-up, the pacing system functioned normally. In September 2009, in the context of a predialysis program, an abdominal computed tomography (CT) scan was performed in another hospital for assessment and evaluation of chronic kidney disease. This procedure was complicated with peripheral thrombophlebitis that was managed appropriately with complete recovery. Eight months later (May 2010), the patient was admitted to our hospital with fever, anemia, and elevated infection parameters. During admission, blood cultures grew Staphylococcus epidermidis. The chest X-ray, lung perfusion scintigraphy, and CT scan depicted pulmonary embolism and infarction. The right ventricular lead threshold was found to be increased to 7 volts with unsuccessful capture. Echocardiography demonstrated vegetations on leads. The entire pacing system was explanted, but the patient expired few days later following percutaneous removal due to multiorgan failure. Conclusions: In heart failure

  5. CD4 lymphocyte dynamics in Tanzanian pulmonary tuberculosis patients with and without hiv co-infection

    PubMed Central

    2012-01-01

    Background The interaction of HIV and tuberculosis (TB) on CD4 levels over time is complex and has been divergently reported. Methods CD4 counts were assessed from time of diagnosis till the end of TB treatment in a cohort of pulmonary TB patients with and without HIV co-infection and compared with cross-sectional data on age- and sex-matched non-TB controls from the same area. Results Of 1,605 study participants, 1,250 were PTB patients and 355 were non-TB controls. At baseline, HIV was associated with 246 (95% CI: 203; 279) cells per μL lower CD4 counts. All PTB patients had 100 cells per μL lower CD4 counts than the healthy controls. The CD4 levels were largely unchanged during a five-month of TB treatment. HIV infected patients not receiving ART at any time and those already on ART at baseline had no increase in CD4 counts after 5 months of TB treatment, whereas those prescribed ART between baseline and 2 months, and between 2 and 5 months increased by 69 (22;117) and 110 (52; 168) CD4 cells per μL after 5 months. Conclusions The increase in circulating CD4 levels observed in PTB in patients is acquired after 2 months of treatment irrespective of HIV status. Initiation of ART is the strongest factor correlated with CD4 increase during TB treatment. Trial registration number Clinical trials.gov: NCT00311298 PMID:22436147

  6. Septic Pulmonary Embolism Caused by Infected Pacemaker Leads After Replacement of a Cardiac Resynchronization Therapy Device.

    PubMed

    Said, Salah A M; Nijhuis, Rogier; Derks, Anita; Droste, Herman

    2016-01-01

    BACKGROUND Cardiac resynchronization therapy (CRT) has been demonstrated to reduce morbidity and mortality in patients with advanced, drug-refractory heart failure. Procedure-related mortality is less than 1% in larger studies. Approximately10% of CRT patients have to undergo surgical revision because of infections, dislocations, or unacceptable electrical behavior manifested as high threshold, unstable sensing, or unwanted phrenic nerve stimulation. CASE REPORT A 70-year-old man with symptomatic congestive heart failure underwent implantation of a biventricular pacemaker on the left anterior chest wall in 2003 and pulse generator exchange in August 2009. The patient responded well to CRT. At follow-up, the pacing system functioned normally. In September 2009, in the context of a predialysis program, an abdominal computed tomography (CT) scan was performed in another hospital for assessment and evaluation of chronic kidney disease. This procedure was complicated with peripheral thrombophlebitis that was managed appropriately with complete recovery. Eight months later (May 2010), the patient was admitted to our hospital with fever, anemia, and elevated infection parameters. During admission, blood cultures grew Staphylococcus epidermidis. The chest X-ray, lung perfusion scintigraphy, and CT scan depicted pulmonary embolism and infarction. The right ventricular lead threshold was found to be increased to 7 volts with unsuccessful capture. Echocardiography demonstrated vegetations on leads. The entire pacing system was explanted, but the patient expired few days later following percutaneous removal due to multiorgan failure. CONCLUSIONS In heart failure, replacement of the CRT device may be complicated by bacterial endocarditis. As noted from this case report, sudden elevation of the pacing lead threshold should prompt thorough and immediate investigation to unravel its causes, not only the electrical characteristics but also the anatomical features. PMID:27435910

  7. The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma.

    PubMed

    Hewitt, Richard; Farne, Hugo; Ritchie, Andrew; Luke, Emma; Johnston, Sebastian L; Mallia, Patrick

    2016-04-01

    Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus-bacteria interactions and therapeutic advances. PMID:26611907

  8. The effect of the weather on pulmonary exacerbations and viral infections among adults with cystic fibrosis

    NASA Astrophysics Data System (ADS)

    Flight, W. G.; Bright-Thomas, R. J.; Sarran, C.; Mutton, K. J.; Morris, J.; Webb, A. K.; Jones, A. M.

    2014-01-01

    The effect of changes in the weather on the respiratory health of patients with cystic fibrosis (CF) is unclear. We conducted a prospective study to determine the impact of climate and season on the incidence of viral respiratory infections (VRI) and pulmonary exacerbations (PEx) among adults with CF. Between December 2010 and April 2012, 98 adults with CF were followed for 12 months. Polymerase chain reaction assays for nine viruses were performed on sputum, nose and throat swabs every 2 months and additionally at onset of PEx. Hourly temperature and relative humidity measurements were recorded throughout the study. Statistical analysis utilized generalized estimating equation (GEE) models. Pre-specified criteria for VRI and PEx were met at 29 % and 37 % of visits, respectively. Rhinovirus accounted for 72 % of identified viruses. Incidence of rhinovirus peaked in autumn while non-rhinovirus VRI peaked in winter. Rhinovirus was associated with increased mean temperatures (OR 1.07; p = 0.001), while non-rhinovirus VRI was associated with lower mean temperatures (OR 0.87; p < 0.001). PEx occurred frequently throughout the study with no clear seasonal pattern observed. There was no significant association between climate variables and the incidence of either PEx or antibiotic prescription. There is a seasonal pattern to VRI in adults with CF. The incidence of VRI but not PEx is associated with changes in ambient temperature.

  9. Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice.

    PubMed

    Lay, Margarita K; Céspedes, Pablo F; Palavecino, Christian E; León, Miguel A; Díaz, Rodrigo A; Salazar, Francisco J; Méndez, Gonzalo P; Bueno, Susan M; Kalergis, Alexis M

    2015-06-01

    Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication. PMID:25763996

  10. In Pulmonary Paracoccidioidomycosis IL-10 Deficiency Leads to Increased Immunity and Regressive Infection without Enhancing Tissue Pathology

    PubMed Central

    Feriotti, Claudia; Araújo, Eliseu F.; Bassi, Ênio J.; Loures, Flávio V.; Calich, Vera L. G.

    2013-01-01

    Background Cellular immunity is the main defense mechanism in paracoccidioidomycosis (PCM), the most important systemic mycosis in Latin America. Th1 immunity and IFN-γ activated macrophages are fundamental to immunoprotection that is antagonized by IL-10, an anti-inflammatory cytokine. Both in human and experimental PCM, several evidences indicate that the suppressive effect of IL-10 causes detrimental effects to infected hosts. Because direct studies have not been performed, this study was aimed to characterize the function of IL-10 in pulmonary PCM. Methodology/Principal Findings Wild type (WT) and IL-10−/− C57BL/6 mice were used to characterize the role of IL-10 in the innate and adaptive immunity against Paracoccidioides brasiliensis (Pb) infection. We verified that Pb-infected peritoneal macrophages from IL-10−/− mice presented higher phagocytic and fungicidal activities than WT macrophages, and these activities were associated with elevated production of IFN-γ, TNF-α, nitric oxide (NO) and MCP-1. For in vivo studies, IL-10−/− and WT mice were i.t. infected with 1×106 Pb yeasts and studied at several post-infection periods. Compared to WT mice, IL-10−/− mice showed increased resistance to P. brasiliensis infection as determined by the progressive control of pulmonary fungal loads and total clearance of fungal cells from dissemination organs. This behavior was accompanied by enhanced delayed-type hypersensitivity reactions, precocious humoral immunity and controlled tissue pathology resulting in increased survival times. In addition, IL-10−/− mice developed precocious T cell immunity mediated by increased numbers of lung infiltrating effector/memory CD4+ and CD8+ T cells. The inflammatory reactions and the production of Th1/Th2/Th17 cytokines were reduced at late phases of infection, paralleling the regressive infection of IL-10−/− mice. Conclusions/Significance Our work demonstrates for the first time that IL-10 plays a detrimental

  11. Comparative Efficacy and Safety of Four Randomized Regimens to Treat Early Pseudomonas aeruginosa Infection in Children with Cystic Fibrosis

    PubMed Central

    Treggiari, Miriam M.; Retsch-Bogart, George; Mayer-Hamblett, Nicole; Khan, Umer; Kulich, Michal; Kronmal, Richard; Williams, Judy; Hiatt, Peter; Gibson, Ronald L.; Spencer, Terry; Orenstein, David; Chatfield, Barbara A.; Froh, Deborah K.; Burns, Jane L.; Rosenfeld, Margaret; Ramsey, Bonnie W.

    2014-01-01

    Context While therapy for early Pa acquisition has been shown to be efficacious, the best regimen to achieve airway clearance has not been delineated. Objectives To investigate the efficacy and safety of four anti-pseudomonal treatments in children with cystic fibrosis (CF) with recently acquired Pa. Design, Setting, and Patients In a multicenter trial in the US, 304 children with CF ages 1–12 years within 6 months of Pa detection were randomized to one of four antibiotic regimens for an 18-month period (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg BID) for 28 days, with oral ciprofloxacin (15–20 mg/kg BID) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive Pa cultures. Main outcome measures The primary endpoints were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of Pa-positive cultures. Results The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio [HR], 0.95, 95%CI, 0.54–1.66) or ciprofloxacin and placebo (HR 1.45, 95%CI, 0.82–2.54). The ORs of Pa positive culture comparing cycled vs. culture-based group were 0.78 (95%CI, 0.49–1.23) and OR 1.10; 95%CI, 0.71–1.71) comparing ciprofloxacin vs. placebo. Adverse events were similar across groups. Conclusions No difference in rate of exacerbation or prevalence of Pa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits. PMID:21893650

  12. A Case of Lower Respiratory Tract Infection with Canine-associated Pasteurella canis in a Patient with Chronic Obstructive Pulmonary Disease

    PubMed Central

    Acharya, Preetam R.; Biranthabail, Dhanashree; Rangnekar, Aseem; Shiragavi, Sachin

    2015-01-01

    This is the report of lower respiratory tract infection with Pasteurella canis in a chronic obstructive pulmonary disease (COPD) patient with history of casual exposure to cats. Pasteurella species are part of the oral and gastrointestinal flora in the canine animals. These organisms are usually implicated in wound infection following animal bites, but can also be associated with a variety of infections including respiratory tract infections. PMID:26435948

  13. Soluble metals in residual oil fly ash alter innate and adaptive pulmonary immune responses to bacterial infection in rats

    SciTech Connect

    Roberts, Jenny R. . E-mail: jur6@cdc.gov; Young, Shih-Houng; Castranova, Vincent; Antonini, James M.

    2007-06-15

    The soluble metals of the pollutant, residual oil fly ash (ROFA), have been shown to alter pulmonary bacterial clearance in rats. The goal of this study was to determine the potential effects on both the innate and adaptive lung immune responses after bacterial infection in rats pre-exposed to the soluble metals in ROFA. Sprague-Dawley rats were intratracheally dosed (i.t.) at day 0 with ROFA (R-Total) (1.0 mg/100 g body weight), the soluble fraction of ROFA (R-Soluble), the soluble sample subject to a chelator (R-Chelex), or phosphate-buffered saline (Saline). On day 3, rats were administered an i.t. dose of 5 x 10{sup 4} Listeria monocytogenes. On days 6, 8, and 10, bacterial pulmonary clearance was monitored and bronchoalveolar lavage (BAL) was performed on days 3 (pre-infection), 6, 8, and 10. A concentrated first fraction of lavage fluid was retained for analysis of lactate dehydrogenase and albumin to assess lung injury. BAL cell number, phenotype, and production of reactive oxygen (ROS) and nitrogen species (RNS) were assessed, and a variety of cytokines were measured in the BAL fluid. Rats pre-treated with R-Soluble showed elevated lung injury/cytotoxicity and increased cellular influx into the lungs. R-Soluble-treatment also altered ROS, RNS, and cytokine levels, and caused a degree of macrophage and T cell inhibition. These effects of R-Soluble result in increased pulmonary bacterial burden after infection. The results suggest that soluble metals in ROFA increase lung injury and inflammation, and alter both innate and adaptive pulmonary immune responses.

  14. Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants.

    PubMed

    Ciofu, Oana; Mandsberg, Lotte F; Bjarnsholt, Thomas; Wassermann, Tina; Høiby, Niels

    2010-04-01

    During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the

  15. Enhanced effect of BCG vaccine against pulmonary Mycobacterium tuberculosis infection in mice with lung Th17 response to mycobacterial heparin-binding hemagglutinin adhesin antigen.

    PubMed

    Fukui, Masayuki; Shinjo, Kikuko; Umemura, Masayuki; Shigeno, Satoko; Harakuni, Tetsuya; Arakawa, Takeshi; Matsuzaki, Goro

    2015-12-01

    Although the BCG vaccine can prevent tuberculosis (TB) in infants, its ability to prevent adult pulmonary TB is reportedly limited. Therefore, development of a novel effective vaccine against pulmonary TB has become an international research priority. We have previously reported that intranasal vaccination of mice with a mycobacterial heparin-binding hemagglutinin adhesin (HBHA) plus mucosal adjuvant cholera toxin (CT) enhances production of IFN-γ and anti-HBHA antibody and suppresses extrapulmonary bacterial dissemination after intranasal infection with BCG. In the present study, the effects of intranasal HBHA + CT vaccine on murine pulmonary Mycobacterium tuberculosis (Mtb) infection were examined. Intranasal HBHA + CT vaccination alone failed to reduce the bacterial burden in the infected lung. However, a combination vaccine consisting of s.c. BCG priming and an intranasal HBHA + CT booster significantly enhanced protective immunity against pulmonary Mtb infection on day 14 compared with BCG vaccine alone. Further, it was found that intranasal HBHA + CT vaccine enhanced not only IFN-γ but also IL-17A production by HBHA-specific T cells in the lung after pulmonary Mtb infection. Therefore, this combination vaccine may be a good candidate for a new vaccine strategy against pulmonary TB. PMID:26577130

  16. Burn sepsis: bacterial interference with Pseudomonas aeruginosa.

    PubMed

    Levenson, S M; Gruber, D K; Gruber, C; Watford, A; Seifter, E

    1981-05-01

    The pathogenicity of several strains of Pseudomonas aeruginosa for burned rats (3 degrees scald burns, 20% body surface) following topical application of the bacteria to the burn within 1 hour after burning was established. Following this, it was demonstrated that purposeful infection of such 3 degrees scald burns of rats by a strain of Ps. aeruginosa of low virulence (JB-77) protects the rats from the lethal effect of subsequent (48-hour) topical contamination of the burn by a highly virulent strain of Ps. aeruginosa (VA-134) (p less than 0.001). This finding was confirmed in a similar experiment beginning with germfree rats. When the challenge with the highly virulent Ps. aeruginosa strain was 24 hours (rather than 48 hours) after the burning and topical contamination of the burn with the low virulence strain of Ps. aeruginosa, there was little protection (p N.S.). When burned rats were given the low virulence strain of Ps. aeruginosa by gavage right after burning, there was not protection to subsequent (48 hours) challenge by topical application of the highly virulent strain of Ps. aeruginosa to the burn (11/12 vs 12/12 dying). Our finding that purposeful infection of a 3 degrees burn of rats (conventional and also germfree) by a strain of Ps. aeruginosa of low virulence protects from the lethal effect of subsequent (48-hour) topical contamination of the burn by a highly virulent strain of Ps. aeruginosa is due, we believe, to direct bacterial interference between the two strains of pseudomonas. PMID:6785444

  17. The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury.

    PubMed

    Stevens, Trevor C; Ochoa, Cristhiaan D; Morrow, K Adam; Robson, Matthew J; Prasain, Nutan; Zhou, Chun; Alvarez, Diego F; Frank, Dara W; Balczon, Ron; Stevens, Troy

    2014-05-15

    Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103ΔexoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (ΔPcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ΔPcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury. PMID:24705722

  18. Inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients: challenges to treatment adherence and strategies to improve outcomes

    PubMed Central

    Bodnár, Réka; Mészáros, Ágnes; Oláh, Máté; Ágh, Tamás

    2016-01-01

    Background Inhaled antibiotics (ABs) are recommended for use in the therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). The aim of this systematic literature review was to identify level of adherence to inhaled ABs and to determine predictors and consequences of nonadherence in CF. Methods A systematic literature search of English-language articles was conducted in April 2015 using Medline and Embase. No publication date limit was applied. The literature screening was conducted by two independent reviewers. All of the included studies were assessed for quality. Results The search yielded 193 publications, of which ten met the inclusion criteria and underwent data extraction. Seven studies focused on inhaled tobramycin, one on inhaled colistimethate, one on inhaled levofloxacin, and one on inhaled aztreonam lysine. Medication adherence to inhaled ABs was analyzed by pharmacy refill history, daily phone diary, parent and child self-reports, vials counting, or electronic monitoring. In randomized controlled trials (n=3), proportion of adherent patients (>75%–80% of required doses taken) ranged from 86% to 97%; in prospective cohort studies (n=3), adherence rates ranged between 36% and 92%, and in retrospective studies (n=4) it ranged between 60% and 70%. The adherence to inhaled ABs in CF was found to be associated with the complexity of treatment, time of drug administration, age of patients, treatment burden (adverse events, taste), and patient satisfaction. Conclusion The high diversity of adherence data was because of the different study designs (randomized controlled trials vs real-world studies) and the lack of a commonly accepted consensus on the definition of adherence in the reviewed articles. Routine adherence monitoring during CF care, discussing the possible reasons of suboptimal adherence with the patient, and changing treatment regimens on the basis of patient burden can individualize CF therapy for patients and

  19. Therapeutic expansion of CD4+FoxP3+ regulatory T cells limits allergic airway inflammation during pulmonary fungal infection.

    PubMed

    Schulze, Bianca; Piehler, Daniel; Eschke, Maria; Heyen, Laura; Protschka, Martina; Köhler, Gabriele; Alber, Gottfried

    2016-06-01

    Allergic asthma can be frequently caused and exacerbated by sensitization to ubiquitous fungal allergens associated with pulmonary mucus production, airway hyperresponsiveness and bronchial constriction, resulting in a complex disease that is often difficult to treat. Fungal infections are frequently complicated by the development of a type 2 immune response that prevents successful elimination of the fungal pathogen. Furthermore, production of type 2 cytokines triggers allergic airway inflammation. Following intranasal infection of BALB/c mice with the fungusCryptococcus neoformans, we recently described a more pronounced type 2 immune response in the absence of regulatory T (Treg) cells. To determine whether Treg cell expansion is able to suppress type 2-related fungal allergic inflammation, we increased Treg cell numbers during pulmonaryC. neoformansinfection by administration of an interleukin (IL)-2/anti-IL-2 complex. Expansion of Treg cells resulted in reduced immunoglobulin E production and decreased allergic airway inflammation including reduced production of pulmonary mucus and type 2 cytokines as well as production of immunosuppressive cytokines such as IL-10 and transforming growth factor-β1. From our data we conclude that Treg cells and/or their suppressive mediators represent potential targets for therapeutic intervention during allergic fungal airway disease. PMID:27001975

  20. CXCL1 Regulates Pulmonary Host Defense to Klebsiella Infection via CXCL2 , CXCL5, NF-κB and MAPKs

    PubMed Central

    Cai, Shanshan; Batra, Sanjay; Lira, Sergio A.; Kolls, Jay K.; Jeyaseelan, Samithamby

    2010-01-01

    Pulmonary bacterial infections are a leading cause of death. Since the introduction of antibiotics, multidrug-resistant Klebsiella pneumoniae (Kp) became an escalating threat. Therefore, development of methods to augment antibacterial defense is warranted. Neutrophil recruitment is critical to clear bacteria and neutrophil migration in the lung requires the production of ELR+ CXC chemokines. Although lung specific CXCL1/KC transgene expression causes neutrophil-mediated clearance of Kp, the mechanisms underlying KC-mediated host defense against Kp have not been explored. Here we delineated the host defense functions of KC during pulmonary Kp infection using KC-/- mice. Our findings demonstrate that KC is important for expression of CXCL2/MIP-2 and CXCL5/LIX and activation of NF-κB, and MAPKs in the lung. Furthermore, KC-derived from both hematopoietic and resident cells contributes to host defense against Kp. Neutrophil depletion in mice prior to Kp infection reveals no differences in the production of MIP-2 and LIX or activation of NF-κB and MAPKs in the lung. Using murine bone marrow-derived (BMMs) and alveolar macrophages, we confirmed KC-mediated upregulation of MIP-2 and activation of NF-κB and MAPKs upon Kp infection. Moreover, neutralizing KC in BMMs prior to Kp challenge decreases bacteria-induced production of KC, MIP-2 and activation of NF-κB and MAPKs. These findings reveal the importance of KC produced by hematopoietic and resident cells in regulating pulmonary host defense against a bacterial pathogen via the activation of transcription factors and MAPKs as well as the expression of cell adhesion molecules and other neutrophil chemoattractants. PMID:20937845

  1. Co-endemicity of Pulmonary Tuberculosis and Intestinal Helminth Infection in the People's Republic of China.

    PubMed

    Li, Xin-Xu; Ren, Zhou-Peng; Wang, Li-Xia; Zhang, Hui; Jiang, Shi-Wen; Chen, Jia-Xu; Wang, Jin-Feng; Zhou, Xiao-Nong

    2016-03-01

    Both pulmonary tuberculosis (PTB) and intestinal helminth infection (IHI) affect millions of individuals every year in China. However, the national-scale estimation of prevalence predictors and prevalence maps for these diseases, as well as co-endemic relative risk (RR) maps of both diseases' prevalence are not well developed. There are co-endemic, high prevalence areas of both diseases, whose delimitation is essential for devising effective control strategies. Bayesian geostatistical logistic regression models including socio-economic, climatic, geographical and environmental predictors were fitted separately for active PTB and IHI based on data from the national surveys for PTB and major human parasitic diseases that were completed in 2010 and 2004, respectively. Prevalence maps and co-endemic RR maps were constructed for both diseases by means of Bayesian Kriging model and Bayesian shared component model capable of appraising the fraction of variance of spatial RRs shared by both diseases, and those specific for each one, under an assumption that there are unobserved covariates common to both diseases. Our results indicate that gross domestic product (GDP) per capita had a negative association, while rural regions, the arid and polar zones and elevation had positive association with active PTB prevalence; for the IHI prevalence, GDP per capita and distance to water bodies had a negative association, the equatorial and warm zones and the normalized difference vegetation index had a positive association. Moderate to high prevalence of active PTB and low prevalence of IHI were predicted in western regions, low to moderate prevalence of active PTB and low prevalence of IHI were predicted in north-central regions and the southeast coastal regions, and moderate to high prevalence of active PTB and high prevalence of IHI were predicted in the south-western regions. Thus, co-endemic areas of active PTB and IHI were located in the south-western regions of China, which

  2. Characterization of human antibody responses to four corners hantavirus infections among patients with hantavirus pulmonary syndrome.

    PubMed Central

    Jenison, S; Yamada, T; Morris, C; Anderson, B; Torrez-Martinez, N; Keller, N; Hjelle, B

    1994-01-01

    Hantavirus pulmonary syndrome (HPS) is a human disease caused by a newly identified hantavirus, which we will refer to as Four Corners virus (FCV). FCV is related most closely to Puumala virus (PUU) and to Prospect Hill virus (PHV). Twenty-five acute HPS serum samples were tested for immunoglobulin G (IgG) and IgM antibody reactivities to FCV-encoded recombinant proteins in Western blot (immunoblot) assays. All HPS serum samples contained both IgG and IgM antibodies to the FCV nucleocapsid (N) protein. FCV N antibodies cross-reacted with PUU N and PHV N proteins. A dominant FCV N epitope was mapped to the segment between amino acids 17 and 59 (QLVTARQKLKDAERAVELDPDDVNKSTLQSRRAAVSALETKLG). All HPS serum samples contained IgG antibodies to the FCV glycoprotein-1 (G1) protein, and 21 of 25 serum samples contained FCV G1 IgM antibodies. The FCV G1 antibodies did not cross-react with PUU G1 and PHV G1 proteins. The FCV G1 type-specific antibody reactivity mapped to a segment between amino acids 59 and 89 (LKIESSCNFDLHVPATTTQKYNQVDWTKKSS). One hundred twenty-eight control serum samples were tested for IgG reactivities to the FCV N and G1 proteins. Nine (7.0%) contained FCV N reactivities, 3 (2.3%) contained FCV G1 reactivities, and one (0.8%) contained both FCV N and FCV G1 reactivities. The epitopes recognized by antibodies present in control serum samples were different from the epitopes recognized by HPS antibodies, suggesting that the control antibody reactivities were unrelated to FCV infections. These reagents constitute a type-specific assay for FCV antibodies. Images PMID:7512156

  3. Innate and adaptive cellular phenotypes contributing to pulmonary disease in mice after respiratory syncytial virus immunization and infection.

    PubMed

    Lee, Young-Tae; Kim, Ki-Hye; Hwang, Hye Suk; Lee, Youri; Kwon, Young-Man; Ko, Eun-Ju; Jung, Yu-Jin; Lee, Yu-Na; Kim, Min-Chul; Kang, Sang-Moo

    2015-11-01

    Respiratory syncytial virus (RSV) is the major leading cause of infantile viral bronchiolitis. However, cellular phenotypes contributing to the RSV protection and vaccine-enhanced disease remain largely unknown. Upon RSV challenge, we analyzed phenotypes and cellularity in the lung of mice that were naïve, immunized with formalin inactivated RSV (FI-RSV), or re-infected with RSV. In comparison with naïve and live RSV re-infected mice, the high levels of eosinophils, neutrophils, plasmacytoid and CD11b(+) dendritic cells, and IL-4(+) CD4(+) T cells were found to be contributing to pulmonary inflammation in FI-RSV immune mice despite lung viral clearance. Alveolar macrophages appeared to play differential roles in protection and inflammation upon RSV infection of different RSV immune mice. These results suggest that multiple innate and adaptive immune components differentially contribute to RSV disease and inflammation. PMID:26196232

  4. Health-related quality of life, comorbidities and mortality in pulmonary nontuberculous mycobacterial infections: A systematic review.

    PubMed

    Yeung, Man Wah; Khoo, Edwin; Brode, Sarah K; Jamieson, Frances B; Kamiya, Hiroyuki; Kwong, Jeffrey C; Macdonald, Liane; Marras, Theodore K; Morimoto, Kozo; Sander, Beate

    2016-08-01

    Nontuberculous mycobacterial (NTM) infections are increasing in disease frequency worldwide. This systematic review examines health-related quality of life (HRQOL), comorbidities and mortality associated with pulmonary NTM disease. We searched MEDLINE, EMBASE, CINAHL, Scopus Life Sciences, conference proceedings and Google (earliest date available to February 2015) for primary studies. Eligible studies compared populations with and without pulmonary NTM disease in high-income jurisdictions. We excluded studies on HIV/AIDS. All languages were accepted. Two reviewers followed MOOSE and PRISMA reporting guidelines and independently appraised quality using STROBE. All studies were summarized qualitatively regardless of quality. Of 3193 citations screened, we included 17 studies mostly from Taiwan (n = 5) and the USA (n = 4). Two studies assessed HRQOL; one assessed comorbidities, 11 assessed mortality, and three assessed multiple outcomes. Populations with pulmonary NTM reported significantly worse or similar HRQOL than the general population, depending on the instruments used. Some suggested greater prevalence of having bronchiectasis (n = 2) and greater risk of developing pulmonary tuberculosis (n = 1). Most (n = 7) suggested no difference in mortality, although only one was age-matched and gender-matched to the general population. Four suggested NTM populations had higher mortality-two of which compared with the general population and were deemed of high quality, while two compared with non-NTM patients from hospital. High clinical heterogeneity in study design may explain discordant results. Bias assessments and controlling for confounding were carried out poorly. No consistent trends were observed although there is suggestion of an increased health burden from respiratory diseases and increased mortality associated with pulmonary NTM disease. PMID:27009804

  5. Infection in cystic fibrosis: impact of the environment and climate.

    PubMed

    Ramsay, K A; Stockwell, R E; Bell, S C; Kidd, T J

    2016-01-01

    In many countries numbers of adults with cystic fibrosis (CF) exceed that of children, with median survival predicted to surpass 50 years. Increasing longevity is, in part, due to intensive therapies including eradication of early infection and suppressive therapies and pulmonary exacerbations. Initial infections with common CF pathogens are thought to arise from the natural environment. We review the impact of climate and environment on infection in CF. Specifically, several studies indicate that higher ambient temperatures, proximity to the equator and the summer season may be linked to the increased prevalence of Pseudomonas aeruginosa in people with CF. The environment may also play an important role in the acquisition of Gram negative organisms other than P. aeruginosa. There is emerging data suggesting that climatic and environmental factors are likely to impact on the risk of infection with NTM and fungi in people which are found extensively throughout the natural environment. PMID:26949990

  6. Pseudomonas aeruginosa Acquisition in Cystic Fibrosis Patients in Context of Otorhinolaryngological Surgery or Dentist Attendance: Case Series and Discussion of Preventive Concepts.

    PubMed

    Mainz, Jochen G; Gerber, Andrea; Lorenz, Michael; Michl, Ruth; Hentschel, Julia; Nader, Anika; Beck, James F; Pletz, Mathias W; Mueller, Andreas H

    2015-01-01

    Introduction. P. aeruginosa is the primary cause for pulmonary destruction and premature death in cystic fibrosis (CF). Therefore, prevention of airway colonization with the pathogen, ubiquitously present in water, is essential. Infection of CF patients with P. aeruginosa after dentist treatment was proven and dental unit waterlines were identified as source, suggesting prophylactic measures. For their almost regular sinonasal involvement, CF patients often require otorhinolaryngological (ORL) attendance. Despite some fields around ORL-procedures with comparable risk for acquisition of P. aeruginosa, such CF cases have not yet been reported. We present four CF patients, who primarily acquired P. aeruginosa around ORL surgery, and one around dentist treatment. Additionally, we discuss risks and preventive strategies for CF patients undergoing ORL-treatment. Perils include contact to pathogen-carriers in waiting rooms, instrumentation, suction, drilling, and flushing fluid, when droplets containing pathogens can be nebulized. Postsurgery mucosal damage and debridement impair sinonasal mucociliary clearance, facilitating pathogen proliferation and infestation. Therefore, sinonasal surgery and dentist treatment of CF patients without chronic P. aeruginosa colonization must be linked to repeated microbiological assessment. Further studies must elaborate whether all CF patients undergoing ORL-surgery require antipseudomonal prophylaxis, including nasal lavages containing antibiotics. Altogether, this underestimated risk requires structured prevention protocols. PMID:25866686

  7. Pseudomonas aeruginosa Acquisition in Cystic Fibrosis Patients in Context of Otorhinolaryngological Surgery or Dentist Attendance: Case Series and Discussion of Preventive Concepts

    PubMed Central

    Mainz, Jochen G.; Gerber, Andrea; Lorenz, Michael; Michl, Ruth; Hentschel, Julia; Nader, Anika; Beck, James F.; Pletz, Mathias W.; Mueller, Andreas H.

    2015-01-01

    Introduction. P. aeruginosa is the primary cause for pulmonary destruction and premature death in cystic fibrosis (CF). Therefore, prevention of airway colonization with the pathogen, ubiquitously present in water, is essential. Infection of CF patients with P. aeruginosa after dentist treatment was proven and dental unit waterlines were identified as source, suggesting prophylactic measures. For their almost regular sinonasal involvement, CF patients often require otorhinolaryngological (ORL) attendance. Despite some fields around ORL-procedures with comparable risk for acquisition of P. aeruginosa, such CF cases have not yet been reported. We present four CF patients, who primarily acquired P. aeruginosa around ORL surgery, and one around dentist treatment. Additionally, we discuss risks and preventive strategies for CF patients undergoing ORL-treatment. Perils include contact to pathogen-carriers in waiting rooms, instrumentation, suction, drilling, and flushing fluid, when droplets containing pathogens can be nebulized. Postsurgery mucosal damage and debridement impair sinonasal mucociliary clearance, facilitating pathogen proliferation and infestation. Therefore, sinonasal surgery and dentist treatment of CF patients without chronic P. aeruginosa colonization must be linked to repeated microbiological assessment. Further studies must elaborate whether all CF patients undergoing ORL-surgery require antipseudomonal prophylaxis, including nasal lavages containing antibiotics. Altogether, this underestimated risk requires structured prevention protocols. PMID:25866686

  8. Regulatory aspects of Phase 3 endpoints for new inhaled antibiotics for cystic fibrosis patients with chronic Pseudomonas aeruginosa infections.

    PubMed

    Montgomery, Alan Bruce; Abuan, Tammy; Yeager, Melissa A

    2012-08-01

    Available regulatory guidelines for developing inhaled anti-infective therapies offer general advice, but specific guidance often provides conflicting and outdated advice in regard to clinical trial design. For instance, the availability of two approved drugs makes the conduct of placebo-controlled trials longer than 28 days problematic. Comparator drugs require use per the product label, making comparator trials difficult to blind as taste, foaming, regimen, device, and delivery time differences are present. Currently, there is no consensus on the most appropriate endpoints for evaluation of aerosolized antimicrobials. FEV(1) is a surrogate endpoint that it is a predictor of mortality--it is standardized, reproducible, noninvasive, simple, and inexpensive to perform but small statistically significant changes may not be clinically important. FEV(1) improvement also has a ceiling effect in patients with mild lung function impairment and spirometry cannot be reliably done in patients under the age of 6 years. A patient-reported outcome is a promising clinical endpoint. However, there is not currently an accepted tool that can be used as a primary endpoint for the FDA or the EMA, although the latter recognizes the CFQ-R as a validated secondary endpoint and the FDA grandfathered acceptance of the CFQ-R respiratory domain in the pivotal aztreonam for inhalation study. Exacerbations are an important clinical endpoint that reflects morbidity and are a major driver of cost of care, but they occur infrequently and a standardized definition has not been reached. Furthermore, an exacerbation endpoint may fail even with an otherwise effective antibiotic therapy. Regulatory authorities will have a difficult time approving any new inhaled antibiotic based on one clinical endpoint alone. PMID:22857271

  9. Candida albicans Airway Exposure Primes the Lung Innate Immune Response against Pseudomonas aeruginosa Infection through Innate Lymphoid Cell Recruitment and Interleukin-22-Associated Mucosal Response

    PubMed Central

    Mear, Jean Baptiste; Gosset, Philippe; Kipnis, Eric; Faure, Emmanuel; Dessein, Rodrigue; Jawhara, Samir; Fradin, Chantal; Faure, Karine; Poulain, Daniel; Sendid, Boualem

    2014-01-01

    Pseudomonas aeruginosa and Candida albicans are two pathogens frequently encountered in the intensive care unit microbial community. We have demonstrated that C. albicans airway exposure protected against P. aeruginosa-induced lung injury. The goal of the present study was to characterize the cellular and molecular mechanisms associated with C. albicans-induced protection. Airway exposure by C. albicans led to the recruitment and activation of natural killer cells, innate lymphoid cells (ILCs), macrophages, and dendritic cells. This recruitment was associated with the secretion of interleukin-22 (IL-22), whose neutralization abolished C. albicans-induced protection. We identified, by flow cytometry, ILCs as the only cellular source of IL-22. Depletion of ILCs by anti-CD90.2 antibodies was associated with a decreased IL-22 secretion and impaired survival after P. aeruginosa challenge. Our results demonstrate that the production of IL-22, mainly by ILCs, is a major and inducible step in protection against P. aeruginosa-induced lung injury. This cytokine may represent a clinical target in Pseudomonas aeruginosa-induced lung injury. PMID:24166952

  10. Efficacy of an unsupervised 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis in HIV-infected adults

    PubMed Central

    Johnson, J. L.; Okwera, A.; Nsubuga, P.; Nakibali, J. G.; Whalen, C. C.; Hom, D.; Cave, M. D.; Yang, Z. H.; Mugerwa, R. D.; Ellner, J. J.

    2010-01-01

    SUMMARY SETTING National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. OBJECTIVE To assess the efficacy of a daily, self-administered 8-month rifampicin-containing regimen for the treatment of pulmonary tuberculosis (TB) in human immunodeficiency virus (HIV) infected adults. DESIGN Treatment outcomes in patients with pulmonary TB treated with a single 8-month regimen and followed in a prospective epidemiological study. RESULTS Two hundred and sixty-five HIV-infected and 26 non-HIV-infected adults with initial episodes of pulmonary tuberculosis were treated with 2 months of daily isoniazid (INH), rifampicin (RMP), ethambutol and pyrazinamide followed by 6 months of daily INH + RMP. Median follow-up was 17.8 months. Ninety-five per cent of the HIV-infected and all of the non-HIV-infected patients who had sputum examined were sputum culture negative after 2 months of treatment. Twenty-two HIV-infected and no non-HIV-infected patients died during treatment. Relapse rates were 8.4% (5.9 per 100 person-years of observation [PYO], 95%CI 3.2–8.6) among HIV-infected patients and 4.5% (2.1/100 PYO, 95%CI 0–7.8) for non-HIV-infected patients. Adverse drug reactions occurred in 37% of the HIV-infected patients; most were minor and self-limiting. CONCLUSION An 8-month RMP-containing regimen was well tolerated and effective in the treatment of HIV-infected adults with initial episodes of pulmonary TB. Relapse rates were similar to those reported with 6-month short-course regimens in HIV-infected individuals. Decisions about the duration of anti-tuberculosis treatment for HIV-infected adults must balance programme resources and the likelihood of poor compliance with longer regimens with the potential for a modest decrease in relapses with longer treatment. PMID:11092715

  11. A Pseudomonas aeruginosa EF-Hand Protein, EfhP (PA4107), Modulates Stress Responses and Virulence at High Calcium Concentration

    PubMed Central

    Sarkisova, Svetlana A.; Lotlikar, Shalaka R.; Guragain, Manita; Kubat, Ryan; Cloud, John

    2014-01-01

    Pseudomonas aeruginosa is a facultative human pathogen, and a major cause of nosocomial infections and severe chronic infections in endocarditis and in cystic fibrosis (CF) patients. Calcium (Ca2+) accumulates in pulmonary fluids of CF patients, and plays a role in the hyperinflamatory response to bacterial infection. Earlier we showed that P. aeruginosa responds to increased Ca2+ levels, primarily through the increased production of secreted virulence factors. Here we describe the role of putative Ca2+-binding protein, with an EF-hand domain, PA4107 (EfhP), in this response. Deletion mutations of efhP were generated in P. aeruginosa strain PAO1 and CF pulmonary isolate, strain FRD1. The lack of EfhP abolished the ability of P. aeruginosa PAO1 to maintain intracellular Ca2+ homeostasis. Quantitative high-resolution 2D-PAGE showed that the efhP deletion also affected the proteomes of both strains during growth with added Ca2+. The greatest proteome effects occurred when the pulmonary isolate was cultured in biofilms. Among the proteins that were significantly less abundant or absent in the mutant strains were proteins involved in iron acquisition, biosynthesis of pyocyanin, proteases, and stress response proteins. In support, the phenotypic responses of FRD1 ΔefhP showed that the mutant strain lost its ability to produce pyocyanin, developed less biofilm, and had decreased resistance to oxidative stress (H2O2) when cultured at high [Ca2+]. Furthermore, the mutant strain was unable to produce alginate when grown at high [Ca2+] and no iron. The effect of the ΔefhP mutations on virulence was determined in a lettuce model of infection. Growth of wild-type P. aeruginosa strains at high [Ca2+] causes an increased area of disease. In contrast, the lack of efhP prevented this Ca2+-induced increase in the diseased zone. The results indicate that EfhP is important for Ca2+ homeostasis and virulence of P. aeruginosa when it encounters host environments with high [Ca2+]. PMID

  12. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  13. Development of potent inhibitors of pyocyanin production in Pseudomonas aeruginosa

    PubMed Central

    Miller, Laura C.; O’Loughlin, Colleen T.; Zhang, Zinan; Siryaporn, Albert; Silpe, Justin E.; Bassler, Bonnie L.; Semmelhack, Martin F.

    2015-01-01

    The development of new approaches for the treatment of antimicrobial-resistant infections is an urgent public health priority. The Pseudomonas aeruginosa pathogen, in particular, is a leading source of infection in hospital settings, with few available treatment options. In the context of an effort to develop antivirulence strategies to combat bacterial infection, we identified a series of highly effective small molecules that inhibit the production of pyocyanin, a redox-active virulence factor produced by P. aeruginosa. Interestingly, these new antagonists appear to suppress P. aeruginosa virulence factor production through a pathway that is independent of LasR and RhlR. PMID:25597392

  14. Pulmonary Function in HIV-Infected Recreational Drug Users in the Era of Anti-Retroviral Therapy

    PubMed Central

    Simonetti, Joseph A; Gingo, Matthew R; Kingsley, Lawrence; Kessinger, Cathy; Lucht, Lorrie; Balasubramani, GK; Leader, Joseph K; Huang, Laurence; Greenblatt, Ruth M; Dermand, John; Kleerup, Eric C; Morris, Alison

    2015-01-01

    Background Individuals with HIV infection commonly have pulmonary function abnormalities, including airflow obstruction and diffusion impairment, which may be more prevalent among recreational drug users. To date, the relationship between drug use and pulmonary function abnormalities among those with HIV remains unclear. Objective To determine associations between recreational drug use and airflow obstruction, diffusion impairment, and radiographic emphysema in men and women with HIV. Methods Cross-sectional analysis of pulmonary function and self-reported recreational drug use data from a cohort of 121 men and 63 women with HIV. Primary outcomes were the presence (yes/no) of: 1) airflow obstruction, (pre- or post-bronchodilator forced expiratory volume in 1 second/forced vital capacity<0.70); 2) moderate diffusion impairment (diffusing capacity for carbon monoxide <60% predicted); and 3) radiographic emphysema (>1% of lung voxels <−950 Hounsfield units). Exposures of interest were frequency of recreational drug use, recent (since last study visit) drug use, and any lifetime drug use. We used logistic regression to determine associations between recreational drug use and the primary outcomes. Results HIV-infected men and women reported recent recreational drug use at 56.0% and 31.0% of their study visits, respectively, and 48.8% of men and 39.7% of women reported drug use since their last study visit. Drug use was not associated with airway obstruction or radiographic emphysema in men or women. Recent crack cocaine use was independently associated with moderate diffusion impairment in women (odds ratio 17.6; 95% confidence interval 1.3–249.6, p=0.03). Conclusions In this cross-sectional analysis, we found that recreational drug use was common among HIV-infected men and women and recent crack cocaine use was associated with moderate diffusion impairment in women. Given the increasing prevalence of HIV infection, any relationship between drug use and prevalence

  15. Is There any Relationship Between Extra-Pulmonary Manifestations of Mycoplasma Pneumoniae Infection and Atopy/Respiratory Allergy in Children?

    PubMed Central

    Poddighe, Dimitri; Marseglia, Gian Luigi

    2016-01-01

    Mycoplasma pneumoniae is a common cause of respiratory infections in children, but sometimes extra-pulmonary diseases can be observed. The immunological mechanisms involved in these extra-respiratory complications are unknown. Here, we report a small case series of Mycoplasma-related diseases including 5 children who developed: i) aseptic meningitis; ii) urticarial rash and pericardial effusion; iii) pleural effusion with severe eosinophilia; iv) Stevens-Johnson syndrome; v) multiform erythema. Interestingly, all children were moderately to highly atopic, as a common immunologic feature. PMID:27114818

  16. In vivo short-term exposure to residual oil fly ash impairs pulmonary innate immune response against environmental mycobacterium infection.

    PubMed

    Delfosse, Verónica C; Tasat, Deborah R; Gioffré, Andrea K

    2015-05-01

    Epidemiological studies have shown that pollution derived from industrial and vehicular transportation induces adverse health effects causing broad ambient respiratory diseases. Therefore, air pollution should be taken into account when microbial diseases are evaluated. Environmental mycobacteria (EM) are opportunist pathogens that can affect a variety of immune compromised patients, which impacts significantly on human morbidity and mortality. The aim of this study was to evaluate the effect of residual oil fly ash (ROFA) pre-exposure on the pulmonary response after challenge with opportunistic mycobacteria by means of an acute short-term in vivo experimental animal model. We exposed BALB/c mice to ROFA and observed a significant reduction on bacterial clearance at 24 h post infection. To study the basis of this impaired response four groups of animals were instilled with (a) saline solution (Control), (b) ROFA (1 mg kg(-1) BW), (c) ROFA and EM-infected (Mycobacterium phlei, 8 × 10(6) CFU), and (d) EM-infected. Animals were sacrificed 24 h postinfection and biomarkers of lung injury and proinflammatory madiators were examined in the bronchoalveolar lavage. Our results indicate that ROFA was able to produce an acute pulmonary injury characterized by an increase in bronchoalveolar polymorphonuclear (PMN) cells influx and a rise in O2 (-) generation. Exposure to ROFA before M. phlei infection reduced total cell number and caused a significant decline in PMN cells recruitment (p < 0.05), O2 (-) generation, TNFα (p < 0.001), and IL-6 (p < 0.001) levels. Hence, our results suggest that, in this animal model, the acute short-term pre-exposure to ROFA reduces early lung response to EM infection. PMID:25915594

  17. Hantavirus Pulmonary Syndrome (HPS)

    MedlinePlus

    ... this page: About CDC.gov . Hantavirus Share Compartir Hantavirus Pulmonary Syndrome (HPS) Severe HPS. Image courtesy D. ... the workers showed evidence of infection or illness. Hantavirus Pulmonary Syndrome (HPS) Topics Transmission Where HPS is ...

  18. Pulmonary infection caused by Talaromyces purpurogenus in a patient with multiple myeloma.

    PubMed

    Atalay, Altay; Koc, Ayse Nedret; Akyol, Gulsah; Cakir, Nuri; Kaynar, Leylagul; Ulu-Kilic, Aysegul

    2016-06-01

    A 66-year-old female patient with multiple myeloma (MM) was admitted to the emergency service on 29.09.2014 with an inability to walk, and urinary and faecal incontinence. She had previously undergone autologous bone marrow transplantation (ABMT) twice. The patient was hospitalized at the Department of Haematology. Further investigations showed findings suggestive of a spinal mass at the T5-T6-T7 level, and a mass lesion in the iliac fossa. The mass lesion was resected and needle biopsy was performed during a colonoscopy. Examination of the specimens revealed plasmacytoma. The patient also had chronic obstructive pulmonary disease (COPD) and was suffering from respiratory distress. After consultation with an infectious diseases specialist the patient was placed on an intravenous antibiotherapy with piperacillin/tazobactam (4.5g x 3) on 17.10.2014. During piperacillin/tazobactam treatment, the patient suffered from drowsiness, her general condition deteriorated, and she had rales on auscultation of the lungs. The patient underwent thoracic computerized tomography (CT) which showed areas of focal consolidation in the lower lobes of the two lungs (more prominent on the left), and increased medullary density. The radiology report suggested that fungal infection could not be ruled out based on the CT images. The sputum sample was sent to the mycology laboratory and direct microscopic examination performed with Gram and Giemsa staining showed the presence of septate hyphae; therefore voriconazole was added to the treatment. Slow growing (at day 10), grey-greenish colonies and red pigment formation were observed in all culture media except cycloheximide-containing Sabouraud dextrose agar (SDA) medium. The isolate was initially considered to be Talaromyces marneffei. However, it was subsequently identified by DNA sequencing analysis as Talaromyces purpurogenus. The patient was discharged at her own wish, as she was willing to continue treatment in her hometown

  19. Pulmonary fungal infections in patients with acute myeloid leukaemia: is it the time to revise the radiological diagnostic criteria?

    PubMed

    Maccioni, Francesca; Vetere, Simone; De Felice, Carlo; Al Ansari, Najwa; Micozzi, Alessandra; Gentile, Giuseppe; Foà, Robin; Girmenia, Corrado

    2016-06-01

    The definition of pulmonary fungal infections (PFI) according to the EORTC-MSG criteria may lack diagnostic sensitivity due to the possible presentation of PFI with different radiological pictures. We evaluated the hypothesis to apply less restrictive radiological criteria to define PFI in patients with acute myeloid leukaemia (AML) submitted to chemotherapy. Overall, 73 consecutive episodes of pulmonary infiltrates associated to positive serum galactomannan test or fungal isolation or galactomannan detection from respiratory specimens were considered. CT scans acquired at the onset of symptoms (time-0) and within 4 weeks (time-1) were analysed to identify specific (group A) or aspecific radiological signs (group B). Pulmonary infiltrates fulfilled the EORTC-MSG criteria in 49 patients (group A), whereas in 24 patients (group B) they did not reach the criteria due to aspecific CT findings at time-0. Eleven of 21 (52.4%) patients of the group B evaluable for the evolution of the radiological findings fulfilled EORTC-MSG criteria at time-1. All the analysed clinical and mycological characteristics, response to antifungal therapy and survival were comparable in the two groups. Our study seems to confirm the possibility to extend the radiological suspicion of PFI to less restrictive chest CT findings when supported by microbiological criteria in high-risk haematological patients. PMID:26865204

  20. Developing an international Pseudomonas aeruginosa reference panel

    PubMed Central

    De Soyza, Anthony; Hall, Amanda J; Mahenthiralingam, Eshwar; Drevinek, Pavel; Kaca, Wieslaw; Drulis-Kawa, Zuzanna; Stoitsova, Stoyanka R; Toth, Veronika; Coenye, Tom; Zlosnik, James E A; Burns, Jane L; Sá-Correia, Isabel; De Vos, Daniel; Pirnay, Jean-Paul; Kidd, Timothy J; Reid, David; Manos, Jim; Klockgether, Jens; Wiehlmann, Lutz; Tümmler, Burkhard; McClean, Siobhán; Winstanley, Craig

    2013-01-01

    Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis (CF) patients and causes a wide range of infections among other susceptible populations. Its inherent resistance to many antimicrobials also makes it difficult to treat infections with this pathogen. Recent evidence has highlighted the diversity of this species, yet despite this, the majority of studies on virulence and pathogenesis focus on a small number of strains. There is a pressing need for a P. aeruginosa reference panel to harmonize and coordinate the collective efforts of the P. aeruginosa research community. We have collated a panel of 43 P. aeruginosa strains that reflects the organism's diversity. In addition to the commonly studied clones, this panel includes transmissible strains, sequential CF isolates, strains with specific virulence characteristics, and strains that represent serotype, genotype or geographic diversity. This focussed panel of P. aeruginosa isolates will help accelerate and consolidate the discovery of virulence determinants, improve our understanding of the pathogenesis of infections caused by this pathogen, and provide the community with a valuable resource for the testing of novel therapeutic agents. PMID:24214409

  1. Glycerol metabolism promotes biofilm formation by Pseudomonas aeruginosa.

    PubMed

    Scoffield, Jessica; Silo-Suh, Laura

    2016-08-01

    Pseudomonas aeruginosa causes persistent infections in the airways of cystic fibrosis (CF) patients. Airway sputum contains various host-derived nutrients that can be utilized by P. aeruginosa, including phosphotidylcholine, a major component of host cell membranes. Phosphotidylcholine can be degraded by P. aeruginosa to glycerol and fatty acids to increase the availability of glycerol in the CF lung. In this study, we explored the role that glycerol metabolism plays in biofilm formation by P. aeruginosa. We report that glycerol metabolism promotes biofilm formation by both a chronic CF isolate (FRD1) and a wound isolate (PAO1) of P. aeruginosa. Moreover, loss of the GlpR regulator, which represses the expression of genes involved in glycerol metabolism, enhances biofilm formation in FRD1 through the upregulation of Pel polysaccharide. Taken together, our results suggest that glycerol metabolism may be a key factor that contributes to P. aeruginosa persistence by promoting biofilm formation. PMID:27392247

  2. Associated factors for treatment delay in pulmonary tuberculosis in HIV-infected individuals: a nested case-control study

    PubMed Central

    2012-01-01

    Background The delay in initiating treatment for tuberculosis (TB) in HIV-infected individuals may lead to the development of a more severe form of the disease, with higher rates of morbidity, mortality and transmissibility. The aim of the present study was to estimate the time interval between the onset of symptoms and initiating treatment for TB in HIV-infected individuals, and to identify the factors associated to this delay. Methods A nested case-control study was undertaken within a cohort of HIV-infected individuals, attended at two HIV referral centers, in the state of Pernambuco, Brazil. Delay in initiating treatment for TB was defined as the period of time, in days, which was greater than the median value between the onset of cough and initiating treatment for TB. The study analyzed biological, clinical, socioeconomic, and lifestyle factors as well as those related to HIV and TB infection, potentially associated to delay. The odds ratios were estimated with the respective confidence intervals and p-values. Results From a cohort of 2365 HIV-infected adults, 274 presented pulmonary TB and of these, 242 participated in the study. Patients were already attending 2 health services at the time they developed a cough (period range: 1 – 552 days), with a median value of 41 days. Factors associated to delay were: systemic symptoms asthenia, chest pain, use of illicit drugs and sputum smear-negative. Conclusion The present study indirectly showed the difficulty of diagnosing TB in HIV-infected individuals and indicated the need for a better assessment of asthenia and chest pain as factors that may be present in co-infected patients. It is also necessary to discuss the role played by negative sputum smear results in diagnosing TB/HIV co-infection as well as the need to assess the best approach for drug users with TB/HIV. PMID:22958583

  3. Label-free quantitative phosphoproteomic analysis reveals differentially regulated proteins and pathway in PRRSV-infected pulmonary alveolar macrophages.

    PubMed

    Luo, Rui; Fang, Liurong; Jin, Hui; Wang, Dang; An, Kang; Xu, Ningzhi; Chen, Huanchun; Xiao, Shaobo

    2014-03-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen of swine worldwide and causes significant economic losses. Through regulating the host proteins phosphorylation, PRRSV was found to manipulate the activities of several signaling molecules to regulate innate immune responses. However, the role of protein phosphorylation during PRRSV infection and the signal pathways responsible for it are relatively unknown. Here liquid chromatography-tandem mass spectrometry for label-free quantitative phosphoproteomics was applied to systematically investigate the global phosphorylation events in PRRSV-infected pulmonary alveolar macrophages. In total, we identified 2125 unique phosphosites, of which the phosphorylation level of 292 phosphosites on 242 proteins and 373 phosphosites on 249 proteins was significantly altered at 12 and 36 h pi, respectively. The phosphoproteomics data were analyzed using ingenuity pathways analysis to identify defined canonical pathways and functional networks. Pathway analysis revealed that PRRSV-induced inflammatory cytokines production was probably due to the activation of mitogen-activated protein kinase and NF-κB signal pathway, which were regulated by several protein kinases during virus infection. Interacting network analysis indicated that altered phosphoproteins were involved in cellular assembly and organization, protein synthesis, molecular transport, and signal transduction in PRRSV infected cells. These pathways and functional networks analysis could provide direct insights into the biological significance of phosphorylation events modulated by PRRSV and may help us elucidate the pathogenic mechanisms of PRRSV infection. PMID:24533505

  4. The Prevalence of Latent Tuberculosis Infection and Smear Positive Pulmonary Tuberculosis in People with Household Close Contact with Tuberculosis in North of Iran

    PubMed Central

    Moosazadeh, Mahmood; Khanjani, Narges; Parsaee, Mohammadreza

    2015-01-01

    One of the recommended strategies for preventing tuberculosis is to screen high-risk populations with respect to Mycobacterium tuberculosis (TB) infection. The aim of the present study was to investigate latent infection and active tuberculosis in people with close household contact. It was a cross-sectional descriptive, analytical study with the sample size of 668 people from homes with one infected resident. In order to diagnose tuberculosis latent infection, the PPD test was done. To determine patients with smear-positive pulmonary tuberculosis, three sputum samples were taken from every patient and were examined using direct microscopy and culture. Data was analyzed by SPSS20 software. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis were 42.8% and 0.9% respectively. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis in people with close household contact were less than that of other studies. However, smear-positive pulmonary tuberculosis in people with close household contact was 199.5 times more than that of the general population. PMID:25821296

  5. [A CASE OF PULMONARY MYCOBACTERIUM ABSCESSUS INFECTION THAT DEVELOPED DURING IMMUNOSUPPRESSIVE THERAPY FOR MYASTHENIA GRAVIS WITH RECURRENT THYMOMA].

    PubMed

    Matsuse, Hiroto; Oshio, Takeshi; Kishimoto, Kumiko; Nakayama, Haruo

    2016-02-01

    A 58-year-old man developed cough, sputum, and low-grade fever during immunosuppressive treatment with corticosteroids and cyclosporine for myasthenia gravis with recurrent thymoma. Since chest CT revealed diffuse nodular opacities in both lung fields, he was referred to our department. Mycobacterium abscessus was repeatedly cultured from his sputum, and he was diagnosed with pulmonary M. abscessus infection. Although both chest radiological findings and clinical symptoms were mild, he required treatment with immunosuppressive agents and systemic anesthesia for resection of the recurrent thymoma. Based on complications and according to the patient's preference, oral treatment with clarithromycin 600 mg/day, levofloxacin 500 mg/day, and faropenem 600 mg/day was initiated on an outpatient basis. Following these treatments, his chest CT findings and clinical symptoms subsided, and the thymoma was successfully resected. Our experience with the present case suggests a possible treatment strategy for M. abscessus infection in immunocompromised and complicated cases. PMID:27263226

  6. Two- and live/real time three-dimensional transthoracic echocardiographic assessment of infective endocarditis of a valved pulmonary conduit.

    PubMed

    Gulotta, John C; Gaba, Saurabh; Bulur, Serkan; Joson, Marisa; Sungur, Aylin; Nanda, Navin C

    2015-02-01

    We describe the use of a nonstandard left infraclavicular approach in making the diagnosis of an infected valved conduit with two-dimensional transthoracic echocardiography. The patient was an adult with tetralogy of Fallot and pulmonary atresia who had undergone multiple surgical repair procedures. The initial diagnosis of infective endocarditis was made by transesophageal echocardiography. Both techniques demonstrated a single, large vegetation in the conduit. Live/real time three-dimensional transthoracic echocardiography, on the other hand, provided further information by demonstrating several additional vegetations in the conduit and more comprehensively assessed their size by enabling measurement of their azimuthal dimensions and volumes. The patient was treated with antibiotics with complete resolution of the vegetations. PMID:25410293

  7. Role of Granulocyte Macrophage Colony-Stimulating Factor in Host Defense Against Pulmonary Cryptococcus neoformans Infection during Murine Allergic Bronchopulmonary Mycosis

    PubMed Central

    Chen, Gwo-Hsiao; Olszewski, Michal A.; McDonald, Roderick A.; Wells, Jason C.; Paine, Robert; Huffnagle, Gary B.; Toews, Galen B.

    2007-01-01

    We investigated the role of granulocyte macrophage colony-stimulating factor (GM-CSF) in host defense in a murine model of pulmonary cryptococcosis induced by intratracheal inoculation of Cryptococcus neoformans. Pulmonary C. neoformans infection of C57BL/6 mice is an established model of an allergic bronchopulmonary mycosis. Our objective was to determine whether GM-CSF regulates the pulmonary Th2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in GM-CSF knockout (GM−/−) mice, resulting in increased pulmonary burden of fungi between weeks 3 and 5. GM-CSF was required for the early influx of macrophages and CD4 and CD8 T cells into the lungs but was not required later in the infection. Lack of GM-CSF also resulted in reduced eosinophil recruitment and delayed recruitment of mononuclear cells into the airspace. Macrophages from GM+/+ mice showed numerous hallmarks of alternatively activated macrophages: higher numbers of intracellular cryptococci, YM1 crystals, and induction of CCL17. These hallmarks are absent in macrophages from GM−/− mice. Mucus-producing goblet cells were abundantly present within the bronchial epithelial layer in GM+/+ mice but not in GM−/− mice at week 5 after infection. Production of both Th1 and Th2 cytokines was impaired in the absence of GM-CSF, consistent with both reduced C. neoformans clearance and absence of allergic lung pathology. PMID:17322386

  8. Evaluation of pulmonary dysfunctions and acid–base imbalances induced by Chlamydia psittaci in a bovine model of respiratory infection

    PubMed Central

    2014-01-01

    Background Chlamydia psittaci (Cp) is a respiratory pathogen capable of inducing acute pulmonary zoonotic disease (psittacosis) or persistent infection. To elucidate the pathogenesis of this infection, a translational large animal model was recently introduced by our group. This study aims at quantifying and differentiating pulmonary dysfunction and acid–base imbalances induced by Cp. Methods Forty-two calves were grouped in (i) animals inoculated with Cp (n = 21) and (ii) controls sham-inoculated with uninfected cell culture (n = 21). For pulmonary function testing, impulse oscillometry, capnography, and FRC (functional residual capacity) measurement were applied to spontaneously breathing animals. Variables of acid–base status were assessed in venous blood using both (i) traditional Henderson-Hasselbalch and (ii) strong ion approach. Results Both obstructive and restrictive pulmonary disorders were induced in calves experimentally inoculated with Cp. Although disorders in respiratory mechanics lasted for 8–11 days, the pattern of spontaneous breathing was mainly altered in the period of acute illness (until 4 days post inoculation, dpi). Expiration was more impaired than inspiration, resulting in elevated FRC. Ventilation was characterised by a reduction in tidal volume (−25%) combined with an increased percentage of dead space volume and a significant reduction of alveolar volume by 10%. Minute ventilation increased significantly (+50%) due to a compensatory doubling of respiratory rate. Hyperventilatory hypocapnia at 2–3 dpi resulted in slightly increased blood pH at 2 dpi. However, the acid–base equilibrium was additionally influenced by metabolic components, i.e. the systemic inflammatory response, all of which were detected with help of the strong ion theory. Decreased concentrations of albumin (2–10 dpi), a negative acute-phase marker, resulted in a decrease in the sum of non-volatile weak acids (Atot), revealing an alkalotic effect

  9. Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System

    PubMed Central

    Price, Katherine E.; Naimie, Amanda A.; Griffin, Edward F.; Bay, Charles

    2015-01-01

    ABSTRACT Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. IMPORTANCE Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions

  10. Infections Acquired via Fresh Water: From Lakes to Hot Tubs.

    PubMed

    Ayi, Bertha

    2015-12-01

    This chapter is unique in its focus on infections that are acquired in water. For those who like to swim and spend time in water parks and pools, the exposure to water and therefore the risk of infection is higher. Recreational water illnesses are illnesses related to recreation in water. Of these recreational water illnesses, infections are the most common because water laden with microorganisms or contaminated by human activity gains access to healthy tissue through the skin and body orifices. Infection occurs by inhalation, ingestion, or direct invasion of the respiratory and gastrointestinal tract. Gastrointestinal infections are the most common. This chapter discusses skin and soft tissue infections, ocular infections, urinary tract infections, pulmonary infections, central nervous system infections, and disseminated infections that can occur as people come into contact with natural nonmarine water bodies as well as manmade aquatic environments. Most of these infections are mild but can occasionally be life threatening. There is a focus on the latest methods to treat these infections. Pseudomonas aeruginosa is a very common pathogen in water. The chapter discusses P. aeruginosa dermatitis at length and also looks at keratitis and pneumonia caused by this organism. The chapter also discusses the latest treatments for primary amoebic meningoencephalitis, a severe life-threatening illness with a high mortality, caused by Naegleria fowleri. Finally, there is an in-depth discussion of the notorious gastrointestinal illnesses such as norovirus and Cryptosporidium parvum that can affect large numbers of people at a time. PMID:27337285

  11. Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails.

    PubMed

    Wlaź, Piotr; Knaga, Sebastian; Kasperek, Kornel; Wlaź, Aleksandra; Poleszak, Ewa; Jeżewska-Witkowska, Grażyna; Winiarczyk, Stanisław; Wyska, Elżbieta; Heinekamp, Thorsten; Rundfeldt, Chris

    2015-08-01

    Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 × 10(6) spores (3 groups) or 5 × 10(7) spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis. PMID:25790942

  12. Prevalence and incidence of pulmonary hypertension among HIV-infected people in Africa: a systematic review and meta-analysis

    PubMed Central

    Bigna, Jean Joel R; Nansseu, Jobert Richie N; Um, Lewis N; Noumegni, Steve Raoul N; Simé, Paule Sandra D; Aminde, Leopold Ndemngue; Koulla-Shiro, Sinata; Noubiap, Jean Jacques N

    2016-01-01

    Objective Patients infected with HIV have a direly increased risk of developing pulmonary hypertension (PH), and of dying from the condition. While Africa carries the greatest burden of HIV infection worldwide, there is unclear data summarising the epidemiology of PH among HIV-infected people in this region. Our objective was to determine the prevalence and incidence of PH among HIV-infected people living across Africa. Design A systematic review and meta-analysis. Participants HIV-infected African people residing in Africa. Outcome Prevalence and incidence of PH diagnosed through echocardiography or right heart catheterisation. Data sources Articles published in PubMed/MEDLINE, EMBASE, African Journals Online and African Index Medicus between 1 January 1980 and 30 June 2016, without any language restriction. Results Overall, 121 studies were screened; 3 were included in this review: 1 from Southern Africa (South Africa), 1 from Eastern Africa (Tanzania) and 1 from Central Africa (Cameroon). These studies included HIV-infected adult patients selected based on presentation with cardiovascular symptoms. No study reported PH incidence or PH incidence/prevalence among children and adolescents. The quality assessment yielded moderate risk of bias. Ages of participants ranged between 18 and 78 years, and the proportion of females varied between 52.3% and 68.8%. The prevalence of PH in the pooled sample of 664 patients was 14% (95% CI 6%–23%). Limitations Only 3 studies were found eligible from 3 regions of the African continent. Conclusions The prevalence of PH among HIV-infected people in Africa seems very high. Further studies are urgently warranted to determine the incidence of HIV-induced PH, which must include all subregions of Africa. Trial registration number Review registration number PROSPERO CRD42016033863. PMID:27554104

  13. IL-17A Promotes Pulmonary B-1a Cell Differentiation via Induction of Blimp-1 Expression during Influenza Virus Infection.

    PubMed

    Wang, Xiaohui; Ma, Kongyang; Chen, Miao; Ko, King-Hung; Zheng, Bo-Jian; Lu, Liwei

    2016-01-01

    B-1 cells play a critical role in early protection during influenza infections by producing natural IgM antibodies. However, the underlying mechanisms involved in regulating this process are largely unknown. Here we found that during influenza infection pleural cavity B-1a cells rapidly infiltrated lungs, where they underwent plasmacytic differentiation with enhanced IgM production. This process was promoted by IL-17A signaling via induction of Blimp-1 expression and NF-κB activation in B-1a cells. Deficiency of IL-17A led to severely impaired B-1a-derived antibody production in the respiratory tract, resulting in a deficiency in viral clearance. Transfer of B-1a-derived natural antibodies rescued Il17a-/- mice from otherwise lethal infections. Together, we identify a critical function of IL-17A in promoting the plasmacytic differentiation of B-1a cells. Our findings provide new insights into the mechanisms underlying the regulation of pulmonary B-1a cell response against influenza infection. PMID:26735852

  14. IL-17A Promotes Pulmonary B-1a Cell Differentiation via Induction of Blimp-1 Expression during Influenza Virus Infection

    PubMed Central

    Wang, Xiaohui; Ma, Kongyang; Chen, Miao; Ko, King-Hung; Zheng, Bo-Jian; Lu, Liwei

    2016-01-01

    B-1 cells play a critical role in early protection during influenza infections by producing natural IgM antibodies. However, the underlying mechanisms involved in regulating this process are largely unknown. Here we found that during influenza infection pleural cavity B-1a cells rapidly infiltrated lungs, where they underwent plasmacytic differentiation with enhanced IgM production. This process was promoted by IL-17A signaling via induction of Blimp-1 expression and NF-κB activation in B-1a cells. Deficiency of IL-17A led to severely impaired B-1a-derived antibody production in the respiratory tract, resulting in a deficiency in viral clearance. Transfer of B-1a-derived natural antibodies rescued Il17a-/- mice from otherwise lethal infections. Together, we identify a critical function of IL-17A in promoting the plasmacytic differentiation of B-1a cells. Our findings provide new insights into the mechanisms underlying the regulation of pulmonary B-1a cell response against influenza infection. PMID:26735852

  15. Oral bacteria modulate invasion and induction of apoptosis in HEp-2 cells by Pseudomonas aeruginosa.

    PubMed

    Pan, Yaping; Teng, Di; Burke, Andrew C; Haase, Elaine M; Scannapieco, Frank A

    2009-02-01

    Pseudomonas aeruginosa is an important opportunistic bacterial pathogen, causing infections of the respiratory and other organ systems in susceptible hosts. P. aeruginosa infection is initiated by adhesion to and invasion of mucosal epithelial cells. The failure of host defenses to eliminate P. aeruginosa from mucosal surfaces results in P. aeruginosa proliferation, sometimes followed by overt infection and tissue destruction. There is growing evidence that associates poor oral health and respiratory infection. An in vitro model system for bacterial invasion of respiratory epithelial cells was used to investigate the influence of oral bacteria on P. aeruginosa epithelial cell invasion. Oral pathogens including Porphyromonas gingivalis, Fusobacterium nucleatum and Aggre