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Sample records for syncytial virus pneumonia

  1. Role of bibersteinia trehalosi, respiratory syncytial virus, and parainfluenza-3 virus in bighorn sheep pneumonia

    USDA-ARS?s Scientific Manuscript database

    Pneumonic bighorn sheep (BHS) have been found to be culture- and/or sero-positive for Bibersteinia trehalosi, respiratory syncytial virus (RSV), and parainfluenza-3 virus (PI-3). The objective of this study was to determine whether these pathogens can cause fatal pneumonia in BHS. In the first study...

  2. Role of Bibersteinia trehalosi, respiratory syncytial virus, and parainfluenza-3 virus in bighorn sheep pneumonia.

    PubMed

    Dassanayake, Rohana P; Shanthalingam, Sudarvili; Subramaniam, Renuka; Herndon, Caroline N; Bavananthasivam, Jegarubee; Haldorson, Gary J; Foreyt, William J; Evermann, James F; Herrmann-Hoesing, Lynn M; Knowles, Donald P; Srikumaran, Subramaniam

    2013-02-22

    Pneumonic bighorn sheep (BHS) have been found to be culture- and/or sero-positive for Bibersteinia trehalosi, respiratory syncytial virus (RSV), and parainfluenza-3 virus (PI-3). The objective of this study was to determine whether these pathogens can cause fatal pneumonia in BHS. In the first study, two groups of four BHS each were intra-tracheally administered with leukotoxin-positive (Group I) or leukotoxin-negative (Group II) B. trehalosi. All four animals in Group I developed severe pneumonia, and two of them died within 3 days. The other two animals showed severe pneumonic lesions on euthanasia and necropsy. Animals in Group II neither died nor showed gross pneumonic lesions on necropsy, suggesting that leukotoxin-positive, but not leukotoxin-negative, B. trehalosi can cause fatal pneumonia in BHS. In the second study, two other groups of four BHS (Groups III and IV) were intra-nasally administered with a mixture of RSV and PI-3. Four days later, RSV/PI-3-inoculated Group IV and another group of four BHS (Group V, positive control) were intra-nasally administered with Mannheimia haemolytica, the pathogen that consistently causes fatal pneumonia in BHS. All four animals in group III developed pneumonia, but did not die during the study period. However all four animals in Group IV, and three animals in Group V developed severe pneumonia and died within two days of M. haemolytica inoculation. The fourth animal in Group V showed severe pneumonic lesions on euthanasia and necropsy. These findings suggest that RSV/PI-3 can cause non-fatal pneumonia, but are not necessary predisposing agents for M. haemolytica-caused pneumonia of BHS.

  3. Proteomic Profiling of a Respiratory Syncytial Virus-Infected Rat Pneumonia Model.

    PubMed

    Wang, Xue-Feng; Zhang, Xiu-Ying; Gao, Xuejuan; Liu, Xiao-Xue; Wang, Yi-Huan

    2016-07-22

    Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in pediatric patients. Our goal was to obtain a detailed understanding of the molecular pathogenesis of RSV infections by studying the protein expression profiles in rats with pneumonia. First, we successfully established a pneumonia rat model by intranasally injecting RSV. The differentially expressed proteins in lung tissues of RSV-infected rats compared with those of the controls were analyzed by using 2-dimensional fluorescence difference gel electrophoresis and MALDI-TOF/TOF MS. In total. 41 differentially expressed protein spots representing 20 unique proteins were successfully identified. Classification analysis showed that most of these proteins are implicated in metabolic processes, cellular processes, cellular component organization or biogenesis, and immune system processes. The significantly elevated expressions levels of 4 proteins namely, T-kininogen 1, T-kininogen 2, haptoglobin, and hemopexin, which might serve as the potential biomarkers of RSV-infected pneumonia, were further validated in RSV-infected rats using western blot and immunohistochemistry. These results provide new insights into the pathogenesis of RSV infection-induced pneumonia and provide important future directions for functional studies and therapeutic design.

  4. Influence of Pneumococcal Vaccines and Respiratory Syncytial Virus on Alveolar Pneumonia, Israel

    PubMed Central

    Givon-Lavi, Noga; Shemer-Avni, Yonat; Bar-Ziv, Jacob; Alonso, Wladimir J.; Greenberg, David; Dagan, Ron

    2013-01-01

    Postlicensure surveillance of pneumonia incidence can be used to estimate whether pneumococcal conjugate vaccines (PCVs) affect incidence. We used Poisson regression models that control for baseline seasonality to determine the impact of PCVs and the possible effects of variations in virus activity in Israel on these surveillance estimates. PCV was associated with significant declines in radiologically confirmed alveolar pneumonia (RCAP) among patients <6 months, 6–17 months, and 18–35 months of age (–31% [95% CI –51% to –15%], –41% [95% CI –52 to –32%], and –34% [95% CI –42% to –25%], respectively). Respiratory syncytial virus (RSV) activity was associated with strong increases in RCAP incidence, with up to 44% of cases attributable to RSV among infants <6 months of age and lower but significant impacts in older children. Seasonal variations, particularly in RSV activity, masked the impact of 7-valent PCVs, especially for young children in the first 2 years after vaccine introduction. PMID:23763864

  5. Respiratory Syncytial Virus

    MedlinePlus

    ... Your 1- to 2-Year-Old Respiratory Syncytial Virus KidsHealth > For Parents > Respiratory Syncytial Virus A A A What's in this article? About ... RSV When to Call the Doctor en español Virus respiratorio sincitial About RSV Respiratory syncytial (sin-SISH- ...

  6. Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo

    PubMed Central

    Nguyen, D. Tien; Louwen, Rogier; Elberse, Karin; van Amerongen, Geert; Yüksel, Selma; Luijendijk, Ad; Osterhaus, Albert D. M. E.; Duprex, W. Paul; de Swart, Rik L.

    2015-01-01

    Human respiratory syncytial virus (HRSV) and Streptococcus pneumoniae are important causative agents of respiratory tract infections. Both pathogens are associated with seasonal disease outbreaks in the pediatric population, and can often be detected simultaneously in infants hospitalized with bronchiolitis or pneumonia. It has been described that respiratory virus infections may predispose for bacterial superinfections, resulting in severe disease. However, studies on the influence of bacterial colonization of the upper respiratory tract on the pathogenesis of subsequent respiratory virus infections are scarce. Here, we have investigated whether pneumococcal colonization enhances subsequent HRSV infection. We used a newly generated recombinant subgroup B HRSV strain that expresses enhanced green fluorescent protein and pneumococcal isolates obtained from healthy children in disease-relevant in vitro and in vivo model systems. Three pneumococcal strains specifically enhanced in vitro HRSV infection of primary well-differentiated normal human bronchial epithelial cells grown at air-liquid interface, whereas two other strains did not. Since previous studies reported that bacterial neuraminidase enhanced HRSV infection in vitro, we measured pneumococcal neuraminidase activity in these cultures but found no correlation with the observed infection enhancement in our model. Subsequently, a selection of pneumococcal strains was used to induce nasal colonization of cotton rats, the best available small animal model for HRSV. Intranasal HRSV infection three days later resulted in strain-specific enhancement of HRSV replication in vivo. One S. pneumoniae strain enhanced HRSV both in vitro and in vivo, and was also associated with enhanced syncytium formation in vivo. However, neither pneumococci nor HRSV were found to spread from the upper to the lower respiratory tract, and neither pathogen was transmitted to naive cage mates by direct contact. These results demonstrate

  7. Streptococcus pneumoniae Enhances Human Respiratory Syncytial Virus Infection In Vitro and In Vivo.

    PubMed

    Nguyen, D Tien; Louwen, Rogier; Elberse, Karin; van Amerongen, Geert; Yüksel, Selma; Luijendijk, Ad; Osterhaus, Albert D M E; Duprex, W Paul; de Swart, Rik L

    2015-01-01

    Human respiratory syncytial virus (HRSV) and Streptococcus pneumoniae are important causative agents of respiratory tract infections. Both pathogens are associated with seasonal disease outbreaks in the pediatric population, and can often be detected simultaneously in infants hospitalized with bronchiolitis or pneumonia. It has been described that respiratory virus infections may predispose for bacterial superinfections, resulting in severe disease. However, studies on the influence of bacterial colonization of the upper respiratory tract on the pathogenesis of subsequent respiratory virus infections are scarce. Here, we have investigated whether pneumococcal colonization enhances subsequent HRSV infection. We used a newly generated recombinant subgroup B HRSV strain that expresses enhanced green fluorescent protein and pneumococcal isolates obtained from healthy children in disease-relevant in vitro and in vivo model systems. Three pneumococcal strains specifically enhanced in vitro HRSV infection of primary well-differentiated normal human bronchial epithelial cells grown at air-liquid interface, whereas two other strains did not. Since previous studies reported that bacterial neuraminidase enhanced HRSV infection in vitro, we measured pneumococcal neuraminidase activity in these cultures but found no correlation with the observed infection enhancement in our model. Subsequently, a selection of pneumococcal strains was used to induce nasal colonization of cotton rats, the best available small animal model for HRSV. Intranasal HRSV infection three days later resulted in strain-specific enhancement of HRSV replication in vivo. One S. pneumoniae strain enhanced HRSV both in vitro and in vivo, and was also associated with enhanced syncytium formation in vivo. However, neither pneumococci nor HRSV were found to spread from the upper to the lower respiratory tract, and neither pathogen was transmitted to naive cage mates by direct contact. These results demonstrate

  8. Titanium dioxide nanoparticles exacerbate pneumonia in respiratory syncytial virus (RSV)-infected mice.

    PubMed

    Hashiguchi, Seiko; Yoshida, Hiroki; Akashi, Toshi; Komemoto, Keiji; Ueda, Tomoyuki; Ikarashi, Yoshiaki; Miyauchi, Aki; Konno, Katsuhiko; Yamanaka, Sayoko; Hirose, Akihiko; Kurokawa, Masahiko; Watanabe, Wataru

    2015-03-01

    To reveal the effects of TiO2 nanoparticles, used in cosmetics and building materials, on the immune response, a respiratory syncytial virus (RSV) infection mouse model was used. BALB/c mice were exposed once intranasally to TiO2 at 0.5mg/kg and infected intranasally with RSV five days later. The levels of IFN-γ and chemokine CCL5, representative markers of pneumonia, in the bronchoalveolar lavage fluids of RSV-infected mice had increased significantly in TiO2-exposed mice compared with the control on day 5 post-infection, but not in uninfected mice. While pulmonary viral titers were not affected by TiO2 exposure, an increase in the infiltration of lymphocytes into the alveolar septa in lung tissues was observed. Immunohistochemical analysis revealed aggregation of TiO2 nanoparticles near inflammatory cells in the severely affected region. Thus, a single exposure to TiO2 nanoparticles affected the immune system and exacerbated pneumonia in RSV-infected mice.

  9. Pneumonia associated with infection with pneumocystis, respiratory syncytial virus, chlamydia, mycoplasma, and cytomegalovirus in children in Papua New Guinea.

    PubMed Central

    Shann, F; Walters, S; Pifer, L L; Graham, D M; Jack, I; Uren, E; Birch, D; Stallman, N D

    1986-01-01

    Paired serum samples were collected from 94 children with pneumonia admitted to Goroka Hospital, Papua New Guinea. All but three of the children were aged 1-24 months. Only nine children were malnourished, with weight for age less than 70% of the Harvard median (three had weight for age less than 60% of the Harvard median). Pneumocystis carinii antigen was detected in the serum of 23 children. Twenty two children had serological evidence of recent infection with respiratory syncytial virus. Five children were probably infected with Chlamydia trachomatis at the time of the study, and there was less convincing serological evidence of current infection in a further 11 children. Five children showed a fourfold rise in antibody to Mycoplasma pneumoniae. Although only one child showed a fourfold rise in antibody to cytomegalovirus, 86 children had this antibody. No child showed a fourfold rise in antibody to Ureaplasma urealyticum or Legionella pneumophila. P carinii, respiratory syncytial virus, C trachomatis, M pneumoniae, and cytomegalovirus may be important causes of pneumonia in children in developing countries. PMID:3002538

  10. Respiratory Syncytial Virus (RSV)

    MedlinePlus

    ... and premature birth: Are you at risk? Zika virus and pregnancy Folic acid Medicine safety and pregnancy ... It's been added to your dashboard . Respiratory syncytial virus (RSV) is a common virus that infects the ...

  11. Respiratory syncytial virus (RSV)

    MedlinePlus

    Respiratory syncytial virus (RSV) is a very common virus that leads to mild, cold-like symptoms in adults and older healthy children. It can be more serious in young babies, especially those in certain high-risk groups.

  12. Respiratory Syncytial Virus Infections

    MedlinePlus

    Respiratory syncytial virus (RSV) causes mild, cold-like symptoms in adults and older healthy children. It can cause serious problems in ... tests can tell if your child has the virus. There is no specific treatment. You should give ...

  13. Respiratory Syncytial Virus

    MedlinePlus

    ... respiratory syncytial virus (RSV) using indirect immunofluorescence technique. Biology & Genetics For more than 50 years, NIAID’s commitment ... Nucleotide Polymorphism Phylogenetics & Ontology Proteomics & Protein Analysis Systems Biology Data Portals Software Applications BCBB Mobyle Interface Designer ( ...

  14. Respiratory syncytial virus infection in cattle

    USDA-ARS?s Scientific Manuscript database

    Bovine respiratory syncytial virus (bRSV) is a cause of respiratory disease in cattle world-wide. It has an integral role in enzootic pneumonia in young dairy calves and summer pneumonia in nursing beef calves. Furthermore, bRSV infection can predispose calves to secondary bacterial infection by org...

  15. A comparison of human metapneumovirus and respiratory syncytial virus WHO-defined severe pneumonia in Moroccan children.

    PubMed

    Jroundi, I; Mahraoui, C; Benmessaoud, R; Moraleda, C; Tligui, H; Seffar, M; El Kettani, S E C; Benjelloun, B S; Chaacho, S; Muñoz-Almagro, C; Ruiz, J; Alonso, P L; Bassat, Q

    2016-02-01

    Acute respiratory infections remain the principal cause of morbidity and mortality in Moroccan children. Besides bacterial infections, respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are prominent among other viruses due to their high prevalence and association with severe clinical episodes. We aimed to describe and compare RSV- and hMPV-associated cases of WHO-defined severe pneumonia in a paediatric population admitted to Morocco's reference hospital. Children aged 2-59 months admitted to the Hôpital d'Enfants de Rabat, Morocco meeting WHO-defined severe pneumonia criteria were recruited during 14 months and thoroughly investigated to ascertain a definitive diagnosis. Viral prevalence of RSV, hMPV and other viruses causing respiratory symptoms was investigated in nasopharyngeal aspirate samples through the use of molecular methods. Of the 683 children recruited and included in the final analysis, 61/683 (8·9%) and 124/683 (18·2%) were infected with hMPV and RSV, respectively. Besides a borderline significant tendency for higher age in hMPV cases, patients infected with either of the viruses behaved similarly in terms of demographics, patient history, past morbidity and comorbidity, vaccination history, socioeconomic background and family environment. Clinical presentation on arrival was also similar for both viruses, but hMPV cases were associated with more severity than RSV cases, had a higher risk of intensive care need, and received antibiotic treatment more frequently. RSV and hMPV are common and potentially life-threatening causes of WHO-defined pneumonia in Moroccan children. Both viruses show indistinctive clinical symptomatology, but in Moroccan children, hMPV was associated with a more severe evolution.

  16. Lethal pneumonia in a captive juvenile chimpanzee (Pan troglodytes) due to human-transmitted human respiratory syncytial virus (HRSV) and infection with Streptococcus pneumoniae.

    PubMed

    Szentiks, Claudia A; Köndgen, Sophie; Silinski, Sandra; Speck, Stephanie; Leendertz, Fabian H

    2009-08-01

    During an outbreak of respiratory disease in captive chimpanzees (Pan troglodytes), gorillas (Gorilla gorilla), Bornean orangutans (Pongo pygmaeus), and red-capped mangabeys (Cercocebus torquatus) also staff members showed non-specific upper respiratory signs. One infant female chimpanzee with severe respiratory symptoms died despite immediate medical treatment and was submitted for necropsy. Routine post mortem, histological and bacteriological examinations were conducted. Additionally lung tissue samples form the chimpanzee and swab samples from the staff members and the other primates were examined by PCR. A severe catarrhal to purulent bronchopneumonia and an interstitial pneumonia were found and human respiratory syncytial virus (HRSV) as well as Streptococcus pneumoniae was detected in lung samples by PCR. Swab samples from one animal keeper revealed the same HRSV sequence as of the chimpanzee. Therefore, it is suggested that the outbreak of respiratory disease within a zoological institution was due to transmission of HRSV between both human and primates.

  17. Role of Human Metapneumovirus, Influenza A Virus and Respiratory Syncytial Virus in Causing WHO-Defined Severe Pneumonia in Children in a Developing Country

    PubMed Central

    Ali, Asad; Khowaja, Asif Raza; Bashir, Maaman Zahoor; Aziz, Fatima; Mustafa, Sultan; Zaidi, Anita

    2013-01-01

    Objective The role of respiratory viruses in causing severe, life threatening pneumonia in children in developing countries is not well established. Our study aims to determine the role of human metapneumovirus (HMPV), influenza A virus and respiratory syncytial virus (RSV) in children, aged 6 weeks to 2 years, hospitalized with WHO defined severe pneumonia (tachypnea plus any general danger sign or chest in-drawing) at a public sector hospital in Karachi, Pakistan. Methods This study was conducted from November 2010 to September 2011 at Abbassi Shaheed Hospital, a large public tertiary care hospital in Karachi, Pakistan. Children admitted with WHO-defined severe pneumonia were enrolled and throat swabs were obtained to detect respiratory viruses using real time RT-PCR. Chest x-rays of all subjects were obtained and independently interpreted by two radiologists to diagnose radiologic pneumonia. Results 169 children were enrolled. HMPV was detected in 24 (14.2%), influenza A virus in 9 (5.3%) and RSV in 30 (17.8%) children admitted with severe pneumonia. Of 9 patients with influenza A, 8 tested positive for H1N1. Viral etiology was found in 18% of radiologically confirmed pneumonia. HMPV infections peaked in February and April, influenza A was prevalent in January, June and November and RSV infections were most prevalent from June to September. Conclusion HMPV, influenza A and RSV are common causes of WHO-defined severe pneumonia in hospitalized children in Karachi. Knowledge regarding the viral etiology of pediatric pneumonia and individual viral seasonality can help in the recommendation and implementation of appropriate management strategies. PMID:24058625

  18. Association of C-Reactive Protein With Bacterial and Respiratory Syncytial Virus-Associated Pneumonia Among Children Aged <5 Years in the PERCH Study.

    PubMed

    Higdon, Melissa M; Le, Tham; O'Brien, Katherine L; Murdoch, David R; Prosperi, Christine; Baggett, Henry C; Brooks, W Abdullah; Feikin, Daniel R; Hammitt, Laura L; Howie, Stephen R C; Kotloff, Karen L; Levine, Orin S; Scott, J Anthony G; Thea, Donald M; Awori, Juliet O; Baillie, Vicky L; Cascio, Stephanie; Chuananon, Somchai; DeLuca, Andrea N; Driscoll, Amanda J; Ebruke, Bernard E; Endtz, Hubert P; Kaewpan, Anek; Kahn, Geoff; Karani, Angela; Karron, Ruth A; Moore, David P; Park, Daniel E; Rahman, Mohammed Ziaur; Salaudeen, Rasheed; Seidenberg, Phil; Somwe, Somwe Wa; Sylla, Mamadou; Tapia, Milagritos D; Zeger, Scott L; Deloria Knoll, Maria; Madhi, Shabir A

    2017-06-15

    Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.

  19. Respiratory Syncytial Virus (RSV)

    MedlinePlus

    ... common virus that infects the lungs and breathing passages. Almost all babies get it before the age ... infection that causes swelling in the smallest air passages in the lungs Pneumonia, an infection in one ...

  20. Factors associated with increased risk of progression to respiratory syncytial virus-associated pneumonia in young Kenyan children

    PubMed Central

    Okiro, Emelda A; Ngama, Mwanajuma; Bett, Ann; Cane, Patricia A; Medley, Graham F; James Nokes, D

    2008-01-01

    Objectives To identify factors associated with developing severe respiratory syncytial virus (RSV) pneumonia and their commonality with all-cause lower respiratory tract infection (LRTI), in order to isolate those risk factors specifically associated with RSV-LRTI and identify targets for control. Methods A birth cohort of rural Kenyan children was intensively monitored for acute respiratory infection (ARI) over three RSV epidemics. RSV was diagnosed by immunofluorescence of nasal washings collected at each ARI episode. Cox regression was used to determine the relative risk of disease for a range of co-factors. Results A total of 469 children provided 937 years of follow-up, and experienced 857 all-cause LRTI, 362 RSV-ARI and 92 RSV-LRTI episodes. Factors associated with RSV-LRTI, but not RSV-ARI, were severe stunting (z-score ≤−2, RR 1.7 95%CI 1.1–2.8), crowding (increased number of children, RR 2.6, 1.0–6.5) and number of siblings under 6 years (RR 2.0, 1.2–3.4). Moderate and severe stunting (z-score ≤−1), crowding and a sibling aged over 5 years sleeping in the same room as the index child were associated with increased risk of all-cause LRTI, whereas higher educational level of the primary caretaker was associated with protection. Conclusion We identify factors related to host nutritional status (stunting) and contact intensity (crowding, siblings) which are distinguishable in their association with RSV severe disease in infant and young child. These factors are broadly in common with those associated with all-cause LRTI. The results support targeted strategies for prevention. PMID:18482199

  1. A high burden of respiratory syncytial virus associated pneumonia in children less than two years of age in a South East Asian refugee population.

    PubMed

    Turner, Claudia; Turner, Paul; Cararra, Verena; Eh Lwe, Naw; Watthanaworawit, Wanitda; Day, Nicholas P; White, Nicholas J; Goldblatt, David; Nosten, François

    2012-01-01

    Pneumonia is a major cause of childhood mortality and morbidity approximately 1.6 million deaths and 150 million episodes occur annually in children <5 years. Respiratory syncytial virus (RSV) may be responsible for up to 25% of cases and 12% of deaths making it an important potential vaccine target, although data from South East Asia is scarce. We followed a birth cohort of Burmese refugee children, born over a one year period, for two years. Pneumonia episodes were diagnosed using WHO criteria. A chest radiograph, nasopharyngeal aspirate and non-specific markers of infection were taken during each episode. The incidence of RSV-associated pneumonia was 0.24 (95% CI 0.22-0.26) episodes per child year. All children with pneumonia received antibiotic treatment, following WHO guidelines. The highest incidence was in the 2-12 month age group. The commonest diagnosis in a child with RSV-associated pneumonia was non-severe pneumonia (239/362:66.0%), however the incidence of RSV-associated severe or very severe pneumonia was 0.08 (95% CI 0.01-0.10) episodes per child year. Birth in the wet season increased the risk of severe disease in children who had their first episode of RSV-associated pneumonia aged 2-11 months (OR 28.7, 95% CI 6.6-125.0, p<0.001). RSV episodes were highly seasonal being responsible for 80.0% of all the pneumonia episodes occurring each October and November over the study period. There was a high incidence of RSV associated pneumonia in this refugee population. Interventions to prevent RSV infection have the potential to reduce the incidence of clinically diagnosed pneumonia and hence unnecessary antibiotic usage in this population.

  2. Respiratory syncytial virus infection: an innate perspective

    PubMed Central

    Johansson, Cecilia

    2016-01-01

    Respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in children and adults. However, infection with this virus sometimes leads to severe lower respiratory disease and is the major cause of infant hospitalisations in the developed world. Several risk factors such as baby prematurity and congenital heart disease are known to predispose towards severe disease but previously healthy, full-term infants can also develop bronchiolitis and viral pneumonia during RSV infection. The causes of severe disease are not fully understood but may include dysregulation of the immune response to the virus, resulting in excessive recruitment and activation of innate and adaptive immune cells that can cause damage. This review highlights recent discoveries on the balancing act of immune-mediated virus clearance versus immunopathology during RSV infection. PMID:28105323

  3. Gold nanorod vaccine for respiratory syncytial virus

    NASA Astrophysics Data System (ADS)

    Stone, John W.; Thornburg, Natalie J.; Blum, David L.; Kuhn, Sam J.; Wright, David W.; Crowe, James E., Jr.

    2013-07-01

    Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, electron microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response.

  4. Respiratory Commensal Bacteria Corynebacterium pseudodiphtheriticum Improves Resistance of Infant Mice to Respiratory Syncytial Virus and Streptococcus pneumoniae Superinfection.

    PubMed

    Kanmani, Paulraj; Clua, Patricia; Vizoso-Pinto, Maria G; Rodriguez, Cecilia; Alvarez, Susana; Melnikov, Vyacheslav; Takahashi, Hideki; Kitazawa, Haruki; Villena, Julio

    2017-01-01

    Corynebacterium pseudodiphtheriticum is a Gram-positive bacterium found as a member of the normal microbiota of the upper respiratory tract. It was suggested that C. pseudodiphtheriticum may be potentially used as a next-generation probiotic for nasal application, although no deep studies were performed in this regard. We hypothesized that human isolate C. pseudodiphtheriticum strain 090104 is able to modulate the respiratory innate immune response and beneficially influence the resistance to viral and bacterial infections. Therefore, in the present study we investigated how the exposure of infant mice to nasal priming with viable or non-viable C. pseudodiphtheriticum 090104 influences the respiratory innate immune response triggered by Toll-like receptor (TLR)-3 activation, the susceptibility to primary Respiratory Synsytial Virus (RSV) infection, and the resistance to secondary Streptococcus pneumoniae pneumonia. We demonstrated that the nasal priming with viable C. pseudodiphtheriticum 090104 differentially modulated TLR3-mediated innate antiviral immune response in the respiratory tract of infant mice, improving their resistance to primary RSV infection, and secondary pneumococcal pneumonia. In association with the protection against RSV-pneumococcal superinfection, we found that viable C. pseudodiphtheriticum improved lung CD3(+)CD4(+)IFN-γ(+), and CD3(+)CD4(+)IL-10(+) T cells as well as CD11c(+)SiglecF(+)IFN-β(+) alveolar macrophages. Of interest, non-viable bacteria did not have the same protective effect, suggesting that C. pseudodiphtheriticum colonization is needed for achieving its protective effect. In conclusion, we present evidence that nasal application of viable C. pseudodiphtheriticum could be thought as an alternative to boost defenses against RSV and secondary pneumococcal pneumonia, which should be further studied and validated in clinical trials. Due to the absence of a long-lasting immunity, re-infection with RSV throughout life is common

  5. Learn about Respiratory Syncytial Virus (RSV)

    MedlinePlus

    ... Virus (RSV) Respiratory syncytial virus (RSV) is a common respiratory virus that can affect people of all ages. In older children and adults, it causes mostly upper respiratory symptoms (colds), but it can cause a serious infection in ...

  6. Characteristics of respiratory syncytial virus-induced bronchiolitis co-infection with Mycoplasma pneumoniae and add-on therapy with montelukast.

    PubMed

    Wu, Sheng-Hua; Chen, Xiao-Qing; Kong, Xia; Yin, Pei-Ling; Dong, Ling; Liao, Pei-Yuan; Wu, Jia-Ming

    2016-02-01

    The influence of Mycoplasma pneumoniae (MP) infection on bronchiolitis remains unclear. Additionally, reports on the efficacies of leukotriene receptor antagonists in the treatment of bronchiolitis have been inconclusive. Children with respiratory syncytial virus (RSV)-induced bronchiolitis were divided into two groups: RSV+MP group and RSV group. Each group was randomly divided into two subgroups: one received routine and placebo treatment, while the other received routine and montelukast treatment for 9 months. The cumulative numbers of wheezing episodes and recurrent respiratory tract infections were recorded. Blood parameters were determined. Patients in the RSV+MP group exhibited an older average age, fever, more frequent flaky and patchy shadows in chest X-rays, more frequent extrapulmonary manifestations, and longer hospital stays compared with patients in the RSV group. Additionally, higher baseline blood eosinophil counts, eosinophil cationic protein (ECP), total immunoglobulin E (IgE), interleukin (IL)-4, IL-5, IL-4/interferon-γ ratios, leukotriene (LT) B4, and LTC4, and lower baseline lipoxin A4 (LXA4)/LTB4 ratios were observed in the RSV+MP group compared with the RSV group. Montelukast treatment decreased the cumulative numbers of recurrent wheezing episodes and recurrent respiratory tract infections at 9 and 12 months. This efficacy may be related to the montelukast-induced reductions in peripheral eosinophil counts, ECP and total IgE, as well as the montelukast-dependent recovery in T helper (Th) 1/Th2 balance and LXA4/LTB4 ratios in children with bronchiolitis. RSV bronchiolitis with MP infection was associated with clinical and laboratory features that differed from those of RSV bronchiolitis without MP infection. Add-on therapy with montelukast for 9 months was beneficial for children with bronchiolitis at 9 and 12 months after the initiation of treatment.

  7. Respiratory syncytial virus infection in cattle.

    PubMed

    Sacco, R E; McGill, J L; Pillatzki, A E; Palmer, M V; Ackermann, M R

    2014-03-01

    Bovine respiratory syncytial virus (RSV) is a cause of respiratory disease in cattle worldwide. It has an integral role in enzootic pneumonia in young dairy calves and summer pneumonia in nursing beef calves. Furthermore, bovine RSV infection can predispose calves to secondary bacterial infection by organisms such as Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, resulting in bovine respiratory disease complex, the most prevalent cause of morbidity and mortality among feedlot cattle. Even in cases where animals do not succumb to bovine respiratory disease complex, there can be long-term losses in production performance. This includes reductions in feed efficiency and rate of gain in the feedlot, as well as reproductive performance, milk production, and longevity in the breeding herd. As a result, economic costs to the cattle industry from bovine respiratory disease have been estimated to approach $1 billion annually due to death losses, reduced performance, and costs of vaccinations and treatment modalities. Human and bovine RSV are closely related viruses with similarities in histopathologic lesions and mechanisms of immune modulation induced following infection. Therefore, where appropriate, we provide comparisons between RSV infections in humans and cattle. This review article discusses key aspects of RSV infection of cattle, including epidemiology and strain variability, clinical signs and diagnosis, experimental infection, gross and microscopic lesions, innate and adaptive immune responses, and vaccination strategies.

  8. Respiratory syncytial virus infection in adults.

    PubMed

    Falsey, Ann R

    2007-04-01

    Respiratory syncytial virus (RSV) is a common winter time respiratory virus that affects persons of all ages and is the major cause of serious lower respiratory tract infections in young children. However, RSV is also an important pathogen in adults, particularly in the elderly, patients with chronic lung disease, or those with impaired immunity. Clinical features of RSV infections overlap with other respiratory viruses, so laboratory tests are required to establish the diagnosis. Reverse transcriptase polymerase chain reaction (RT-PCR) of samples from nasal swabs, sputum, or bronchoalveolar lavage is a sensitive test to substantiate the diagnosis. Serologies are useful in epidemiological surveys. The clinical course of RSV infections is variable. In infants, RSV presents as bronchiolitis. In adults, mild to moderate upper respiratory tract illness is characteristic. However, severe pneumonia can occur, particularly in the elderly with comorbidities or compromised immune status. Humoral antibodies confer partial immunity to RSV infection and disease severity; cellular immunity is important to eradicate RSV in established infections. Treatment of RSV infections is often supportive. Aerosolized ribavirin is approved for RSV infections in infants; its role in adults is controversial. Infection control measures are critical to limit spread of RSV. Currently, RSV vaccines are not available, but candidate vaccines are being developed.

  9. Neonatal calf infection with respiratory syncytial virus: drawing parallels to the disease in human infants

    USDA-ARS?s Scientific Manuscript database

    Respiratory syncytial virus (RSV) is the most common viral cause of childhood acute lower respiratory tract infections. It is estimated that RSV infections result in more than 100,000 deaths annually worldwide. Bovine RSV is a cause of enzootic pneumonia in young dairy calves and summer pneumonia ...

  10. 21 CFR 866.3480 - Respiratory syncytial virus serological reagents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia. (b... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Respiratory syncytial virus serological reagents... Respiratory syncytial virus serological reagents. (a) Identification. Respiratory syncytial virus serological...

  11. 21 CFR 866.3480 - Respiratory syncytial virus serological reagents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia. (b... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Respiratory syncytial virus serological reagents... Respiratory syncytial virus serological reagents. (a) Identification. Respiratory syncytial virus serological...

  12. 21 CFR 866.3480 - Respiratory syncytial virus serological reagents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia. (b... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Respiratory syncytial virus serological reagents... Respiratory syncytial virus serological reagents. (a) Identification. Respiratory syncytial virus serological...

  13. 21 CFR 866.3480 - Respiratory syncytial virus serological reagents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia. (b... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Respiratory syncytial virus serological reagents... Respiratory syncytial virus serological reagents. (a) Identification. Respiratory syncytial virus serological...

  14. 21 CFR 866.3480 - Respiratory syncytial virus serological reagents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... respiratory tract infections, including the common cold, pharyngitis, and infantile bronchopneumonia. (b... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Respiratory syncytial virus serological reagents... Respiratory syncytial virus serological reagents. (a) Identification. Respiratory syncytial virus serological...

  15. Respiratory syncytial virus: not just for kids.

    PubMed

    Murry, A R; Dowell, S F

    1997-07-15

    Respiratory syncytial virus (RSV) earned its reputation as a pediatric pathogen, especially in children under two years of age. RSV infection in adults was considered a significant problem only for certain high-risk populations. Evidence now indicates that the infection occurs frequently in previously healthy adults. Clinical presentation varies greatly.

  16. Molecular mechanism of respiratory syncytial virus fusion inhibitors

    SciTech Connect

    Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M.; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H. M.; Koul, Anil; Arnoult, Eric; Peeples, Mark E.; Roymans, Dirk; McLellan, Jason S.

    2015-12-07

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

  17. Animal models of human respiratory syncytial virus disease

    PubMed Central

    Domachowske, Joseph B.; Rosenberg, Helene F.

    2011-01-01

    Infection with the human pneumovirus pathogen, respiratory syncytial virus (hRSV), causes a wide spectrum of respiratory disease, notably among infants and the elderly. Laboratory animal studies permit detailed experimental modeling of hRSV disease and are therefore indispensable in the search for novel therapies and preventative strategies. Present animal models include several target species for hRSV, including chimpanzees, cattle, sheep, cotton rats, and mice, as well as alternative animal pneumovirus models, such as bovine RSV and pneumonia virus of mice. These diverse animal models reproduce different features of hRSV disease, and their utilization should therefore be based on the scientific hypothesis under investigation. The purpose of this review is to summarize the strengths and limitations of each of these animal models. Our intent is to provide a resource for investigators and an impetus for future research. PMID:21571908

  18. Animal models of human respiratory syncytial virus disease.

    PubMed

    Bem, Reinout A; Domachowske, Joseph B; Rosenberg, Helene F

    2011-08-01

    Infection with the human pneumovirus pathogen, respiratory syncytial virus (hRSV), causes a wide spectrum of respiratory disease, notably among infants and the elderly. Laboratory animal studies permit detailed experimental modeling of hRSV disease and are therefore indispensable in the search for novel therapies and preventative strategies. Present animal models include several target species for hRSV, including chimpanzees, cattle, sheep, cotton rats, and mice, as well as alternative animal pneumovirus models, such as bovine RSV and pneumonia virus of mice. These diverse animal models reproduce different features of hRSV disease, and their utilization should therefore be based on the scientific hypothesis under investigation. The purpose of this review is to summarize the strengths and limitations of each of these animal models. Our intent is to provide a resource for investigators and an impetus for future research.

  19. Molecular mechanism of respiratory syncytial virus fusion inhibitors

    PubMed Central

    Battles, Michael B; Langedijk, Johannes P; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H M; Koul, Anil; Arnoult, Eric; Peeples, Mark E; Roymans, Dirk; McLellan, Jason S

    2016-01-01

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors. PMID:26641933

  20. Animal models of respiratory syncytial virus infection.

    PubMed

    Taylor, Geraldine

    2017-01-11

    Human respiratory syncytial virus (hRSV) is a major cause of respiratory disease and hospitalisation of infants, worldwide, and is also responsible for significant morbidity in adults and excess deaths in the elderly. There is no licensed hRSV vaccine or effective therapeutic agent. However, there are a growing number of hRSV vaccine candidates that have been developed targeting different populations at risk of hRSV infection. Animal models of hRSV play an important role in the preclinical testing of hRSV vaccine candidates and although many have shown efficacy in preclinical studies, few have progressed to clinical trials or they have had only limited success. This is, at least in part, due to the lack of animal models that fully recapitulate the pathogenesis of hRSV infection in humans. This review summarises the strengths and limitations of animal models of hRSV, which include those in which hRSV is used to infect non-human mammalian hosts, and those in which non-human pneumoviruses, such as bovine (b)RSV and pneumonia virus of mice (PVM) are studied in their natural host. Apart from chimpanzees, other non-human primates (NHP) are only semi-permissive for hRSV replication and experimental infection with large doses of virus result in little or no clinical signs of disease, and generally only mild pulmonary pathology. Other animal models such as cotton rats, mice, ferrets, guinea pigs, hamsters, chinchillas, and neonatal lambs are also only semi-permissive for hRSV. Nevertheless, mice and cotton rats have been of value in the development of monoclonal antibody prophylaxis for infants at high risk of severe hRSV infection and have provided insights into mechanisms of immunity to and pathogenesis of hRSV. However, the extent to which they predict hRSV vaccine efficacy and safety is unclear and several hRSV vaccine candidates that are completely protective in rodent models are poorly effective in chimpanzees and other NHP, such as African Green monkeys. Furthermore

  1. Respiratory Syncytial Virus Infection (RSV): Transmission and Prevention

    MedlinePlus

    ... CDC Cancel Submit Search The CDC Respiratory Syncytial Virus Infection (RSV) Note: Javascript is disabled or is ... if you touch a surface that has the virus on it, like a doorknob, and then touch ...

  2. Emerging drugs for respiratory syncytial virus infection.

    PubMed

    Olszewska, Wieslawa; Openshaw, Peter

    2009-06-01

    Although respiratory syncytial virus (RSV) was discovered > 40 years ago, treatment remains largely supportive. There are no safe and effective vaccines or specific treatments other than prophylaxis with passive antibody therapy (palivizumab). However, there are good reasons to think that the scene may soon change. As the pace of development of anti-viral drugs accelerates and optimism over vaccines increases, novel therapies are set to make a major impact in the management of this very common infection. The use and effect of such interventions are not easy to anticipate, but could ultimately include the interruption of RSV's transmission resulting in profound changes to the impact of RSV on human health.

  3. Aptamers for respiratory syncytial virus detection.

    PubMed

    Percze, Krisztina; Szakács, Zoltán; Scholz, Éva; András, Judit; Szeitner, Zsuzsanna; Kieboom, Corné H van den; Ferwerda, Gerben; Jonge, Marien I de; Gyurcsányi, Róbert E; Mészáros, Tamás

    2017-02-21

    The identification of the infectious agents is pivotal for appropriate care of patients with viral diseases. Current viral diagnostics rely on selective detection of viral nucleic acid or protein components. In general, detection of proteins rather than nucleic acids is technically more suitable for rapid tests. However, protein-based virus identification methods depend on antibodies limiting the practical applicability of these approaches. Aptamers rival antibodies in target selectivity and binding affinity, and excel in terms of robustness and cost of synthesis. Although aptamers have been generated for virus identification in laboratory settings, their introduction into routine virus diagnostics has not been realized, yet. Here, we demonstrate that the rationally designed SELEX protocol can be applied on whole virus to select aptamers, which can potentially be applied for viral diagnostics. This approach does not require purified virus protein or complicated virus purification. The presented data also illustrate that corroborating the functionality of aptamers with various approaches is essential to pinpoint the most appropriate aptamer amongst the panel of candidates obtained by the selection. Our protocol yielded aptamers capable of detecting respiratory syncytial virus (RSV), an important pathogen causing severe disease especially in young infants, at clinically relevant concentrations in complex matrices.

  4. Aptamers for respiratory syncytial virus detection

    PubMed Central

    Percze, Krisztina; Szakács, Zoltán; Scholz, Éva; András, Judit; Szeitner, Zsuzsanna; Kieboom, Corné H. van den; Ferwerda, Gerben; Jonge, Marien I. de; Gyurcsányi, Róbert E.; Mészáros, Tamás

    2017-01-01

    The identification of the infectious agents is pivotal for appropriate care of patients with viral diseases. Current viral diagnostics rely on selective detection of viral nucleic acid or protein components. In general, detection of proteins rather than nucleic acids is technically more suitable for rapid tests. However, protein-based virus identification methods depend on antibodies limiting the practical applicability of these approaches. Aptamers rival antibodies in target selectivity and binding affinity, and excel in terms of robustness and cost of synthesis. Although aptamers have been generated for virus identification in laboratory settings, their introduction into routine virus diagnostics has not been realized, yet. Here, we demonstrate that the rationally designed SELEX protocol can be applied on whole virus to select aptamers, which can potentially be applied for viral diagnostics. This approach does not require purified virus protein or complicated virus purification. The presented data also illustrate that corroborating the functionality of aptamers with various approaches is essential to pinpoint the most appropriate aptamer amongst the panel of candidates obtained by the selection. Our protocol yielded aptamers capable of detecting respiratory syncytial virus (RSV), an important pathogen causing severe disease especially in young infants, at clinically relevant concentrations in complex matrices. PMID:28220811

  5. [Illnesses by the human respiratory syncytial virus].

    PubMed

    Stock, Ingo

    2006-09-01

    Human respiratory syncytial virus (HRSV) is a single-stranded, enveloped RNA virus of the Paramyxoviridae family. Worldwide, HRSV represents the leading cause of respiratory tract infections in infants and young children. Approximately up to 70% of infants are infected during their first year of life. Recently, an increasing number of reports have described the causal association of HRSV with several respiratory infections in adult patients. Serious illnesses have been documented in especially immunocompromised hosts or in individuals revealing immunosuppressive treatment regimes. Viable options for the prevention or treatment of HRSV infections are limited. Current guidelines do no contain specific recommendations for the causal treatment of HRSV infections. Immunoprophylactic and hygienic measures represent the most effective strategies for prevention of disease.

  6. Respiratory syncytial virus and influenza are the key viral pathogens in children <2 years hospitalized with bronchiolitis and pneumonia in Islamabad Pakistan.

    PubMed

    Bashir, Uzma; Nisar, Nadia; Arshad, Yasir; Alam, Muhammad Masroor; Ashraf, Asiya; Sadia, Hajra; Kazi, Birjees Mazher; Zaidi, Syed Sohail Zahoor

    2017-03-01

    Pneumonia remains a leading cause of morbidity and mortality in developing countries. Comprehensive surveillance data are needed to review the prevention and control strategies. We conducted active surveillance of acute lower respiratory infections among children aged <2 years hospitalized at two hospitals of Islamabad, Pakistan. Viral etiology was determined using real-time PCR on respiratory specimens collected during March 2011-April 2012. The overall mean age was 7.83 ± 5.25 months while no statistical difference between age or sex distribution of patients with positive and negative viral etiology (p > 0.05). The average weight of the study group was 6.1 ± 2.25 kg. ≥1 viral pathogens were detected in 75% cases. Major respiratory viruses included RSV-A: 44%, RSV-B: 23%, Influenza-A: 24.5%, Influenza-B: 7%, Adenovirus: 8.4% and HmPV: 5.2%. A single, dual or multiple viral pathogens were detected in 43%, 27% and 5.2% patients respectively. Common symptoms were cough (95%), apnoea (84%), fever (78%), wheeze (64.5%), nasal congestion (55%) and rhinorrhea (48%). Among the RSV positive cases, 2-6 months age group had highest detection rate for RSV-A (30%, n = 21/69) and RSV-B (20%, n = 14/69) while patients infected with Influenza-A were in 2.1-6 months age group (61%, 23/38). Statistically significant difference was observed between RSV-positive and negative cases for nutrition status (p = 0.001), cigarette/wood smoke exposure (p = 0.001) and concomitant clinical findings. Most patients had successful outcome on combination therapy with bronchodilators, inhaled steroids and antibiotics. Our findings underscore high burden of ALRI in Pakistan. Interventions targeting viral pathogens coupled with improved diagnostic approaches are critical for better prevention and control.

  7. Human Respiratory Syncytial Virus: Infection and Pathology.

    PubMed

    Bohmwald, Karen; Espinoza, Janyra A; Rey-Jurado, Emma; Gómez, Roberto S; González, Pablo A; Bueno, Susan M; Riedel, Claudia A; Kalergis, Alexis M

    2016-08-01

    The human respiratory syncytial virus (hRSV) is by far the major cause of acute lower respiratory tract infections (ALRTIs) worldwide in infants and children younger than 2 years. The overwhelming number of hospitalizations due to hRSV-induced ALRTI each year is due, at least in part, to the lack of licensed vaccines against this virus. Thus, hRSV infection is considered a major public health problem and economic burden in most countries. The lung pathology developed in hRSV-infected individuals is characterized by an exacerbated proinflammatory and unbalanced Th2-type immune response. In addition to the adverse effects in airway tissues, hRSV infection can also cause neurologic manifestations in the host, such as seizures and encephalopathy. Although the origins of these extrapulmonary symptoms remain unclear, studies with patients suffering from neurological alterations suggest an involvement of the inflammatory response against hRSV. Furthermore, hRSV has evolved numerous mechanisms to modulate and evade the immune response in the host. Several studies have focused on elucidating the interactions between hRSV virulence factors and the host immune system, to rationally design new vaccines and therapies against this virus. Here, we discuss about the infection, pathology, and immune response triggered by hRSV in the host.

  8. Animal models of respiratory syncytial virus infection and disease.

    PubMed

    Sacco, Randy E; Durbin, Russell K; Durbin, Joan E

    2015-08-01

    The study of human respiratory syncytial virus pathogenesis and immunity has been hampered by its exquisite host specificity, and the difficulties encountered in adapting this virus to a murine host. The reasons for this obstacle are not well understood, but appear to reflect, at least in part, the inability of the virus to block the interferon response in any but the human host. This review addresses some of the issues encountered in mouse models of respiratory syncytial virus infection, and describes the advantages and disadvantages of alternative model systems.

  9. Animal Models of Respiratory Syncytial Virus Infection and Disease

    PubMed Central

    Sacco, Randy E.; Durbin, Russell K.; Durbin, Joan E.

    2015-01-01

    The study of human respiratory syncytial virus pathogenesis and immunity has been hampered by its exquisite host specificity, and the difficulties encountered in adapting this virus to a murine host. The reasons for this obstacle are not well understood, but appear to reflect, at least in part, the inability of the virus to block the interferon response in any but the human host. This review addresses some of the issues encountered in mouse models of respiratory syncytial virus infection, and describes the advantages and disadvantages of alternative model systems. PMID:26176495

  10. Phosphatidylinositol inhibits respiratory syncytial virus infection

    PubMed Central

    Numata, Mari; Kandasamy, Pitchaimani; Nagashima, Yoji; Fickes, Rachel; Murphy, Robert C.; Voelker, Dennis R.

    2015-01-01

    Respiratory syncytial virus (RSV) infects nearly all children under age 2, and reinfection occurs throughout life, seriously impacting adults with chronic pulmonary diseases. Recent data demonstrate that the anionic pulmonary surfactant lipid phosphatidylglycerol (PG) exerts a potent antiviral effect against RSV in vitro and in vivo. Phosphatidylinositol (PI) is also an anionic pulmonary surfactant phospholipid, and we tested its antiviral activity. PI liposomes completely suppress interleukin-8 production from BEAS2B epithelial cells challenged with RSV. The presence of PI during viral challenge in vitro reduces infection by a factor of >103. PI binds RSV with high affinity, preventing virus attachment to epithelial cells. Intranasal inoculation with PI along with RSV in mice reduces the viral burden 30-fold, eliminates the influx of inflammatory cells, and reduces tissue histopathology. Pharmacological doses of PI persist for >6 h in mouse lung. Pretreatment of mice with PI at 2 h prior to viral infection effectively suppresses inflammation and reduces the viral burden by 85%. These data demonstrate that PI has potent antiviral properties, a long residence time in the extracellular bronchoalveolar compartment, and a significant prophylaxis window. The findings demonstrate PG and PI have complementary roles as intrinsic, innate immune antiviral mediators in the lung. PMID:25561461

  11. Clinical experience with respiratory syncytial virus vaccines.

    PubMed

    Piedra, Pedro A

    2003-02-01

    Respiratory syncytial virus (RSV) infection is at times associated with life-threatening lower respiratory tract illness in infancy. Severe infection during the first year of life may be an important risk factor or indicator for the development of asthma in early childhood. Severe infections primarily occur in healthy infants, and young infants and children with specific risk factors. However, RSV causes respiratory infections in all age groups. Indeed it is now recognized that RSV disease is responsible for significant morbidity and mortality in the geriatric population. RSV infection remains difficult to treat, and prevention is a worldwide goal. For this reason there has been an intensive effort to develop an effective and safe RSV vaccine. Initial infection with RSV affords limited protection to reinfection, yet repeated episodes decrease the risk for lower respiratory tract illness. In the 20 years from 1960 to 1980, trials of several candidate RSV vaccines failed to attain the desired safety and protection against natural infection. Some vaccine types either failed to elicit immunogenicity, as with the live subcutaneous vaccine, or resulted in exaggerated disease on natural exposure to the virus, as with the formalin-inactivated (FI) type. Currently vaccine candidates are being developed based on the molecular virology of RSV. Recent formulations of candidate RSV vaccines have focused on subunit vaccines [such as purified fusion protein (PFP)], subunit vaccines combined with nonspecific immune activating adjuvants, live attenuated vaccines (including cold passaged, temperature-sensitive or cpts mutants), genetically engineered live attenuated vaccines and polypeptide vaccines.

  12. Molecular mechanism of respiratory syncytial virus fusion inhibitors

    DOE PAGES

    Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina; ...

    2015-12-07

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitorsmore » or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.« less

  13. WITHDRAWN: Immunoglobulin treatment for respiratory syncytial virus infection.

    PubMed

    Fuller, Hannah L; Del Mar, Chris B

    2010-09-08

    Respiratory syncytial virus (RSV) bronchiolitis and pneumonia hospitalise hundreds of thousands of infants every year. Treatment is largely supportive therapy, (for example, oxygen, fluids and occasionally mechanical ventilation). Ribavirin, an antiviral agent, is licensed for severe RSV infection, although systematic reviews find it of no benefit. Passive protection against RSV can be achieved through monthly intramuscular injections of the humanised monoclonal anti-RSV antibody palivizumab (Synagis), and yields a 55% reduction in RSV hospitalisation in susceptible infants. This review assesses immunoglobulin treatment of RSV infection rather than its role as a prophylactic measure. To assess the efficacy of adding human or humanised immunoglobulin therapy to supportive therapy in infants hospitalised with laboratory-determined RSV infection. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2006, issue 1) which contains the Acute Respiratory Infections Group's specialized regsiter, MEDLINE (1966 to Week 4, January 2006) and EMBASE (1980 to September 2005). We also ran searches of reference lists of relevant trials and review articles and searches of personal files. We did not impose any language restrictions. We selected randomised controlled trials (RCTs) that compared immunoglobulin treatment with a placebo control in children hospitalised for RSV infection with bronchiolitis or pneumonia or other lower respiratory tract infection (LRTI) with laboratory-documented RSV infection. The primary outcomes of interest were mortality, length of hospitalisation, length of ventilation and oxygen dependence. Secondary outcome measures were pulmonary function and re-hospitalisations for recurrent breathing difficulties in subsequent years. Any adverse effects of the treatments were also noted, for example, hypersensitivity reactions. Data were extracted but cross-comparison was not possible due to the shortage of studies and

  14. Host response to respiratory syncytial virus infection.

    PubMed

    Arruvito, Lourdes; Raiden, Silvina; Geffner, Jorge

    2015-06-01

    Respiratory syncytial virus (RSV) infection is the leading cause of bronchiolitis and hospitalization in young infants and causes 100, 000-200, 000 deaths annually. There is still no licensed vaccine against RSV infection and the therapeutic options are mainly supportive. Despite almost six decades of research, important knowledge gaps remain with respect to the characterization of immune mechanisms responsible for protection and pathogenesis, as well as to the identification of risk factors that predict the severity of infection. Observations made in mouse models and young children suggest that the early innate immune response plays a major role in the pathogenesis of bronchiolitis due to RSV infection. Recent studies have improved our understanding of the role of the adaptive immune response mediated by TH1, TH2, TH17, regulatory T cells, and CD8 T cells in the pathogenesis and resolution of RSV infection. Moreover, investigations performed in the last years have made important contributions to our knowledge of the immune response in young children, the principal risk group for severe disease. A comprehensive understanding of how the protective and deleterious immune response during the course of RSV infection is induced in young children remains a challenge over the coming years.

  15. Animal models of respiratory syncytial virus infection and disease

    USDA-ARS?s Scientific Manuscript database

    The study of human respiratory syncytial virus pathogenesis and immunity has been hampered by its exquisite host specificity, and the difficulties encountered in adapting this virus to a murine host. The reasons for this obstacle are not well understood, but appear to reflect, at least in part, the ...

  16. Hot topics in the prevention of respiratory syncytial virus disease.

    PubMed

    Habibi, Maximillian S; Patel, Sanjay; Openshaw, Peter

    2011-03-01

    The 7th International Respiratory Syncytial Virus Symposium took place in Hotel Blijdorp, Rotterdam, The Netherlands. The series has been running since 1996; this meeting took place after a 3-year gap, and was attended by approximately 200 clinicians, scientists and industry representatives from all over the world. The conference covered all aspects of respiratory syncytial virus disease, including virology, cell biology, pathogenesis, clinical presentation, diagnosis, immunology, vaccines, antivirals and other therapeutic approaches. Reviews by invited keynote speakers were accompanied by oral and poster presentations, with ample opportunity for discussion of unpublished work. This article summarizes a small selection of hot topics from the meeting, focused on pathogenesis, therapeutics and vaccine development.

  17. Respiratory syncytial virus--a comprehensive review.

    PubMed

    Borchers, Andrea T; Chang, Christopher; Gershwin, M Eric; Gershwin, Laurel J

    2013-12-01

    Respiratory syncytial virus (RSV) is amongst the most important pathogenic infections of childhood and is associated with significant morbidity and mortality. Although there have been extensive studies of epidemiology, clinical manifestations, diagnostic techniques, animal models and the immunobiology of infection, there is not yet a convincing and safe vaccine available. The major histopathologic characteristics of RSV infection are acute bronchiolitis, mucosal and submucosal edema, and luminal occlusion by cellular debris of sloughed epithelial cells mixed with macrophages, strands of fibrin, and some mucin. There is a single RSV serotype with two major antigenic subgroups, A and B. Strains of both subtypes often co-circulate, but usually one subtype predominates. In temperate climates, RSV infections reflect a distinct seasonality with onset in late fall or early winter. It is believed that most children will experience at least one RSV infection by the age of 2 years. There are several key animal models of RSV. These include a model in mice and, more importantly, a bovine model; the latter reflects distinct similarity to the human disease. Importantly, the prevalence of asthma is significantly higher amongst children who are hospitalized with RSV in infancy or early childhood. However, there have been only limited investigations of candidate genes that have the potential to explain this increase in susceptibility. An atopic predisposition appears to predispose to subsequent development of asthma and it is likely that subsequent development of asthma is secondary to the pathogenic inflammatory response involving cytokines, chemokines and their cognate receptors. Numerous approaches to the development of RSV vaccines are being evaluated, as are the use of newer antiviral agents to mitigate disease. There is also significant attention being placed on the potential impact of co-infection and defining the natural history of RSV. Clearly, more research is required

  18. Detection of antibody to respiratory syncytial virus by membrane fluorescence.

    PubMed Central

    Scott, R; De Landazuri, M O; Gardner, P S; Owen, J J

    1976-01-01

    An indirect membrane fluorescent antibody technique was established to study HEp 2 cells infected with respiratory syncytial (RS) virus. It was possible to detect IgG and IgM antibody to RS virus in the sera of patients with respiratory infections using this technique. The technique was further applied to the detection of IgA antibody to the same virus in colostrum. PMID:793751

  19. Application of Traditional Chinese Medical Herbs in Prevention and Treatment of Respiratory Syncytial Virus

    PubMed Central

    Lin, Li Li; Xie, Tong; Xu, Jian Ya; Shen, Cun Si; Di, Liu Qing; Chen, Jia Bin

    2016-01-01

    Respiratory syncytial virus (RSV) is a common viral pathogen of the lower respiratory tract, which, in the absence of effective management, causes millions of cases of severe illness per year. Many of these infections develop into fatal pneumonia. In a review of English and Chinese medical literature, recent traditional Chinese medical herb- (TCMH-) based progress in the area of prevention and treatment was identified, and the potential anti-RSV compounds, herbs, and formulas were explored. Traditional Chinese medical herbs have a positive effect on inhibiting viral attachment, inhibiting viral internalization, syncytial formation, alleviation of airway inflammation, and stimulation of interferon secretion and immune system; however, the anti-RSV mechanisms of TCMHs are complicated, which should be further investigated. PMID:27688789

  20. Distinguishing between respiratory syncytial virus subgroups by protein profile analysis.

    PubMed Central

    Walpita, P; Mufson, M A; Stanek, R J; Pfeifer, D; Connor, J D

    1992-01-01

    We subgrouped 75 strains of respiratory syncytial virus by a protein profile method (PPM) which relies on different mobilities of the phosphoprotein in one-dimensional polyacrylamide gel electrophoresis and does not require monoclonal antibodies. When compared with enzyme immunoassay, PPM correctly subgrouped 54 of 56 subgroup A and all 19 subgroup B strains. Images PMID:1572961

  1. Epidemiological characteristics and immune status of children with Respiratory Syncytial Virus.

    PubMed

    Ye, Qing; Shao, Wen-Xia; Shang, Shi-Qiang; Pan, Yan-Xiang; Shen, Hong-Qiang; Chen, Xue-Jun

    2015-02-01

    Respiratory Syncytial Virus (RSV) infections are the dominant cause of pneumonia in children. In order to determine the epidemiological characteristics and immune status of children with Respiratory Syncytial Virus, a prospective study was performed among patients with RSV infection. Comparisons between RSV pneumonia group and normal control group, RSV pneumonia group had lower IL-2 (median levels, pg/ml: 3.8 vs. 5.1, P < 0.01), and higher IL-4 (median levels, pg/ml: 3.2 vs. 2.4, P < 0.01), IL-10 (median levels, pg/ml: 12.2 vs. 2.3, P < 0.01), and IFN-γ (median levels, pg/ml: 13.4 vs. 4.6, P < 0.01). The level of IgE among pneumonia patients caused by RSV increased sharply (median levels, mg/L: 48.1 vs. 8.8, P < 0.01). Another amazing finding is that after birth, the degree of IgE of the children infected by RSV increases gradually with age. This effect is at its peak in 0.6 years old. The IgE and eosinophil levels were higher when patients suffered from RSV pneumonia with wheeze (IgE median levels, IU/ml: with wheeze: 72.74 vs. without wheeze: 11.5, P < 0.05; eosinophil median levels, ×10(9) /l: with wheeze: 0.21 vs. without wheeze: 0.05, P < 0.05). The main morbidity crowd is the children under the age of 1 year old. The downregulation of IL2 and the upregulation of IL-4, IL-10, IFN-γ, and IgE happen after RSV infection.

  2. Spread and Evolution of Respiratory Syncytial Virus A Genotype ON1, Coastal Kenya, 2010–2015

    PubMed Central

    Kamau, Everlyn M.; Agoti, Charles N.; Lewa, Clement; Otieno, Grieven; Bett, Ann; Ngama, Mwanajuma; Cane, Patricia A.; Nokes, D. James

    2017-01-01

    In February 2012, the novel respiratory syncytial virus (RSV) group A, genotype ON1, was detected in Kilifi County, coastal Kenya. ON1 is characterized by a 72-nt duplication within the highly variable G gene (encoding the immunogenic attachment surface protein). Cases were diagnosed through surveillance of pneumonia in children at the county hospital. Analysis of epidemiologic, clinical, and sequence data of RSV-A viruses detected over 5 RSV seasons (2010/2011 to 2014/2015) indicated the following: 1) replacement of previously circulating genotype GA2 ON1, 2) an abrupt expansion in the number of ON1 variants detected in the 2014/2015 epidemic, 3) recently accumulation of amino acid substitutions within the ON1 duplicated sequence, and 4) no clear evidence of altered pathogenicity relative to GA2. The study demonstrates the public health importance of molecular surveillance in defining the spread, clinical effects, and evolution of novel respiratory virus variants. PMID:28098528

  3. Identification of subgroups of bovine respiratory syncytial virus.

    PubMed Central

    Baker, J C; Wilson, E G; McKay, G L; Stanek, R J; Underwood, W J; Velicer, L F; Mufson, M A

    1992-01-01

    The occurrence of antigenic variation among nine isolates of bovine respiratory syncytial virus (BRSV) was determined by examining their reaction patterns to human respiratory syncytial virus (HRSV) subgroup A and B monoclonal antibodies (MAbs) by enzyme immunoassay and radioimmunoprecipitation with fractionation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis by using MAbs and polyclonal antisera to HRSV and BRSV. Shared epitopes were demonstrated on four of five structural proteins between BRSV and both subgroups A and B of HRSV. The nine isolates of BRSV showed different patterns of reactivity in enzyme immunoassays with panels of MAbs to HRSV subgroups A and B. Major variations in the molecular weights of the P (phosphoprotein) and F (fusion protein) proteins were demonstrated among the BRSV isolates tested. These results suggest that BRSV belongs to a different antigenic grouping than HRSV and that BRSV is composed of two distinct subgroups. Images PMID:1583108

  4. Structural basis of respiratory syncytial virus neutralization by motavizumab

    SciTech Connect

    McLellan, Jason S.; Chen, Man; Kim, Albert; Yang, Yongping; Graham, Barney S.; Kwong, Peter D.

    2010-04-13

    Motavizumab is {approx}tenfold more potent than its predecessor, palivizumab (Synagis), the FDA-approved monoclonal antibody used to prevent respiratory syncytial virus (RSV) infection. The structure of motavizumab in complex with a 24-residue peptide corresponding to its epitope on the RSV fusion (F) glycoprotein reveals the structural basis for this greater potency. Modeling suggests that motavizumab recognizes a different quaternary configuration of the F glycoprotein than that observed in a homologous structure.

  5. Understanding respiratory syncytial virus infection to improve treatment and immunity.

    PubMed

    González, P A; Carreño, L J; Bueno, S M; Riedel, C A; Kalergis, A M

    2013-08-01

    Despite significant research since it was discovered more than 50 years ago, respiratory syncytial virus (RSV) continues to be the leading agent causing infant hospitalization and respiratory distress worldwide. Although RSV normally does not cause mortality, this virus is recognized as a major public health and economic burden around the globe. RSV can modulate host immunity leading to an inflammatory response that produces lung damage and virus dissemination in the host airways. Remarkably, infection with the virus elicits poor immunity that in most cases fails to protect against subsequent exposures. Here, we review advances made on the understanding of the lifecycle of the virus, some of the molecular mechanisms it has evolved to cause pathology and ineffective immunity during infection. Hopefully, ongoing research will contribute to developing new drugs and candidate vaccines that will decrease the health burden caused by this virus.

  6. Genotype circulation pattern of human respiratory syncytial virus in Iran.

    PubMed

    Faghihloo, Ebrahim; Yavarian, Jila; Jandaghi, Nazanin Zahra Shafiei; Shadab, Azadeh; Azad, Talat Mokhtari

    2014-03-01

    In order to have information on the molecular epidemiology and genetic circulation pattern of human respiratory syncytial virus (HRSV) in Iran, we studied the genetic variability of both group A and B HRSV strains during seven consecutive years by sequencing the hypervariable C-terminal domain of G protein. A total of 485 children <2years of age who were negative for influenza viruses, screened for the presence of HRSV in this research. HRSV was detected in 94 (19.38%) of the samples using nested RT-PCR. Group A viruses were isolated during each year, while group B viruses were isolated during 2009 and 2013. Phylogenetic analysis showed that all HRSV group A viruses belonged to three genotypes: GA1, GA2, GA5 and the group B viruses were in BA genotype.

  7. Noninvasive ventilation in acute respiratory failure from respiratory syncytial virus bronchiolitis

    PubMed Central

    Nizarali, Zahara; Cabral, Marta; Silvestre, Catarina; Abadesso, Clara; Nunes, Pedro; Loureiro, Helena; Almeida, Helena

    2012-01-01

    Objectives The present study focused on respiratory syncytial virus bronchiolitis with respiratory failure. The aim of the study was to determine whether noninvasive ventilation reduces the need for endotracheal intubation or slows the clinical progression of acute respiratory syncytial virus bronchiolitis by reducing the incidence of infectious complications. Methods The present study was a retrospective cohort study. Cohort A was comprised of children who were admitted to the pediatric intensive and special care unit from 2003-2005 before starting noninvasive ventilation; cohort B was comprised of children who were admitted to the pediatric intensive and special care unit from 2006-2008 after starting noninvasive ventilation. With the exception of noninvasive ventilation, the therapeutic support was the same for the two groups. All children who were diagnosed with respiratory syncytial virus bronchiolitis and respiratory failure between November 2003 and March 2008 were included in the cohort. Demographic, clinical and blood gas variables were analyzed. Results A total of 162 children were included; 75% of the subjects were less than 3 months old. Group A included 64 children, and group B included 98 children. In group B, 34 of the children required noninvasive ventilation. The distributions of the variables age, preterm birth, congenital heart disease, cerebral palsy and chronic lung disease were similar between the two groups. On admission, the data for blood gas analysis and the number of apneas were not significantly different between the groups. In group B, fewer children required invasive ventilation (group A: 12/64 versus group B: 7/98; p=0.02), and there was a reduction in the number of cases of bacterial pneumonia (group A: 19/64 versus group B: 12/98; p=0.008). There was no record of mortality in either of the groups. Conclusion By comparing children with the same disease both before and after noninvasive ventilation was used for ventilation support, we

  8. Influenza and respiratory syncytial virus are the major respiratory viruses detected from prospective testing of pediatric and adult coronial autopsies.

    PubMed

    Speers, David J; Moss, Daniel M; Minney-Smith, Cara; Levy, Avram; Smith, David W

    2013-11-01

    To ascertain the full mortality of influenza and other respiratory viruses, the testing of community autopsy specimens is essential. Respiratory virus PCR and culture were performed on 2418 fresh unfrozen respiratory samples collected from 1611 coronial cases where the death was either unknown or infection was suspected, from July 2007 to June 2011, to detect the common respiratory viruses in children and adults, using standardized microbiological testing. The respiratory virus positive rate was 8·3% (134 cases) with a peak of 28% (42 of 151 cases) in children under 10 years of age. Influenza virus was the commonest respiratory virus (50 cases, 3%), followed by respiratory syncytial virus (RSV) (30 cases, 2%). All tested respiratory viruses were found in children, most commonly adenovirus, enterovirus and RSV, and influenza A and RSV predominated in those over 60 years, but coinfection was uncommon. Almost all influenza cases occurred when influenza was widely circulating in the community but few were diagnosed pre-mortem. Influenza and RSV detection was associated with bronchitis or bronchiolitis in 7 (9%) of the 80 cases and caused pneumonia in 14 (0·8%) deaths overall. Our prospective review of respiratory viruses using standardized testing found a single lower respiratory tract autopsy specimen for respiratory virus PCR would detect most community infections at the time of death. © 2013 John Wiley & Sons Ltd.

  9. Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis.

    PubMed

    Heath, Paul T; Culley, Fiona J; Jones, Christine E; Kampmann, Beate; Le Doare, Kirsty; Nunes, Marta C; Sadarangani, Manish; Chaudhry, Zain; Baker, Carol J; Openshaw, Peter J M

    2017-07-01

    Group B streptococcus and respiratory syncytial virus are leading causes of infant morbidity and mortality worldwide. No licensed vaccines are available for either disease, but vaccines for both are under development. Severe respiratory syncytial virus disease can be prevented by passively administered antibody. The presence of maternal IgG antibody specific to respiratory syncytial virus is associated with reduced prevalence and severity of respiratory syncytial virus disease in the first few weeks of life, whereas maternal serotype-specific anticapsular antibody is associated with protection against both early-onset and late-onset group B streptococcus disease. Therefore, vaccination in pregnancy might protect infants against both diseases. This report describes what is known about immune protection against group B streptococcus and respiratory syncytial virus, identifies knowledge gaps regarding the immunobiology of both diseases, and aims to prioritise research directions in maternal immunisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. The mouse model of respiratory syncytial virus disease.

    PubMed

    Openshaw, Peter J

    2013-01-01

    The laboratory mouse is the species of choice for most immunological studies, ranging from simple vaccine testing to the intricate dissection of fundamental immunopathogenic mechanisms. Although not fully mouse adapted, some strains of respiratory syncytial virus (RSV) replicate in the murine respiratory tract and induce specific T and B cell responses. Passive transfer of neutralising antibody is protective and assist in viral clearance. In addition, many of RSV's complex behaviours are recapitulated in the mouse (including enhancement of disease by vaccination and delayed effects of neonatal infection). However, human studies remain essential to confirm or refute predictions from animal models.

  11. Dimerization of Matrix Protein Is Required for Budding of Respiratory Syncytial Virus

    PubMed Central

    Förster, Andreas; Maertens, Goedele N.; Farrell, Paul J.

    2015-01-01

    ABSTRACT Respiratory syncytial virus (RSV) infects epithelial cells of the respiratory tract and is a major cause of bronchiolitis and pneumonia in children and the elderly. The virus assembles and buds through the plasma membrane, forming elongated membrane filaments, but details of how this happens remain obscure. Oligomerization of the matrix protein (M) is a key step in the process of assembly and infectious virus production. In addition, it was suggested to affect the conformation of the fusion protein, the major current target for RSV antivirals, in the mature virus. The structure and assembly of M are thus key parameters in the RSV antiviral development strategy. The structure of RSV M was previously published as a monomer. Other paramyxovirus M proteins have been shown to dimerize, and biochemical data suggest that RSV M also dimerizes. Here, using size exclusion chromatography-multiangle laser light scattering, we show that the protein is dimeric in solution. We also crystallized M in two crystal forms and show that it assembles into equivalent dimers in both lattices. Dimerization interface mutations destabilize the M dimer in vitro. To assess the biological relevance of dimerization, we used confocal imaging to show that dimerization interface mutants of M fail to assemble into viral filaments on the plasma membrane. Additionally, budding and release of virus-like particles are prevented in M mutants that fail to form filaments. Importantly, we show that M is biologically active as a dimer and that the switch from M dimers to higher-order oligomers triggers viral filament assembly and virus production. IMPORTANCE Human respiratory syncytial virus (RSV) is the most frequent cause of infantile bronchiolitis and pneumonia. The enormous burden of RSV makes it a major unmet target for a vaccine and antiviral drug therapy. Oligomerization of the matrix protein is a key step in the process of assembly and production of infectious virus, but the molecular

  12. 4EBP1 Is Dephosphorylated by Respiratory Syncytial Virus Infection.

    PubMed

    Pérez-Gil, Gustavo; Landa-Cardeña, Adriana; Coutiño, Rocío; García-Román, Rebeca; Sampieri, Clara L; Mora, Silvia I; Montero, Hilda

    2015-01-01

    Respiratory syncytial virus (RSV) requires protein biosynthesis machinery to generate progeny. There is evidence that RSV might alter some translation components since stress granules are formed in their host cells. Consistent with these observations, we found that RSV induces dephosphorylation of 4EBP1 (eIF4E-binding protein), an important cellular translation factor. Our results show no correlation between the 4EBP1 dephosphorylation time and the decrease in the global rate of protein synthesis. Interestingly, treatment with rapamycin stimulates virus generation. The results suggest that RSV is a virus that still contains unknown mechanisms involved in the translation of their mRNAs through the alteration or modification of some translation factors, such as 4EBP1, possibly to favor its replicative cycle.

  13. Respiratory syncytial virus (RSV) and its propensity for causing bronchiolitis.

    PubMed

    Pickles, Raymond J; DeVincenzo, John P

    2015-01-01

    Infants and young children with acute onset of wheezing and reduced respiratory airflows are often diagnosed with obstruction and inflammation of the small bronchiolar airways, ie bronchiolitis. The most common aetological agents causing bronchiolitis in young children are the respiratory viruses, and of the commonly encountered respiratory viruses, respiratory syncytial virus (RSV) has a propensity for causing bronchiolitis. Indeed, RSV bronchiolitis remains the major reason why previously healthy infants are admitted to hospital. Why RSV infection is such a predominant cause of bronchiolitis is the subject of this review. By reviewing the available histopathology of RSV bronchiolitis, both in humans and relevant animal models, we identify hallmark features of RSV infection of the distal airways and focus attention on the consequences of columnar cell cytopathology occurring in the bronchioles, which directly impacts the development of bronchiolar obstruction, inflammation and disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  14. Cytokines in the nasal washes of children with respiratory syncytial virus bronchiolitis.

    PubMed

    Midulla, F; Tromba, V; Lo Russo, L; Mileto, F; Sabatino, G; Sgarrella, M; Panuska, J R; Manganozzi, L; Korn, D; Moretti, C

    2006-01-01

    Although respiratory syncytial (RS) virus is the major cause of bronchiolitis and pneumonia in young children, the factors that regulate the associated lung inflammation have not been defined. The levels of interleukin (IL)10, IL-12, and interferon (IFN) were determined in the nasal wash samples from 20 infants with a clinical diagnosis of bronchiolitis, seven with confirmed RS virus infections and 9 control children without respiratory illnesses. IL-10 levels were significantly higher in acute nasal wash samples (1-4 d post hospitalization) from RS virus-infected infants than in convalescent samples from these children (14-21 d post-hospitalization), from children with other forms of bronchiolitis and from control children. In contrast, only one RS virus-infected infant had detectable IL-12 in an acute nasal wash sample. IFN activity was not detected in any samples from RS virus-infected children. RS virus infection stimulates IL-10 expression but not IL-12 and IFN, possibly contributing to an ineffective cell-mediated immune response.

  15. Pneumonia (For Parents)

    MedlinePlus

    ... Dysplasia (BPD) Respiratory Syncytial Virus Coughing Lungs and Respiratory System Croup Fever and Taking Your Child's Temperature Influenza ( ... Haemophilus Influenzae Type b) Bronchitis Pneumonia Lungs and Respiratory System Contact Us Print Resources Send to a friend ...

  16. Trends of Respiratory Syncytial Virus Infections in Children under 2 Years of Age in Puerto Rico.

    PubMed

    Matías, Israel; García, Inés; García-Fragoso, Lourdes; Puig, Gilberto; Pedraza, Lourdes; Rodríguez, Luis; Santaella, Alvaro; Arce, Sylvia; Toledo, Marilyn; Soto, Edwin; Valcárcel, Marta

    2015-06-01

    The respiratory syncytial virus (RSV) is the most significant viral pathogen causing bronchiolitis and pneumonia in infants, today. In tropical climates the RSV infection may occur throughout the year. The purpose of this study was to asses RSV infections during the 2009‒2010 RSV season in children under 2 years of age and to evaluate the trend of positive RSV tests in the period of 2007 to 2009. A retrospective review of data collected from 6 hospitals in Puerto Rico was performed. Patients with confirmed RSV bronchiolitis were included in the study. A total of 4,678 patients were included. The mean age of the patients was 7 months. Data showed that RSV infection occurred throughout the studied months. Data confirms a year-round presence of RSV in Puerto Rico. The RSV surveillance system needs to be reinforced to establish and understand the epidemiology of RSV and to review the current immunoprophylaxis guidelines.

  17. In Hot Pursuit of the First Vaccine Against Respiratory Syncytial Virus

    PubMed Central

    Kim, Joo Young

    2016-01-01

    Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection, such as bronchiolitis, bronchitis, or pneumonia, in both infants and the elderly. Despite the global burden of diseases attributable to RSV infection, no clinically approved vaccine is available, and a humanized monoclonal antibody for prophylaxis is not readily affordable in developing countries. There are several hurdles to the successful development of RSV vaccines: immune-vulnerable target populations such as premature infants, pregnant women, and immunocompromised people; safety concerns associated with vaccine-enhanced diseases; repeated infection; and waning memory. To develop successful strategies for the prevention of RSV infection, it is necessary to understand the protective and pathologic roles of host immune responses to RSV infection. In this review, we will summarize the positive and negative relationship between RSV infection and host immunity and discuss strategies for the development of the first successful RSV vaccine. PMID:27189271

  18. Respiratory syncytial virus: how, why and what to do.

    PubMed

    Rodriguez, Rosa; Ramilo, Octavio

    2014-01-01

    Bronchiolitis is the leading cause of hospitalization of infants and young children worldwide. Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Studies conducted using molecular diagnostic assays confirmed that RSV accounts for over 50% of bronchiolitis in young children requiring hospitalization. Those studies demonstrate that it is common to identify RSV in association with a second viral agent but it is yet unclear whether the simultaneous detection of two or even three viruses is associated with increased disease severity. Despite extensive efforts, a vaccine for prevention of RSV infection is not yet available. Palivizumab a humanized monoclonal antibody directed against the F protein of RSV is the only agent licensed to prevent severe RSV disease in high-risk children. Among the new antivirals being developed for treatment of RSV infections, an RNA-interference based agent has demonstrated promising results for treatment of lung transplant recipients with acute RSV infection.

  19. Immune responses and disease enhancement during respiratory syncytial virus infection.

    PubMed

    Openshaw, Peter J M; Tregoning, John S

    2005-07-01

    Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis.

  20. Incidence of bacterial coinfection with respiratory syncytial virus bronchopulmonary infection in pediatric inpatients.

    PubMed

    Hishiki, Haruka; Ishiwada, Naruhiko; Fukasawa, Chie; Abe, Katsuaki; Hoshino, Tadashi; Aizawa, Jiro; Ishikawa, Nobuyasu; Kohno, Yoichi

    2011-02-01

    Bacterial coinfection occurs in pediatric bronchopulmonary infections caused by respiratory syncytial virus (RSV), but the incidence is uncertain. Our subjects are 188 pediatric inpatients having RSV bronchopulmonary infection in two hospitals in Chiba Prefecture between 2005 and 2007. On admission, antigen detection kits using nasopharyngeal aspirate were performed to detect RSV infection and washed sputum bacterial culture was performed to detect bacterial infection. Of the 188 pediatric inpatients with RSV bronchopulmonary infection, 95 (50.5%) patients were aged less than 1 year, 57 (30.3%) were aged 1-2 years, and 36 (19.1%) were aged 2 years or more. Thirty-six (19.1%) patients were associated with bronchial asthma attacks. Pathogenic bacteria were predominantly isolated from 43.6% of the patients. The three most frequently isolated bacteria were Haemophilus influenzae (43.9%), Streptococcus pneumoniae (36.6%), and Moraxella catarrhalis (29.3%). We found that 38.9% of H. influenzae strains were β-lactamase-nonproducing ampicillin-resistant strains. All S. pneumoniae strains were penicillin G (PcG) sensitive. However, 21.9% of S. pneumoniae strains showed PcG minimum inhibitory concentration values of 2 μg/ml. RSV bronchopulmonary infections in hospitalized children are often associated with antimicrobial-resistant bacterial infection in their lower airways. These results indicate that we should be aware of bacterial coinfections in the management of pediatric inpatients with RSV bronchopulmonary infection.

  1. Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus.

    PubMed

    Wen, Xiaolin; Mousa, Jarrod J; Bates, John T; Lamb, Robert A; Crowe, James E; Jardetzky, Theodore S

    2017-01-30

    Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are two closely related viruses that cause bronchiolitis and pneumonia in infants and the elderly(1), with a significant health burden(2-6). There are no licensed vaccines or small-molecule antiviral treatments specific to these two viruses at present. A humanized murine monoclonal antibody (palivizumab) is approved to treat high-risk infants for RSV infection(7,8), but other treatments, as well as vaccines, for both viruses are still in development. Recent epidemiological modelling suggests that cross-immunity between RSV, HMPV and human parainfluenzaviruses may contribute to their periodic outbreaks(9), suggesting that a deeper understanding of host immunity to these viruses may lead to enhanced strategies for their control. Cross-reactive neutralizing antibodies to the RSV and HMPV fusion (F) proteins have been identified(10,11). Here, we examine the structural basis for cross-reactive antibody binding to RSV and HMPV F protein by two related, independently isolated antibodies, MPE8 and 25P13. We solved the structure of the MPE8 antibody bound to RSV F protein and identified the 25P13 antibody from an independent blood donor. Our results indicate that both antibodies use germline residues to interact with a conserved surface on F protein that could guide the emergence of cross-reactivity. The induction of similar cross-reactive neutralizing antibodies using structural vaccinology approaches could enhance intrinsic cross-immunity to these paramyxoviruses and approaches to controlling recurring outbreaks.

  2. The development of a mimotope-based synthetic peptide vaccine against respiratory syncytial virus.

    PubMed

    Steward, M W

    2001-01-01

    Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in infants and young children worldwide and the development of a synthetic peptide epitope-based vaccine to induce virus-neutralising antibodies against RSV would seem to be a valid approach to the production of an effective vaccine against infection.A combinatorial solid-phase peptide library has been screened with a virus-neutralising, protective monoclonal antibody (MAb19) directed towards a conserved and conformationally-determined epitope of the Fusion (F) protein of the virus. Two of the sequences identified from the peptide library using MAb19 reacted specifically with the antibody and amino acid substitution experiments identified four sequences from one of the mimotopes which showed increased reactivity with MAb19. Immunisation of BALB/c mice with these mimotopes, presented as MAPs, resulted in the induction of anti-peptide antibodies that inhibited the binding of MAb19 to the virus and neutralised viral infection in vitro, with titres equivalent to those in sera from RSV-infected animals. Following RSV challenge of mimotope-immunised mice, a significant reduction in the titre of virus and a greatly reduced cell infiltration into the lungs of immunised mice compared to that in controls was observed. The induction of virus-specific cytotoxic T-lymphocyte responses as well as virus-specific antibodies are likely to be necessary in an effective vaccine. The incorporation of a peptide representing a CTL epitope from the M2 protein of the virus together with peptides inducing T-helper and anti-mimotope responses in a peptide cocktail vaccine resulted in a more effective clearance of the virus from immunised, challenged mice than peptide-induced humoral or cellular immunity alone.

  3. Respiratory syncytial virus: co-infection and paediatric lower respiratory tract infections.

    PubMed

    Yoshida, Lay-Myint; Suzuki, Motoi; Nguyen, Hien Anh; Le, Minh Nhat; Dinh Vu, Thiem; Yoshino, Hiroshi; Schmidt, Wolf-Peter; Nguyen, Thi Thuy Ai; Le, Huu Tho; Morimoto, Konosuke; Moriuchi, Hiroyuki; Dang, Duc Anh; Ariyoshi, Koya

    2013-08-01

    Comprehensive population-based data on the role of respiratory viruses in the development of lower respiratory tract infections (LRTIs) remain unclear. We investigated the incidence and effect of single and multiple infections with respiratory viruses on the risk of LRTIs in Vietnam. Population-based prospective surveillance and a case-control study of hospitalised paediatric patients with acute respiratory infection (ARI) were conducted from April 2007 through to March 2010. Healthy controls were randomly recruited from the same community. Nasopharyngeal samples were collected and tested for 13 respiratory viruses using multiplex PCRs. 1992 hospitalised ARI episodes, including 397 (19.9%) with LRTIs, were enrolled. Incidence of hospitalised LRTIs among children aged <24 months was 2171.9 per 100 000 (95% CI 1947.9-2419.7). The majority of ARI cases (60.9%) were positive for at least one virus. Human rhinovirus (24.2%), respiratory syncytial virus (20.1%) and influenza A virus (12.0%) were the most common and 9.5% had multiple-viral infections. Respiratory syncytial virus and human metapneumovirus infections independently increased the risk of LRTIs. Respiratory syncytial virus further increased the risk, when co-infected with human rhinovirus, human metapneumovirus and parainfluenza virus-3 but not with influenza A virus. The case-control analysis revealed that respiratory syncytial virus and influenza A virus increased the risk of ARI hospitalisation but not human rhinovirus. Respiratory syncytial virus is the leading pathogen associated with risk of ARI hospitalisation and LRTIs in Vietnam.

  4. Epidemiology, molecular epidemiology and evolution of bovine respiratory syncytial virus.

    PubMed

    Sarmiento-Silva, Rosa Elena; Nakamura-Lopez, Yuko; Vaughan, Gilberto

    2012-11-30

    The bovine respiratory syncytial virus (BRSV) is an enveloped, negative sense, single-stranded RNA virus belonging to the pneumovirus genus within the family Paramyxoviridae. BRSV has been recognized as a major cause of respiratory disease in young calves since the early 1970s. The analysis of BRSV infection was originally hampered by its characteristic lability and poor growth in vitro. However, the advent of numerous immunological and molecular methods has facilitated the study of BRSV enormously. The knowledge gained from these studies has also provided the opportunity to develop safe, stable, attenuated virus vaccine candidates. Nonetheless, many aspects of the epidemiology, molecular epidemiology and evolution of the virus are still not fully understood. The natural course of infection is rather complex and further complicates diagnosis, treatment and the implementation of preventive measures aimed to control the disease. Therefore, understanding the mechanisms by which BRSV is able to establish infection is needed to prevent viral and disease spread. This review discusses important information regarding the epidemiology and molecular epidemiology of BRSV worldwide, and it highlights the importance of viral evolution in virus transmission.

  5. Perinatal Lamb Model of Respiratory Syncytial Virus (RSV) Infection

    PubMed Central

    Derscheid, Rachel J.; Ackermann, Mark R.

    2012-01-01

    Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term) lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO) oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation) and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines. PMID:23202468

  6. Perinatal lamb model of respiratory syncytial virus (RSV) infection.

    PubMed

    Derscheid, Rachel J; Ackermann, Mark R

    2012-10-23

    Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. Many animal models are used to study RSV, but most studies investigate disease in adult animals which does not address the unique physiology and immunology that makes infants more susceptible. The perinatal (preterm and term) lamb is a useful model of infant RSV disease as lambs have similar pulmonary structure including airway branching, Clara and type II cells, submucosal glands and Duox/lactoperoxidase (LPO) oxidative system, and prenatal alveologenesis. Lambs can be born preterm (90% gestation) and survive for experimentation although both preterm and term lambs are susceptible to ovine, bovine and human strains of RSV and develop clinical symptoms including fever, tachypnea, and malaise as well as mild to moderate gross and histologic lesions including bronchiolitis with epithelial injury, neutrophil infiltration and syncytial cell formation. RSV disease in preterm lambs is more severe than in term lambs; disease is progressively less in adults and age-dependent susceptibility is a feature similar to humans. Innate and adaptive immune responses by perinatal lambs closely parallel those of infants. The model is used to test therapeutic regimens, risk factors such as maternal ethanol consumption, and formalin inactivated RSV vaccines.

  7. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.

    PubMed

    Scheltema, Nienke M; Gentile, Angela; Lucion, Florencia; Nokes, D James; Munywoki, Patrick K; Madhi, Shabir A; Groome, Michelle J; Cohen, Cheryl; Moyes, Jocelyn; Thorburn, Kentigern; Thamthitiwat, Somsak; Oshitani, Hitoshi; Lupisan, Socorro P; Gordon, Aubree; Sánchez, José F; O'Brien, Katherine L; Gessner, Bradford D; Sutanto, Agustinus; Mejias, Asuncion; Ramilo, Octavio; Khuri-Bulos, Najwa; Halasa, Natasha; de-Paris, Fernanda; Pires, Márcia Rosane; Spaeder, Michael C; Paes, Bosco A; Simões, Eric A F; Leung, Ting F; da Costa Oliveira, Maria Tereza; de Freitas Lázaro Emediato, Carla Cecília; Bassat, Quique; Butt, Warwick; Chi, Hsin; Aamir, Uzma Bashir; Ali, Asad; Lucero, Marilla G; Fasce, Rodrigo A; Lopez, Olga; Rath, Barbara A; Polack, Fernando P; Papenburg, Jesse; Roglić, Srđan; Ito, Hisato; Goka, Edward A; Grobbee, Diederick E; Nair, Harish; Bont, Louis J

    2017-10-01

    Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3-11·0) in low-income or lower middle-income countries, 4·0 years (2·0-10·0) in upper middle

  8. Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design

    PubMed Central

    Rey-Jurado, Emma; Kalergis, Alexis M.

    2017-01-01

    The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th)-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus. PMID:28273842

  9. Respiratory syncytial virus infection and virus-induced inflammation are modified by contaminants of indoor air

    PubMed Central

    Foster, Serene; Bedford, Kirk J; Gould, Melanie E L; Coward, William R; Hewitt, Colin R A

    2003-01-01

    The airway epithelium is the first cellular component of the lung to be encountered by the particles and pathogens present in inhaled air. In addition to its role as a physical barrier, the immunological activity of the airway epithelium is an essential part of the pulmonary immune system. This means that the symptoms of lung diseases that involve immunological mechanisms are frequently exacerbated by infection of the airway epithelium with respiratory viruses. The virus-induced enhancement of immunological activity in infected epithelial cells is well characterized. However, the effects that contaminants of inhaled air have upon the infectivity and replication of respiratory viruses and the inflammation they cause, are comparatively unknown. In this study, we have shown that pre-exposure of airway epithelial cells to bacterial lipopolysaccharides or a proteolytically active house dust mite allergen, is able to, respectively, inhibit or enhance the level of cellular infection with respiratory syncytial virus and similarly alter virus-induced expression of the inflammatory chemokine interleukin-8. These results suggest that respiratory syncytial virus infection and the inflammation caused by respiratory syncytial virus may be modified by the biologically active contaminants of indoor air. PMID:12519309

  10. [Potential neurocognitive consequences of infection by human respiratory syncytial virus].

    PubMed

    Flores, Juan Carlos; Bohmwald, Karen; Espinoza, Janyra; Jara, Crlstlna; Peña, Marcela; Hoyos-Bachiloglu, Rodrigo; Iturriaga, Carolina; Kalergis, Alexis M; Borzutzky, Arturo

    2016-10-01

    Human respiratory syncytial virus (RSV) infection remains as a major cause of morbidity and mortality among pediatric population. Immune response is poor and unable to establish a long term effective protection against this virus. Of particular interest has been the description of extrapulmonary manifestations of RSV infection in liver, kidney, endocrine system, heart and brain, associated to infection of peripheral blood. In the central nervous system (CNS), recent studies in animals have suggested long term neurocognitive impairment due to a direct damage from the virus. This was prevented in rats by a recombinant BCG vaccine expressing a nucleoprotein N of RSV that produces an effective immune response against the virus, not allowing its dissemination to the CNS. These findings in animal models highlight the importance of conducting more specific studies in children affected with severe infection by RSV. Therefore, our group is currently conducting an assessment of the possible long-term cognitive impairment in children under 2 years. The results of this study could be a strong argument to continue looking for an effective method for protecting against RSV infection.

  11. Prevention of Respiratory Syncytial Virus Infection: From Vaccine to Antibody.

    PubMed

    Huang, Kelly; Wu, Herren

    2014-08-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children. Initial efforts to develop a vaccine to prevent RSV lower respiratory tract disease in children were halted because of serious adverse events that occurred when children were infected with RSV following vaccination, including vaccine-related deaths. Subsequently, a major focus for researchers was to understand what led to these adverse events. Investment in a vaccine for RSV continues, and new strategies are under development. Success to prevent RSV disease was met by the development of immunoprophylaxis, first with intravenous immunoglobulin and then with recombinant monoclonal antibody. The story of immunoprophylaxis for RSV includes the first-in-class use of antibody technology for infectious disease, and palivizumab currently remains the only way to prevent serious lower respiratory tract disease due to RSV infection.

  12. Respiratory syncytial virus--viral biology and the host response.

    PubMed

    Hacking, D; Hull, J

    2002-07-01

    Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. We have an incomplete understanding of the reasons why some infants are more severely affected by RSV than others. There is no effective antiviral treatment for the infection. Advances in our understanding of the biology of RSV, particularly in relation to the attachment protein G and the fusion protein F, have revealed potential targets for new antiviral therapies and vaccine development. In response to RSV infection an intense inflammatory response is triggered, mediated initially by the infected airway epithelial cells. Cell mediated responses are important in controlling the extent of infection and in viral clearance. Humoral responses are important in protection. There is early evidence that genetic variation of the host response can influence the outcome of RSV-induced bronchiolitis.

  13. Recent Advances in Developing Antiviral Therapies for Respiratory Syncytial Virus.

    PubMed

    Shook, Brian C; Lin, Kai

    2017-04-01

    Respiratory syncytial virus (RSV) infection presents a significant health challenge in small children, the elderly and immunocompromised patients. There is still a high unmet medical need among patients with RSV infection, and no specific antiviral therapy is available. The only approved agents are palivizumab, which has to be given prophylactically, mainly in high-risk infants, and ribavirin, which is rarely used due to toxicity concerns and questionable benefits. Efforts to develop new antiviral agents have been hampered by the perceived need for high safety hurdles in pediatric patient populations use and the lack of well-characterized druggable targets. Despite these challenges, significant progress has been made in discovering multiple classes of inhibitors targeting various stages of the viral life cycle. Several recent proof-of-concept human studies with specific antivirals have shown promising results and completely reinvigorated the field. In this review we discuss the current status of RSV drug development, remaining challenges and future directions.

  14. A recombinant influenza virus vaccine expressing the F protein of respiratory syncytial virus

    PubMed Central

    Fonseca, Wendy; Ozawa, Makoto; Hatta, Masato; Orozco, Esther; Martínez, Máximo B; Kawaoka, Yoshihiro

    2014-01-01

    Infections with influenza and respiratory syncytial virus (RSV) rank high among the most common human respiratory diseases worldwide. Previously, we developed a replication-incompetent influenza virus by replacing the coding sequence of the PB2 gene, which encodes one of the viral RNA polymerase subunits, with that of a reporter gene. Here, we generated a PB2-knockout recombinant influenza virus expressing the F protein of RSV (PB2-RSVF virus) and tested its potential as a bivalent vaccine. In mice intranasally immunized with the PB2-RSVF virus, we detected high levels of antibodies against influenza virus, but not RSV. PB2-RSVF virus-immunized mice were protected from a lethal challenge with influenza virus but experienced severe body weight loss when challenged with RSV, indicating that PB2-RSVF vaccination enhanced RSV-associated disease. These results highlight one of the difficulties of developing an effective bivalent vaccine against influenza virus and RSV infections. PMID:24292020

  15. Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus.

    PubMed

    Andries, Koen; Moeremans, Marc; Gevers, Tom; Willebrords, Rudy; Sommen, Cois; Lacrampe, Jean; Janssens, Frans; Wyde, Philip R

    2003-11-01

    A cell-based assay was used to discover compounds inhibiting respiratory syncytial virus (RSV)-induced fusion in HeLa/M cells. A lead compound was identified and subsequent synthesis of >300 analogues led to the identification of JNJ 2408068 (R170591), a low molecular weight (MW 395) benzimidazole derivative with an EC(50) (0.16 nM) against some lab strains almost 100,000 times better than that of ribavirin (15 microM). Antiviral activity was confirmed for subgroup A and B clinical isolates of human RSV and for a bovine RSV isolate. The compound did not inhibit the growth of representative viruses from other Paramyxovirus genera, i.e. HPIV2 and Mumps Virus (genus Rubulavirus), HPIV3 (genus Respirovirus), Measles virus (genus Morbillivirus) and hMPV. Efficacy in cytopathic effect inhibition assays correlated well with efficacy in virus yield reduction assays. A concentration of 10nM reduced RSV production 1000-fold in multi-cycle experiments, irrespective of the multiplicity of infection. Time of addition studies pointed to a dual mode of action: inhibition of virus-cell fusion early in the infection cycle and inhibition of cell-cell fusion at the end of the replication cycle. Two resistant mutants were raised and shown to have single point mutations in the F-gene (S398L and D486N). JNJ 2408068 was also shown to inhibit the release of proinflammatory cytokines IL-6, IL-8 and Rantes from RSV-infected A549 cells.

  16. Acute and Chronic Airway Disease After Human Respiratory Syncytial Virus Infection in Cotton Rats (Sigmodon hispidus).

    PubMed

    Grieves, Jessica L; Yin, Zhiwei; Durbin, Russell K; Durbin, Joan E

    2015-08-01

    Infection with respiratory syncytial virus (RSV) generally presents as a mild, upper airway disease in human patients but may cause severe lower airway disease in the very young and very old. Progress toward understanding the mechanisms of RSV pathogenesis has been hampered by a lack of relevant rodent models. Mice, the species most commonly used in RSV research, are resistant to upper respiratory infection and do not recapitulate the pattern of virus spread in the human host. To address the need for better rodent models of RSV infection, we have characterized the acute and chronic pathology of RSV infection of a relatively permissive host, cotton rats (Sigmodon hispidus). We demonstrate that virus delivered to the upper airway results in widespread RSV replication in the ciliated respiratory epithelial cells of the nasal cavity and, to a lesser extent, of the lung. Although acute inflammation is relatively mild and rapidly eliminated after viral clearance, chronic, eosinophilic lung pathology persists. These data support the use of cotton rats as a robust rodent model of human RSV disease, including the association between RSV pneumonia and subsequent development of allergic asthma.

  17. Acute and Chronic Airway Disease After Human Respiratory Syncytial Virus Infection in Cotton Rats (Sigmodon hispidus)

    PubMed Central

    Grieves, Jessica L; Yin, Zhiwei; Durbin, Russell K; Durbin, Joan E

    2015-01-01

    Infection with respiratory syncytial virus (RSV) generally presents as a mild, upper airway disease in human patients but may cause severe lower airway disease in the very young and very old. Progress toward understanding the mechanisms of RSV pathogenesis has been hampered by a lack of relevant rodent models. Mice, the species most commonly used in RSV research, are resistant to upper respiratory infection and do not recapitulate the pattern of virus spread in the human host. To address the need for better rodent models of RSV infection, we have characterized the acute and chronic pathology of RSV infection of a relatively permissive host, cotton rats (Sigmodon hispidus). We demonstrate that virus delivered to the upper airway results in widespread RSV replication in the ciliated respiratory epithelial cells of the nasal cavity and, to a lesser extent, of the lung. Although acute inflammation is relatively mild and rapidly eliminated after viral clearance, chronic, eosinophilic lung pathology persists. These data support the use of cotton rats as a robust rodent model of human RSV disease, including the association between RSV pneumonia and subsequent development of allergic asthma. PMID:26310461

  18. Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

    PubMed

    Farrag, Mohamed A; Almajhdi, Fahad N

    2016-01-01

    Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed.

  19. Ameliorating Effect of Dietary Xylitol on Human Respiratory Syncytial Virus (hRSV) Infection.

    PubMed

    Xu, Mei Ling; Wi, Ga Ram; Kim, Hyoung Jin; Kim, Hong-Jin

    2016-01-01

    Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in infants. The lack of proper prophylactics and therapeutics for controlling hRSV infection has been of great concern worldwide. Xylitol is a well-known sugar substitute and its effect against bacteria in the oral cavity is well known. However, little is known of its effect on viral infections. In this study, the effect of dietary xylitol on hRSV infection was investigated in a mouse model for the first time. Mice received xylitol for 14 d prior to virus challenge and for a further 3 d post challenge. Significantly larger reductions in lung virus titers were observed in the mice receiving xylitol than in the controls receiving phosphate-buffered saline (PBS). In addition, fewer CD3(+) and CD3(+)CD8(+) lymphocytes, whose numbers reflect inflammatory status, were recruited in the mice receiving xylitol. These results indicate that dietary xylitol can ameliorate hRSV infections and reduce inflammation-associated immune responses to hRSV infection.

  20. Host cytoskeleton in respiratory syncytial virus assembly and budding.

    PubMed

    Shahriari, Shadi; Gordon, James; Ghildyal, Reena

    2016-09-26

    Respiratory syncytial virus (RSV) is one of the major pathogens responsible for lower respiratory tract infections (LRTI) in young children, the elderly, and the immunosuppressed. Currently, there are no antiviral drugs or vaccines available that effectively target RSV infections, proving a significant challenge in regards to prevention and treatment. An in-depth understanding of the host-virus interactions that underlie assembly and budding would inform new targets for antiviral development.Current research suggests that the polymerised form of actin, the filamentous or F-actin, plays a role in RSV assembly and budding. Treatment with cytochalasin D, which disrupts F-actin, has been shown to inhibit virus release. In addition, the actin cytoskeleton has been shown to interact with the RSV matrix (M) protein, which plays a central role in RSV assembly. For this reason, the interaction between these two components is hypothesised to facilitate the movement of viral components in the cytoplasm and to the budding site. Despite increases in our knowledge of RSV assembly and budding, M-actin interactions are not well understood. In this review, we discuss the current literature on the role of actin cytoskeleton during assembly and budding of RSV with the aim to integrate disparate studies to build a hypothetical model of the various molecular interactions between actin and RSV M protein that facilitate RSV assembly and budding.

  1. Identification of syncytial mutations in a clinical isolate of herpes simplex virus 2

    SciTech Connect

    Muggeridge, Martin I. . E-mail: mmugge@lsuhsc.edu; Grantham, Michael L.; Johnson, F. Brent

    2004-10-25

    Small polykaryocytes resulting from cell fusion are found in herpes simplex virus (HSV) lesions in patients, but their significance for viral spread and pathogenesis is unclear. Although syncytial variants causing extensive fusion in tissue culture can be readily isolated from laboratory strains, they are rarely found in clinical isolates, suggesting that extensive cell fusion may be deleterious in vivo. Syncytial mutations have previously been identified for several laboratory strains, but not for clinical isolates of HSV type 2. To address this deficiency, we studied a recent syncytial clinical isolate, finding it to be a mixture of two syncytial and one nonsyncytial strain. The two syncytial strains have novel mutations in glycoprotein B, and in vitro cell fusion assays confirmed that they are responsible for syncytium formation. This panel of clinical strains may be ideal for examining the effect of increased cell fusion on pathogenesis.

  2. Climatic, temporal, and geographic characteristics of respiratory syncytial virus disease in a tropical island population

    PubMed Central

    OMER, S. B.; SUTANTO, A.; SARWO, H.; LINEHAN, M.; DJELANTIK, I. G. G.; MERCER, D.; MONIAGA, V.; MOULTON, L. H.; WIDJAYA, A.; MULJATI, P.; GESSNER, B. D.; STEINHOFF, M. C.

    2008-01-01

    SUMMARY Respiratory syncytial virus (RSV) is an important cause of morbidity in children worldwide, although data from equatorial regions are limited. We analysed climatic, spatial, and temporal data for children presenting to hospitals in Lombok island, Indonesia with clinical pneumonia. During the study period, 2878 children presented and 741 RSV cases were identified. In multivariate analysis with an 8-day lag, occurrence of rain was associated with 64% higher incidence of RSV disease [incidence rate ratio (IRR) 1·64, 95% confidence interval (CI) 1·13–2·38]. A 1% rise in mean relative humidity and 1°C increase in mean air temperature was associated with a 6% (IRR 1·06, 95% CI 1·03–1·10) and 44% (IRR 1·44, 95% CI 1·24–1·66) increase in RSV cases, respectively. Four statistically significant local clusters of RSV pneumonia were identified within the annual island-wide epidemics. This study demonstrates statistical association of monsoon-associated weather in equatorial Indonesia with RSV. Moreover, within the island-wide epidemics, localized RSV outbreaks suggest local factors influence RSV disease. PMID:18177515

  3. Climatic, temporal, and geographic characteristics of respiratory syncytial virus disease in a tropical island population.

    PubMed

    Omer, S B; Sutanto, A; Sarwo, H; Linehan, M; Djelantik, I G G; Mercer, D; Moniaga, V; Moulton, L H; Widjaya, A; Muljati, P; Gessner, B D; Steinhoff, M C

    2008-10-01

    Respiratory syncytial virus (RSV) is an important cause of morbidity in children worldwide, although data from equatorial regions are limited. We analysed climatic, spatial, and temporal data for children presenting to hospitals in Lombok island, Indonesia with clinical pneumonia. During the study period, 2878 children presented and 741 RSV cases were identified. In multivariate analysis with an 8-day lag, occurrence of rain was associated with 64% higher incidence of RSV disease [incidence rate ratio (IRR) 1.64, 95% confidence interval (CI) 1.13-2.38]. A 1% rise in mean relative humidity and 1 degree C increase in mean air temperature was associated with a 6% (IRR 1.06, 95% CI 1.03-1.10) and 44% (IRR 1.44, 95% CI 1.24-1.66) increase in RSV cases, respectively. Four statistically significant local clusters of RSV pneumonia were identified within the annual island-wide epidemics. This study demonstrates statistical association of monsoon-associated weather in equatorial Indonesia with RSV. Moreover, within the island-wide epidemics, localized RSV outbreaks suggest local factors influence RSV disease.

  4. Respiratory syncytial virus prophylaxis--the story so far.

    PubMed

    Simoes, E A F; Groothuis, J R

    2002-04-01

    Respiratory syncytial virus (RSV) is a common and highly contagious pathogen that infects nearly all children by the age of 2 years. It is responsible for significant morbidity and mortality worldwide among certain high-risk paediatric populations. Therapy is sub-optimal for RSV, thus treatment focuses on ameliorating symptoms. Since discovery of the virus in the 1950s, efforts have been ongoing to develop a safe and effective vaccine. These efforts have met with serious obstacles. Passive immunoprophylaxis presents a viable alternative to active immunization. In 1998, the genetically engineered humanized monoclonal antibody (palivizumab) was granted FDA (Food and Drug Administration) approval for prophylaxis of high-risk children in the United States; EMEA (European Agency for the Evaluation of Medicinal Products) approval followed in 1999 for Europe. It is now approved in over 45 countries worldwide. Palivizumab was shown to significantly reduce RSV-related hospitalizations in North America and Europe with few adverse effects. Clinical trial and outcomes data documenting experience with palivizumab to date continue to extend the initial safety and efficacy observations.

  5. Respiratory Syncytial Virus Persistence in Macrophages Upregulates Fcgamma Receptors Expression

    PubMed Central

    Gaona, Jorge; Santiago-Olivares, Carlos; Ortega, Enrique; Gómez, Beatriz

    2014-01-01

    Viruses can persist in differentiated cells (i.e., macrophages) over long periods of time, altering host cells functions but not inducing their death. We had previously reported that, in early passages (14–40) of a murine macrophage-like cell line persistently infected with respiratory syncytial virus (RSV) (MɸP), FcγR-mediated phagocytosis and expression of FcγRIIB/RIII on the cell membrane were increased with respect to mock-infected macrophages (MɸN). In this work, we explored the mechanism underlying such effects. Increases in FcγR expression and FcγR-mediated phagocytosis are preserved after more than 87 passages of the persistently infected culture. We analyzed the expression of FcγR isoforms at both mRNA and protein levels, and found out that RSV persistence distinctly affects the expression of FcγR isoforms. We also observed that the increase in FcγRs expression results neither from soluble factors (cytokines) or viral products released by the infected cells, nor from an increase in the rate of FcγR internalization. Our results suggest that RSV persistence in macrophages induce intracellular effects that have an impact on FcγRs gene expression at both mRNA and protein levels, and that the characteristics of RSV persistence were preserved for over 87 passages. PMID:24509813

  6. Bovine respiratory syncytial virus: infection dynamics within and between herds

    PubMed Central

    Klem, T. B.; Gulliksen, S. M.; Lie, K.-I.; Løken, T.; Østerås, O.; Stokstad, M.

    2013-01-01

    The infection dynamics of bovine respiratory syncytial virus (BRSV) were studied in randomly selected Norwegian dairy herds. A total of 134 herds were tested twice, six months apart. The herds were classified as positive for BRSV if at least one animal between 150 and 365 days old tested positive for antibodies against BRSV, thereby representing herds that had most likely had the virus present during the previous year. The prevalence of positive herds at the first and second sampling was 34 per cent and at 41 per cent, respectively, but varied greatly between regions. Negative herds were found in close proximity to positive herds. Some of these herds remained negative despite several new infections nearby. Of the herds initially being negative, 42 per cent changed status to positive during the six months. This occurred at the same rate during summer as winter, but a higher rate of animals in the herds was positive if it took place during winter. Of the herds initially being positive, 33 per cent changed to negative. This indicates that an effective strategy to lower the prevalence and the impact of BRSV could be to employ close surveillance and place a high biosecurity focus on the negative herds. PMID:24158321

  7. Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

    PubMed Central

    Acosta, Patricio L.; Caballero, Mauricio T.

    2015-01-01

    In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a “peribronchiolar monocytic infiltration with some excess in eosinophils.” Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4+ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates. PMID:26677198

  8. Respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease.

    PubMed

    Collins, Peter L; Fearns, Rachel; Graham, Barney S

    2013-01-01

    Human respiratory syncytial virus (RSV) is an enveloped, nonsegmented negative-strand RNA virus of family Paramyxoviridae. RSV is the most complex member of the family in terms of the number of genes and proteins. It is also relatively divergent and distinct from the prototype members of the family. In the past 30 years, we have seen a tremendous increase in our understanding of the molecular biology of RSV based on a succession of advances involving molecular cloning, reverse genetics, and detailed studies of protein function and structure. Much remains to be learned. RSV disease is complex and variable, and the host and viral factors that determine tropism and disease are poorly understood. RSV is notable for a historic vaccine failure in the 1960s involving a formalin-inactivated vaccine that primed for enhanced disease in RSV naïve recipients. Live vaccine candidates have been shown to be free of this complication. However, development of subunit or other protein-based vaccines for pediatric use is hampered by the possibility of enhanced disease and the difficulty of reliably demonstrating its absence in preclinical studies.

  9. Novel therapies and vaccines against the human respiratory syncytial virus.

    PubMed

    Rivera, Claudia A; Gómez, Roberto S; Díaz, Rodrigo A; Céspedes, Pablo F; Espinoza, Janyra A; González, Pablo A; Riedel, Claudia A; Bueno, Susan M; Kalergis, Alexis M

    2015-01-01

    Human respiratory syncytial virus (hRSV) is the leading cause of acute lower respiratory tract infections worldwide in infants, as well as an important pathogen affecting the elderly and immunocompromised individuals. Despite more than a half a century of research, no licensed vaccines are available and only palivizumab has been approved to use in humans, mostly recommended or limited to high risk infants. Therefore, novel therapeutic and preventive drugs need to be developed to fight this major human pathogen. This review discusses current therapeutic approaches in preclinical and clinical stages, aimed at controlling or preventing hRSV infection. These methods include passive immunization, experimental drugs, vaccine candidates and maternal immunization. Based on the results of various immunization strategies and therapeutic approaches, it is likely that the most effective strategy against hRSV will be a prophylactic tool aimed at developing a strong antiviral T-cell response capable of both, promoting the generation of hRSV-specific high affinity antibodies and leading the protective immunity required to prevent the disease caused by this virus. Alternatively, if prophylactic strategies fail, antiviral drugs and novel passive immunity strategies could significantly contribute to reducing hospitalization rates in susceptible individuals.

  10. Influenza and respiratory syncytial virus infections in British Hajj pilgrims.

    PubMed

    Rashid, H; Shafi, S; Booy, R; El Bashir, H; Ali, K; Zambon, Mc; Memish, Za; Ellis, J; Coen, Pg; Haworth, E

    2008-01-01

    Viral respiratory infections including influenza and respiratory syncytial virus (RSV) have been reported during the Hajj among international pilgrims. To help establish the burden of these infections at the Hajj, we set up a study to confirm these diagnoses in symptomatic British pilgrims who attended the 2005 Hajj. UK pilgrims with symptoms of upper respiratory tract infection (URTI) were invited to participate; after taking medical history, nasal swabs were collected for point-of-care testing (PoCT) of influenza and for subsequent PCR analysis for influenza and RSV. Of the 205 patients recruited, 37 (18%) were positive for either influenza or RSV. Influenza A (H3) accounted for 54% (20/37) of the virus-positive samples, followed by RSV 24% (9/37), influenza B 19% (7/37), and influenza A (H1) 3% (1/37). Of the influenza-positive cases, 29% (8/28) had recently had a flu immunisation. Influenza was more common in those who gave a history of contact with a pilgrim with a respiratory illness than those who did not (17 versus 9%). The overall rate of RSV was 4% (9/202). This study confirms that influenza and RSV cause acute respiratory infections in British Hajj pilgrims. Continuing surveillance and a programme of interventions to contain the spread of infection are needed at the Hajj, particularly when the world is preparing for an influenza pandemic.

  11. Influenza and respiratory syncytial virus infections in British Hajj pilgrims

    PubMed Central

    Rashid, H; Shafi, S; Booy, R; El Bashir, H; Ali, K; Zambon, MC; Memish, ZA; Ellis, J; Coen, PG; Haworth, E

    2008-01-01

    Viral respiratory infections including influenza and respiratory syncytial virus (RSV) have been reported during the Hajj among international pilgrims. To help establish the burden of these infections at the Hajj, we set up a study to confirm these diagnoses in symptomatic British pilgrims who attended the 2005 Hajj. UK pilgrims with symptoms of upper respiratory tract infection (URTI) were invited to participate; after taking medical history, nasal swabs were collected for point-of-care testing (PoCT) of influenza and for subsequent PCR analysis for influenza and RSV. Of the 205 patients recruited, 37 (18%) were positive for either influenza or RSV. Influenza A (H3) accounted for 54% (20/37) of the virus-positive samples, followed by RSV 24% (9/37), influenza B 19% (7/37), and influenza A (H1) 3% (1/37). Of the influenza-positive cases, 29% (8/28) had recently had a flu immunisation. Influenza was more common in those who gave a history of contact with a pilgrim with a respiratory illness than those who did not (17 versus 9%). The overall rate of RSV was 4% (9/202). This study confirms that influenza and RSV cause acute respiratory infections in British Hajj pilgrims. Continuing surveillance and a programme of interventions to contain the spread of infection are needed at the Hajj, particularly when the world is preparing for an influenza pandemic. PMID:22460211

  12. Contribution of viruses, Chlamydia spp. and Mycoplasma pneumoniae to acute respiratory infections in Iranian children.

    PubMed

    Naghipour, Mohammadreza; Cuevas, Luis E; Bakhshinejad, Tahereh; Mansour-Ghanaei, Fariborz; Noursalehi, Smaeil; Alavy, Ali; Dove, Winifred; Hart, Charles Anthony

    2007-06-01

    The study reports the frequency and clinical presentation of respiratory syncytial virus (RSV), human metapneumovirus, influenza (Inf V), parainfluenza, adenovirus (Adv), Chlamydia spp. and Mycoplasma pneumoniae in children with acute respiratory infections (ARI) in Rasht, Iran. Nasopharyngeal aspirates and swabs were collected from 261 children in 2003 and 2004. Pathogens were detected using polymerase chain reaction (PCR) and reverse transcription-PCR (RT-PCR), confirmed with sequence analysis. Ninety-three pathogens were detected in 83 children. RSV was present in 39 (15%), Adv in 37 (14%), Inf A in 11 (4%), C. trachomatis in 4 (2%) and M. pneumoniae, in 2 (1%) children. Neither parainfluenza nor metapneumovirus were detected. RSV, Inf A and C. trachomatis were more frequent in children with lower respiratory infections. Adv presented more frequently as upper respiratory infection. All pathogens, except M. pneumoniae, were detected in children with severe pneumonia. Viruses play a significant role in Iranian children with community-acquired ARI.

  13. Experimental reproduction of respiratory tract disease with bovine respiratory syncytial virus.

    PubMed

    Ciszewski, D K; Baker, J C; Slocombe, R F; Reindel, J F; Haines, D M; Clark, E G

    1991-06-01

    An experiment was conducted to reproduce respiratory tract disease with bovine respiratory syncytial virus (BRSV) in one-month-old, colostrum-fed calves. The hypothesized role of viral hypersensitivity and persistent infection in the pathogenesis of BRSV pneumonia was also investigated. For BRSV inoculation a field isolate of BRSV, at the fifth passage level in cell culture, was administered by a combined respiratory tract route (intranasal and intratracheal) for four consecutive days. Four groups of calves were utilized as follows: Group I, 6 calves sham inoculated with uninfected tissue culture fluid and necropsied 21 days after the last inoculation; Group II, 6 calves inoculated with BRSV and necropsied at the time of maximal clinical response (4-6 days after the last inoculation); Group III, 6 calves inoculated with BRSV and necropsied at 21 days after the last inoculation; Group IV, 6 calves inoculated with BRSV, rechallenged with BRSV 10 days after initial exposure, and necropsied at 21 days after the initial inoculation. Clinical response was evaluated by daily monitoring of body temperature, heart rate, respiratory rate, arterial blood gas tensions, hematocrit, total protein, white blood cell count, and fibrinogen. Calves were necropsied and pulmonary surface lesions were quantitated by computer digitization. Viral pneumonia was reporduced in each principal group. Lesions were most extensive in Group II. Disease was not apparent in Group I (controls). Significant differences (p less than 0.05) in body temperature, heart rate, respiratory rate, arterial oxygen tension, and pneumonic surface area were demonstrated between control and infected calves. Results indicate that severe disease and lesions can be induced by BRSV in one-month-old calves that were colostrum-fed and seropositive to BRSV. BRSV rechallenge had minimal effect on disease progression. Based on clinical and pathological response, results did not support viral hypersensitivity or persistent

  14. Evaluation of immunoglobulin E-specific antibodies and viral antigens in nasopharyngeal secretions of children with respiratory syncytial virus infections.

    PubMed Central

    Russi, J C; Delfraro, A; Borthagaray, M D; Velazquez, B; García-Barreno, B; Hortal, M

    1993-01-01

    Enzyme immunoassays were developed to detect the presence of specific immunoglobulin E (IgE) antibodies and respiratory syncytial (RS) virus structural proteins in nasopharyngeal secretions in order to improve the knowledge on some aspects of the pathogenesis of severe acute lower respiratory tract infections caused by RS virus. These assays were used to analyze clinical specimens from children with RS virus-associated infections (bronchiolitis and pneumonia), and the findings were correlated with the patients' clinical symptoms. The results indicate the presence of specific IgE against the two external glycoproteins (G and F) and the absence of detectable IgE levels for the internal viral antigens. There was a correlation between the levels of IgE-specific antibodies and the amount of viral protein F in the secretions, indicating that the IgE response against the viral glycoproteins might be related to the antigen load. In addition, a correlation was found between higher levels of both viral protein F-specific IgE and F antigen with higher respiratory rates in children with pneumonia. These findings may be relevant because they suggest an association between the virus load and the immune response in the pathogenesis of RS virus infections. PMID:8463392

  15. Respiratory syncytial virus disease mechanisms implicated by human, animal model, and in vitro data facilitate vaccine strategies and new therapeutics.

    PubMed

    Moore, Martin L; Peebles, R Stokes

    2006-11-01

    Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis, pneumonia, mechanical ventilation, and respiratory failure in infants in the US. No effective post-infection treatments are widely available, and currently there is no vaccine. RSV disease is the result of virus-induced airway damage and complex inflammatory processes. The outcome of infection depends on host and viral genetics. Here, we review disease mechanisms in primary RSV infection that are implicated by clinical studies, in vitro systems, and animal models. Defining RSV disease mechanisms is difficult because there is a wide range of RSV disease phenotypes in humans, and there are disparities in RSV disease phenotypes among the animal models of RSV infection. However, host factors identified by multiple lines of investigation as playing important roles in RSV pathogenesis are providing key insights. A better understanding of RSV molecular biology and RSV pathogenesis is facilitating rational vaccine design strategies and molecular targets for new therapeutics.

  16. Diagnostic virology practices for respiratory syncytial virus and influenza virus among children in the hospital setting: a national survey.

    PubMed

    Jafri, Hasan S; Ramilo, Octavio; Makari, Doris; Charsha-May, Deborah; Romero, José R

    2007-10-01

    A survey was sent to the emergency room and laboratory directors of 400 randomly selected US hospitals to assess the diagnostic testing practices for respiratory syncytial virus and influenza virus in children. The results demonstrate that the majority of hospitals routinely perform viral testing for both viruses and use virology testing practices appropriate for the reasons reported for testing.

  17. Impaired learning resulting from Respiratory Syncytial Virus infection

    PubMed Central

    Espinoza, Janyra A.; Bohmwald, Karen; Céspedes, Pablo F.; Gómez, Roberto S.; Riquelme, Sebastián A.; Cortés, Claudia M.; Valenzuela, Javier A.; Sandoval, Rodrigo A.; Pancetti, Floria C.; Bueno, Susan M.; Riedel, Claudia A.; Kalergis, Alexis M.

    2013-01-01

    Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain—such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem—of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette–Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV. PMID:23650398

  18. Occurrence of human respiratory syncytial virus in summer in Japan.

    PubMed

    Shobugawa, Y; Takeuchi, T; Hibino, A; Hassan, M R; Yagami, R; Kondo, H; Odagiri, T; Saito, R

    2017-01-01

    In temperate zones, human respiratory syncytial virus (HRSV) outbreaks typically occur in cold weather, i.e. in late autumn and winter. However, recent outbreaks in Japan have tended to start during summer and autumn. This study examined associations of meteorological conditions with the numbers of HRSV cases reported in summer in Japan. Using data from the HRSV national surveillance system and national meteorological data for summer during the period 2007-2014, we utilized negative binomial logistic regression analysis to identify associations between meteorological conditions and reported cases of HRSV. HRSV cases increased when summer temperatures rose and when relative humidity increased. Consideration of the interaction term temperature × relative humidity enabled us to show synergistic effects of high temperature with HRSV occurrence. In particular, HRSV cases synergistically increased when relative humidity increased while the temperature was ⩾28·2 °C. Seasonal-trend decomposition analysis using the HRSV national surveillance data divided by 11 climate divisions showed that summer HRSV cases occurred in South Japan (Okinawa Island), Kyushu, and Nankai climate divisions, which are located in southwest Japan. Higher temperature and higher relative humidity were necessary conditions for HRSV occurrence in summer in Japan. Paediatricians in temperate zones should be mindful of possible HRSV cases in summer, when suitable conditions are present.

  19. Effect of climatological factors on respiratory syncytial virus epidemics

    PubMed Central

    NOYOLA, D. E.; MANDEVILLE, P. B.

    2008-01-01

    SUMMARY Respiratory syncytial virus (RSV) presents as yearly epidemics in temperate climates. We analysed the association of atmospheric conditions to RSV epidemics in San Luis Potosí, S.L.P., Mexico. The weekly number of RSV detections between October 2002 and May 2006 were correlated to ambient temperature, barometric pressure, relative humidity, vapour tension, dew point, precipitation, and hours of light using time-series and regression analyses. Of the variation in RSV cases, 49·8% was explained by the study variables. Of the explained variation in RSV cases, 32·5% was explained by the study week and 17·3% was explained by meteorological variables (average daily temperature, maximum daily temperature, temperature at 08:00 hours, and relative humidity at 08:00 hours). We concluded that atmospheric conditions, particularly temperature, partly explain the year to year variability in RSV activity. Identification of additional factors that affect RSV seasonality may help develop a model to predict the onset of RSV epidemics. PMID:18177520

  20. Local variability in respiratory syncytial virus disease severity

    PubMed Central

    Brandenburg, A.; Jeannet, P.; Steensel-Moll, H.; Ott, A.; Rothbarth, P.; Wunderli, W.; Suter, S.; Neijens, H.; Osterhaus, A.; Siegrist, C.

    1997-01-01

    

 Respiratory syncytial virus (RSV) lower respiratory tract infections are considered to be a serious disease in centres such as the Sophia Children's Hospital (Rotterdam, the Netherlands), but as more benign infections in others such as the Geneva Children's Hospital (Switzerland). To assess the clinical severity of RSV infections at the two sites, 151 infants primarily admitted with a virologically confirmed RSV infection were studied prospectively (1994-5) and retrospectively (1993-4) (55 infants in Geneva and 96 in Rotterdam). Parameters of RSV morbidity which were more severe in Rotterdam during the two winter seasons were apnoea (1.8 v 23.9%), the rate of admission to the intensive care unit (3.6 v 28.1%), mechanical ventilation (0 v 7.3%), and length of stay in hospital (6.8 v 9.1 days). In Geneva higher respiratory rates (59.2 v 51.2), more wheezing (65.5 v 28.8%), and more retractions (81.8 v 63.3%) were recorded. Fewer infants younger than 4 months (54.9 v 68.7%), but more breast fed infants (94.1 v 38.5%), were admitted in Geneva, although the morbidity parameters remained different after correction for these two variables in multivariate analyses. Thus unidentified local factors influence the pattern and severity of RSV infection and may affect the results of multicentre prophylactic and therapeutic studies.

 PMID:9487963

  1. Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics

    PubMed Central

    Simões, Eric A. F.; DeVincenzo, John P.; Boeckh, Michael; Bont, Louis; Crowe, James E.; Griffiths, Paul; Hayden, Frederick G.; Hodinka, Richard L.; Smyth, Rosalind L.; Spencer, Keith; Thirstrup, Steffen; Walsh, Edward E.; Whitley, Richard J.

    2015-01-01

    Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence. PMID:25713060

  2. Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

    PubMed Central

    Song, Weifeng; Yu, Zhihong; Doran, Stephen F.; Ambalavanan, Namasivayam; Steele, Chad; Garantziotis, Stavros

    2015-01-01

    Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments. PMID:26071553

  3. Respiratory syncytial virus infection: a decade of contributions.

    PubMed

    Blanco del Val, Alfredo; Eiros Bouza, José María; Mayo Iscar, Agustín; Bachillar Luque, M Rosario; Blanco del Val, Beatriz; Sánchez Porto, Antonio; Ortiz de Lejarzu, Raúl

    2012-09-01

    Respiratory Syncytial Virus (RSV) is the main cause of acute lower respiratory tract infections in children under 2 years, its distribution is worldwide and even in very different climatic conditions, it appears to have similar features, certainly knowing it will produce a significant amount of infections each year. We present the results of a retrospective review of positive cases for RSV detected in the Microbiology Laboratory of the Hospital Clinico Universitario of Valladolid in the period between 1990 and 2000, dealing with its presentation at the given time with the weather variables of temperature and humidity. Every year, we have observed as the clustering of cases was associated with two outbreaks, one at the beginning and the other at the end of the year, coinciding with the coldest and wettest months. This pattern has been repeated every revised year, according to an annual rate, with the onset of the first insulation between the months of October and February, and of the last ending between March and June, showing the highest peaks of isolation during the month of February. Therefore, every year we observe a break or seasonal slip matching the months with higher temperatures and lower humidity.

  4. Challenges and opportunities in developing respiratory syncytial virus therapeutics.

    PubMed

    Simões, Eric A F; DeVincenzo, John P; Boeckh, Michael; Bont, Louis; Crowe, James E; Griffiths, Paul; Hayden, Frederick G; Hodinka, Richard L; Smyth, Rosalind L; Spencer, Keith; Thirstrup, Steffen; Walsh, Edward E; Whitley, Richard J

    2015-03-15

    Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.

  5. Prevalence of human respiratory syncytial virus circulating in Iran.

    PubMed

    Salimi, Vahid; Tavakoli-Yaraki, Masoumeh; Yavarian, Jila; Bont, Louis; Mokhtari-Azad, Talat

    2016-01-01

    Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection during early childhood and is associated with a great burden on patients, parents, and society. While no treatment is yet available, results from recent phase 2 clinical trials of cell-entry inhibitors and RSV vaccines are promising. To prepare for introduction of these novel therapeutics, good understanding of its molecular epidemiology and continuous RSV surveillance data are necessary. This paper provides an overview of RSV prevalence and genotype distribution in Iran from 1996 to 2013. This meta-analysis includes 21 published studies. In total, 775 (18.7%) of 4140 respiratory specimens were positive for RSV infection. The male-female ratio of RSV-positive patients was 1.5:1. Significant peaks of RSV infection were detected during the cold season (November-March). RSV infection was mainly observed in patients <2 years of age. Phylogenetic studies showed that genotypes GA1, GA2, GA5, and BA co-circulated in Iran in 2007-2013. This review highlights the necessity of introducing standard molecular surveillance programs to inform the epidemiological, clinical, and pathological characteristics of various RSV genotypes. Improved understanding of the molecular epidemiology will be useful for development of novel RSV therapeutics.

  6. Respiratory syncytial virus envelope glycoprotein (G) has a novel structure.

    PubMed Central

    Satake, M; Coligan, J E; Elango, N; Norrby, E; Venkatesan, S

    1985-01-01

    Amino acid sequence of human respiratory syncytial virus envelope glycoprotein (G) was deduced from the DNA sequence of a recombinant plasmid and confirmed by limited amino acid microsequencing of purified 90K G protein. The calculated molecular mass of the protein encoded by the only long open reading frame of 298 amino acids was 32,588 daltons and was somewhat smaller than the 36K polypeptide translated in vitro from mRNA selected by this plasmid. Inspection of the sequence revealed a single hydrophobic domain of 23 amino acids capable of membrane insertion at 41 residues from the N-terminus. There was no N-terminal signal sequence and the hydrophilic N-terminal 20 residues probably represent the cytoplasmic tail of the protein. The N-terminally oriented membrane insertion was somewhat analogous to paramyxovirus hemagglutinin-neuraminidase (HN) and influenza neuraminidase (NA). The protein was moderately hydrophilic and rich in hydroxy-amino acids. It was both N- and O-glycosylated with the latter contributing significantly to the net molecular mass 90K. Images PMID:4069997

  7. Respiratory syncytial virus infections in infants affected by primary immunodeficiency.

    PubMed

    Lanari, Marcello; Vandini, Silvia; Capretti, Maria Grazia; Lazzarotto, Tiziana; Faldella, Giacomo

    2014-01-01

    Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population.

  8. Matrix Metalloproteinase 9 Exerts Antiviral Activity against Respiratory Syncytial Virus

    PubMed Central

    Dabo, Abdoulaye J.; Cummins, Neville; Eden, Edward; Geraghty, Patrick

    2015-01-01

    Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of Mmp9 expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, Mmp9-/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in Mmp9-/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR. PMID:26284919

  9. Respiratory Syncytial Virus Infections in Infants Affected by Primary Immunodeficiency

    PubMed Central

    Capretti, Maria Grazia; Lazzarotto, Tiziana; Faldella, Giacomo

    2014-01-01

    Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population. PMID:25089282

  10. Host and viral factors affecting clinical performance of a rapid diagnostic test for respiratory syncytial virus in hospitalized children.

    PubMed

    Papenburg, Jesse; Buckeridge, David L; De Serres, Gaston; Boivin, Guy

    2013-09-01

    Respiratory syncytial virus rapid antigen detection tests (RADT) are used widely. RADT exhibited high specificity (97%) and moderate sensitivity (80%) compared with reverse-transcriptase polymerase chain reaction in 720 hospitalized children <3 years old. Older age, prolonged symptoms, and respiratory syncytial virus genotype-B infection were significantly associated with false-negative results of RADT.

  11. Febrile status epilepticus due to respiratory syncytial virus infection.

    PubMed

    Uda, Kazuhiro; Kitazawa, Katsuhiko

    2017-08-01

    Febrile status epilepticus can have neurological sequelae. The type of sequelae, however, depend on the etiology, including infection due to viral agents such as the influenza virus. Respiratory syncytial virus (RSV) infection in childhood may also contribute to this. The aim of this study was therefore to characterize febrile status epilepticus associated with RSV infection, and to determine whether this type of infection is a risk factor for neurological sequelae in febrile status epilepticus. We reviewed the medical records of children aged ≤3 years with febrile status epilepticus who were admitted to a tertiary hospital between January 2007 and December 2011. The differences between the RSV-positive and RSV-negative groups were evaluated according to the demographic and clinical data. A total of 99 patients with febrile status epilepticus who had been tested for RSV infection were identified. Three patients in the RSV-positive group (n = 19) and four in the RSV-negative group (n = 80) presented with bronchiolitis. The incidence of intubation and anti-seizure drug treatment in the RSV-positive group was significantly higher than in the -negative group. While all of the patients in the RSV-negative group recovered completely, six patients in the RSV-positive group developed encephalopathy and profound neurological sequelae. In five of the six patients, diffusion-weighted magnetic resonance imaging showed subcortical white matter lesions. RSV infection in the absence of bronchiolitis can initially present as febrile status epilepticus and subsequently develop into acute encephalopathy with profound neurological sequelae. © 2017 Japan Pediatric Society.

  12. Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

    PubMed

    Geoghegan, Sarah; Erviti, Anabella; Caballero, Mauricio T; Vallone, Fernando; Zanone, Stella M; Losada, Juan Ves; Bianchi, Alejandra; Acosta, Patricio L; Talarico, Laura B; Ferretti, Adrian; Grimaldi, Luciano Alva; Sancilio, Andrea; Dueñas, Karina; Sastre, Gustavo; Rodriguez, Andrea; Ferrero, Fernando; Barboza, Edgar; Gago, Guadalupe Fernández; Nocito, Celina; Flamenco, Edgardo; Perez, Alberto Rodriguez; Rebec, Beatriz; Ferolla, F Martin; Libster, Romina; Karron, Ruth A; Bergel, Eduardo; Polack, Fernando P

    2017-01-01

    Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low-income regions is unclear. To determine the burden and risk factors for mortality due to RSV in a low-income population of 84,840 infants. This was a prospective, population-based, cross-sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All-cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14-21.16 for RF) (OR, 119.39; 95% CI, 50.98-273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07-21.01 for RF) (OR, 65.49; 95% CI, 28.90-139.17 for death) were the main determinants of poor outcomes. RSV was the most frequent cause of mortality in low-income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.

  13. A comparative study of thin-section CT findings between seasonal influenza virus pneumonia and Streptococcus pneumoniae pneumonia

    PubMed Central

    Okada, F; Takata, S; Hiramatsu, K; Ando, Y; Nakayama, T; Maeda, T; Mori, H

    2014-01-01

    Objective: To compare the pulmonary thin-section CT findings in patients with seasonal influenza virus pneumonia with Streptococcus pneumoniae pneumonia. Methods: The study group included 30 patients (20 males and 10 females; age range, 20–91 years; mean age, 55.9 years) with seasonal influenza virus pneumonia and 71 patients (47 males and 24 females; age range, 27–92 years; mean age, 67.5 years) with S. pneumoniae pneumonia. Results: The proportion of community-acquired infection was significantly higher in patients with influenza virus pneumonia than with S. pneumoniae pneumonia (p = 0.001). CT findings of ground-glass attenuation (GGA) (p = 0.012) and crazy-paving appearance (p = 0.03) were significantly more frequent in patients with influenza virus pneumonia than with S. pneumoniae pneumonia. Conversely, consolidation (p < 0.001), mucoid impaction (p < 0.001), centrilobular nodules (p = 0.04) and pleural effusion (p = 0.003) were significantly more frequent in patients with S. pneumoniae pneumonia than in those with influenza virus pneumonia. Conclusion: Pulmonary thin-section CT findings, such as consolidation and mucoid impaction may be useful in distinguishing between seasonal influenza virus pneumonia and S. pneumoniae pneumonia. Advances in knowledge: (1) Distinguishing seasonal influenza virus pneumonia with S. pneumoniae pneumonia is important. (2) The CT findings of GGA and crazy-paving appearance were more frequently found in patients with influenza virus pneumonia than in patients with S. pneumoniae pneumonia, whereas consolidation, mucoid impaction, centrilobular nodules and pleural effusion were more frequently found in patients with S. pneumoniae pneumonia. PMID:24834476

  14. A comparative study of thin-section CT findings between seasonal influenza virus pneumonia and Streptococcus pneumoniae pneumonia.

    PubMed

    Ono, A; Okada, F; Takata, S; Hiramatsu, K; Ando, Y; Nakayama, T; Maeda, T; Mori, H

    2014-07-01

    To compare the pulmonary thin-section CT findings in patients with seasonal influenza virus pneumonia with Streptococcus pneumoniae pneumonia. The study group included 30 patients (20 males and 10 females; age range, 20-91 years; mean age, 55.9 years) with seasonal influenza virus pneumonia and 71 patients (47 males and 24 females; age range, 27-92 years; mean age, 67.5 years) with S. pneumoniae pneumonia. The proportion of community-acquired infection was significantly higher in patients with influenza virus pneumonia than with S. pneumoniae pneumonia (p = 0.001). CT findings of ground-glass attenuation (GGA) (p = 0.012) and crazy-paving appearance (p = 0.03) were significantly more frequent in patients with influenza virus pneumonia than with S. pneumoniae pneumonia. Conversely, consolidation (p < 0.001), mucoid impaction (p < 0.001), centrilobular nodules (p = 0.04) and pleural effusion (p = 0.003) were significantly more frequent in patients with S. pneumoniae pneumonia than in those with influenza virus pneumonia. Pulmonary thin-section CT findings, such as consolidation and mucoid impaction may be useful in distinguishing between seasonal influenza virus pneumonia and S. pneumoniae pneumonia. (1) Distinguishing seasonal influenza virus pneumonia with S. pneumoniae pneumonia is important. (2) The CT findings of GGA and crazy-paving appearance were more frequently found in patients with influenza virus pneumonia than in patients with S. pneumoniae pneumonia, whereas consolidation, mucoid impaction, centrilobular nodules and pleural effusion were more frequently found in patients with S. pneumoniae pneumonia.

  15. Antiviral activity of carnosic acid against respiratory syncytial virus

    PubMed Central

    2013-01-01

    Background Human respiratory syncytial virus (hRSV) is a leading cause of severe lower respiratory infection and a major public health threat worldwide. To date, no vaccine or effective therapeutic agent has been developed. In a screen for potential therapeutic agents against hRSV, we discovered that an extract of Rosmarinus officinalis exerted a strong inhibitory effect against hRSV infection. Subsequent studies identified carnosic acid as a bioactive constituent responsible for anti-hRSV activity. Carnosic acid has been shown to exhibit potent antioxidant and anti-cancer activities. Anti-RSV activity of carnosic acid was further investigated in this study. Methods Effects of extracts from various plants and subfractions from R. officinalis on hRSV replication were determined by microneutralization assay and plaque assay. Several constituents were isolated from ethyl acetate fraction of R. officinalis and their anti-RSV activities were assessed by plaque assay as well as reverse-transcription quantitative PCR to determine the synthesis of viral RNAs. Results Among the tested bioactive constituents of R. officinalis, carnosic acid displayed the most potent anti-hRSV activity and was effective against both A- and B-type viruses. Carnosic acid efficiently suppressed the replication of hRSV in a concentration-dependent manner. Carnosic acid effectively suppressed viral gene expression without inducing type-I interferon production or affecting cell viability, suggesting that it may directly affect viral factors. A time course analysis showed that addition of carnosic acid 8 hours after infection still effectively blocked the expression of hRSV genes, further suggesting that carnosic acid directly inhibited the replication of hRSV. Conclusions The current study demonstrates that carnosic acid, a natural compound that has already been shown to be safe for human consumption, has anti-viral activity against hRSV, efficiently blocking the replication of this virus. Carnosic

  16. Respiratory syncytial virus hospitalisation trends in children with haemodynamically significant heart disease, 1997-2012.

    PubMed

    Chu, Patricia Y; Hornik, Christoph P; Li, Jennifer S; Campbell, Michael J; Hill, Kevin D

    2017-01-01

    The aim of the study was to evaluate the trends in respiratory syncytial virus-related hospitalisations and associated outcomes in children with haemodynamically significant heart disease in the United States of America. Study design The Kids' Inpatient Databases (1997-2012) were used to estimate the incidence of respiratory syncytial virus hospitalisation among children ⩽24 months with or without haemodynamically significant heart disease. Weighted multivariable logistic regression and chi-square tests were used to evaluate the trends over time and factors associated with hospitalisation, comparing eras before and after publication of the 2003 American Academy of Pediatrics palivizumab immunoprophylaxis guidelines. Secondary outcomes included in-hospital mortality, morbidity, length of stay, and cost. Overall, 549,265 respiratory syncytial virus-related hospitalisations were evaluated, including 2518 (0.5%) in children with haemodynamically significant heart disease. The incidence of respiratory syncytial virus hospitalisation in children with haemodynamically significant heart disease decreased by 36% when comparing pre- and post-palivizumab guideline eras versus an 8% decline in children without haemodynamically significant heart disease (p<0.001). Children with haemodynamically significant heart disease had higher rates of respiratory syncytial virus-associated mortality (4.9 versus 0.1%, p<0.001) and morbidity (31.5 versus 3.5%, p<0.001) and longer hospital length of stay (17.9 versus 3.9 days, p<0.001) compared with children without haemodynamically significant heart disease. The mean cost of respiratory syncytial virus hospitalisation in 2009 was $58,166 (95% CI:$46,017, $70,315). These data provide stakeholders with a means to evaluate the cost-utility of various immunoprophylaxis strategies.

  17. Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations

    PubMed Central

    Freitas, André Ricardo Ribas; Donalisio, Maria Rita

    2016-01-01

    Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID-10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV. PMID:27120006

  18. Respiratory syncytial virus pneumonitis in immunocompromised adults: clinical features and outcome.

    PubMed

    Ebbert, Jon O; Limper, Andrew H

    2005-01-01

    Though predominantly an infection of children, respiratory syncytial virus (RSV) also infects adults, particularly those with immune compromise. To define the clinical spectrum and impact of RSV pneumonitis on hospitalized, immunocompromised adults. Retrospective chart review. Clinical parameters including premorbid conditions, presentation, radiologic findings, treatment and outcome were examined in a consecutive patients series from an inpatient tertiary-care center. Eleven immunocompromised adults who had undergone bronchoalveolar lavage (BAL) between January 1987 and December 1996 and who had culture-verified RSV pneumonitis were evaluated. This series consisted primarily of patients undergoing chemotherapy or bone marrow transplantation for lymphoma or leukemia. Two were immunosuppressed due to high-dose corticosteroids. A majority (91%) were admitted between November and May, with dyspnea and productive cough. In contrast to earlier studies, there was a paucity of upper respiratory infection symptoms (i.e. sinus congestion, sore throat) and a preponderance of lower respiratory physical exam findings (i.e. wheezing, bibasilar rales). Patients were typically hypoxemic and febrile prior to BAL. Eight demonstrated co-isolates of bacterial or fungi on BAL. The chest radiographs generally revealed diffuse patchy infiltrates, including alveolar opacities. Histology demonstrated diffuse alveolar damage, bronchiolitis with organizing pneumonia, and hyaline membrane formation. Over half required intubation, and 55% died. Although ribavirin therapy may be beneficial in some intubated patients, its overall efficacy cannot be established from this series. RSV is a serious cause of morbidity and mortality in immunocompromised adults. Further development and implementation of an effective vaccine and additional therapeutic interventions are needed.

  19. [Respiratory infections caused by respiratory syncytial virus in the adult population: description of 16 cases].

    PubMed

    Reina, Jordi; López, Carla

    2013-08-17

    Respiratory infections of viral etiology are frequent in the adult population. Those caused by respiratory syncytial virus (RSV) are a little known entity. The aim of this study was to determine the clinical and epidemiological characteristics of adult patients with respiratory infection due to RSV. We performed a prospective study from October 2012 to March 2013 on respiratory infections caused by RSV. Viral detection was performed using a technique of reverse transcription polymerase chain reaction genomic amplification in real time. We diagnosed 16 patients, 12 (75%) requiring hospitalization. Patients were grouped into immunocompromised (7 [43.7%]) and immunocompetent cases (9 cases 56.3%]). The first group included 3 patients with HIV infection (42.8%) and 4 hematologic patients (57.2%). The second group included those who had a baseline disease, 5 cases (55.5%), and those who lacked it, 4 cases (44.4%), and did not require hospitalization. The main clinical manifestations of patients prompting them to attend the Emergency Department were cough (50%), dyspnea (43.5%), fever (25%), expectoration (25%) and flu symptoms (25%). The most frequent diagnoses at discharge were pneumonia (37.5%) and flu syndrome (31.2%). Respiratory infections caused by RSV represent a rare condition that mainly affects immunocompromised patients. The underlying pathology determines the evolution of the process, which is favorable except in cases of severe immunosuppression. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  20. Central nervous system alterations caused by infection with the human respiratory syncytial virus.

    PubMed

    Bohmwald, Karen; Espinoza, Janyra A; González, Pablo A; Bueno, Susan M; Riedel, Claudia A; Kalergis, Alexis M

    2014-11-01

    Worldwide, the human respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization because of acute respiratory tract infections, including severe bronchiolitis and pneumonia. Despite intense research, to date there is neither vaccine nor treatment available to control hRSV disease burden globally. After infection, an incubation period of 3-5 days is usually followed by symptoms, such as cough and low-grade fever. However, hRSV infection can also produce a larger variety of symptoms, some of which relate to the individual's age at infection. Indeed, infants can display severe symptoms, such as dyspnea and chest wall retractions. Upon examination, crackles and wheezes are also common features that suggest infection by hRSV. Additionally, infection in infants younger than 1 year is associated with several non-specific symptoms, such as failure to thrive, periodic breathing or apnea, and feeding difficulties that usually require hospitalization. Recently, neurological symptoms have also been associated with hRSV respiratory infection and include seizures, central apnea, lethargy, feeding or swallowing difficulties, abnormalities in muscle tone, strabismus, abnormalities in the CSF, and encephalopathy. Here, we discuss recent findings linking the neurological, extrapulmonary effects of hRSV with infection and functional impairment of the CNS.

  1. Intranasal nanoemulsion-based inactivated respiratory syncytial virus vaccines protect against viral challenge in cotton rats.

    PubMed

    O'Konek, Jessica J; Makidon, Paul E; Landers, Jeffrey J; Cao, Zhengyi; Malinczak, Carrie-Anne; Pannu, Jessie; Sun, Jennifer; Bitko, Vira; Ciotti, Susan; Hamouda, Tarek; Wojcinski, Zbigniew W; Lukacs, Nicholas W; Fattom, Ali; Baker, James R

    2015-01-01

    Respiratory Syncytial Virus is a leading cause of bronchiolitis and pneumonia in infants, the elderly and individuals with compromised immune systems. Despite decades of research, there is currently no available vaccine for RSV. Our group has previously demonstrated that intranasal immunization of mice with RSV inactivated by and adjuvanted with W805EC nanoemulsion elicits robust humoral and cellular immune responses, resulting in protection against RSV infection. This protection was achieved without the induction of airway hyper-reactivity or a Th2-skewed immune response. The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of RSV disease. Thus, we extended these rodent studies to the more permissive cotton rat model. Intranasal immunization of the nanoemulsion-adjuvanted RSV vaccines induced high antibody titers and a robust Th1-skewed cellular response. Importantly, vaccination provided sterilizing cross-protective immunity against a heterologous RSV challenge and did not induce marked or severe histological effects or eosinophilia in the lung after viral challenge. Overall, these data demonstrate that nanoemulsion-formulated whole RSV vaccines are both safe and effective for immunization in multiple animal models.

  2. Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children.

    PubMed Central

    Hemming, V G; Rodriguez, W; Kim, H W; Brandt, C D; Parrott, R H; Burch, B; Prince, G A; Baron, P A; Fink, R J; Reaman, G

    1987-01-01

    Respiratory syncytial virus (RSV)-infected cotton rats (Sigmadon hispidus) and owl monkeys (Aotus trivirgatus) showed significant reductions in RSV shedding from their respiratory tracts following parenteral therapy with human intravenous immunoglobulin (IVIG) containing high titers of RSV-neutralizing antibody. Because this therapy was well tolerated and appeared safe, a double-blind, placebo-controlled IVIG immunotherapy pilot study was performed on 35 hospitalized, RSV-infected infants and children. The treatment was well tolerated and resulted in significant reductions in nasal RSV shedding and in improvements in transcutaneous oximetry readings. However, the mean duration of hospitalization was not reduced by IVIG treatment. Followup to date has revealed no harmful effects resulting from immunotherapy of RSV infections. These studies appear to refute the hypothesis that passively acquired antibody may exacerbate RSV bronchiolitis or pneumonia in infants. Studies with larger numbers of seriously ill children will be required to determine if immunoglobulin G immunotherapy of RSV infections in infants is of clinical value. PMID:3439796

  3. The Use of Humanized Monoclonal Antibodies for the Prevention of Respiratory Syncytial Virus Infection

    PubMed Central

    Arcuri, Santo; Galletti, Silvia; Faldella, Giacomo

    2013-01-01

    Monoclonal antibodies are widely used both in infants and in adults for several indications. Humanized monoclonal antibodies (palivizumab) have been used for many years for the prevention of respiratory syncytial virus infection in pediatric populations (preterm infants, infants with chronic lung disease or congenital heart disease) at high risk of severe and potentially lethal course of the infection. This drug was reported to be safe, well tolerated and effective to decrease the hospitalization rate and mortality in these groups of infants by several clinical trials. In the present paper we report the development and the current use of monoclonal antibodies for prophylaxis against respiratory syncytial virus. PMID:23840240

  4. Laboratory testing trends for respiratory syncytial virus, 2007-2011.

    PubMed

    Rabon-Stith, Karma M; McGuiness, Catherine Balderston; Saunders, Brett; Edelman, Laurel; Kumar, Veena R; Boron, Marnie L

    2013-11-01

    Antigen detection tests have been the most common diagnostic assay used to detect and diagnose respiratory syncytial virus (RSV). The utility and increased sensitivity of polymerase chain reaction (PCR) tests have been reported; however, their use in US hospital laboratories is not well characterized. To describe changes in RSV test types used by US hospital-affiliated laboratories, focusing on PCR testing prevalence. Data were collected from 480 to 666 laboratories each RSV season (2007-2008 through 2010-2011) across 50 states, the District of Columbia, and Puerto Rico. A descriptive analysis was conducted using this convenience sample of RSV tests conducted from November to April each season. Total numbers and types of RSV tests performed were reported weekly and weekly proportions by test type were calculated. Kendall τ rank correlation was used to quantify associations between time and proportions of each test type. PCR tests accounted for 2%, 3%, 16%, and 21% of weekly tests (total range, 381,068-481,654 over 4 seasons) conducted each season from 2007 to 2011, respectively. The proportion of laboratories reporting ≥1 PCR tests was 4%, 5%, 10%, and 16%, respectively. Decreases in antigen testing and viral culture were similarly observed. Although antigen detection was the predominant test type reported in the sample of US hospital laboratories for RSV testing, PCR use increased to >20% of tests reported. These results demonstrate the increasing contribution of PCR to RSV surveillance. RSV surveillance systems relying solely on antigen detection results will not capture an increasing proportion of RSV test results. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Determinants of asthma after severe respiratory syncytial virus bronchiolitis

    PubMed Central

    Bacharier, Leonard B.; Cohen, Rebecca; Schweiger, Toni; Yin-DeClue, Huiquing; Christie, Chandrika; Zheng, Jie; Schechtman, Kenneth B.; Strunk, Robert C.; Castro, Mario

    2013-01-01

    Background The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined. Objectives We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy. Methods We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells. Results Forty-eight percent of children had physician-diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7-15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3-7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1-55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04-0.84; P = .029) had a decreased risk of physician-diagnosed asthma. Conclusions Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma. PMID:22444510

  6. The Burden of Respiratory Syncytial Virus Infection in Young Children

    PubMed Central

    Hall, Caroline Breese; Weinberg, Geoffrey A.; Iwane, Marika K.; Blumkin, Aaron K.; Edwards, Kathryn M.; Staat, Mary A.; Auinger, Peggy; Griffin, Marie R.; Poehling, Katherine A.; Erdman, Dean; Grijalva, Carlos G.; Zhu, Yuwei; Szilagyi, Peter

    2016-01-01

    Background The primary role of respiratory syncytial virus (RSV) in causing infant hospitalizations is well recognized, but the total burden of RSV infection among young children remains poorly defined. Methods We conducted prospective, population-based surveillance of acute respiratory infections among children under 5 years of age in three U.S. counties. We enrolled hospitalized children from 2000 through 2004 and children presenting as outpatients in emergency departments and pediatric offices from 2002 through 2004. RSV was detected by culture and reverse-transcriptase polymerase chain reaction. Clinical information was obtained from parents and medical records. We calculated population-based rates of hospitalization associated with RSV infection and estimated the rates of RSV-associated outpatient visits. Results Among 5067 children enrolled in the study, 919 (18%) had RSV infections. Overall, RSV was associated with 20% of hospitalizations, 18% of emergency department visits, and 15% of office visits for acute respiratory infections from November through April. Average annual hospitalization rates were 17 per 1000 children under 6 months of age and 3 per 1000 children under 5 years of age. Most of the children had no coexisting illnesses. Only prematurity and a young age were independent risk factors for hospitalization. Estimated rates of RSV-associated office visits among children under 5 years of age were three times those in emergency departments. Outpatients had moderately severe RSV-associated illness, but few of the illnesses (3%) were diagnosed as being caused by RSV. Conclusions RSV infection is associated with substantial morbidity in U.S. children in both inpatient and outpatient settings. Most children with RSV infection were previously healthy, suggesting that control strategies targeting only high-risk children will have a limited effect on the total disease burden of RSV infection. PMID:19196675

  7. Clinical and epidemiologic features of respiratory syncytial virus.

    PubMed

    Hall, Caroline B; Simőes, Eric A F; Anderson, Larry J

    2013-01-01

    Since its discovery in 1955, respiratory syncytial virus (RSV) has consistently been noted to be the single most important cause of lower respiratory tract illness in infants <1 year of age. RSV also causes repeat infections and significant disease throughout life. In addition to the young child, persons with compromised immune, pulmonary or cardiac systems, and the elderly have significant risk from infection. Though RSV causes the full spectrum of acute respiratory illnesses, it is most notably associated with signs and symptoms of increased airway resistance manifested as wheezing and, in the young child, diagnosed as bronchiolitis. In temperate climates, RSV occurs as yearly outbreaks usually between late fall and early spring lasting 3-4 months in a community. The timing of outbreaks varies between years and in the same year between regions and even between nearby communities. RSV can be a serious nosocomial pathogen in high risk individuals but nosocomial transmission that can often be prevented with meticulous attention to good infection control practices. High risk groups include the premature infants and persons of any age with compromised cardiac, pulmonary, or immune systems. Risk factors for infection include increased number of children in the household and day care center attendance. There are reasonable estimates of the sizable burden of RSV disease in infants and young children and the elderly but less data on disease in older children, the role of RSV in later reactive airway disease (see chapter by M.T. Lotz et al. , this volume), and RSV-associated mortality in developing countries. The available data on burden of disease suggests there are at least four potential target populations for a vaccine, the young infant, young children >4-6 months of age, pregnant women, and the elderly. A link between infection in the young infant and later reactive airway disease and mortality in developing countries is needed. Each target population has different

  8. CD8+ T cell immunity against human respiratory syncytial virus.

    PubMed

    Rossey, Iebe; Sedeyn, Koen; De Baets, Sarah; Schepens, Bert; Saelens, Xavier

    2014-10-21

    Human respiratory syncytial virus (HRSV) was first discovered in the 1950s, but despite decades of research, a licensed vaccine against it is not available. Epidemiological studies indicate that antibodies directed against the fusion protein (F) partially correlate with protection. In addition, an F-specific monoclonal antibody is licensed as a prophylactic treatment in children who are at high risk of developing complications following HRSV infection. Therefore, most HRSV-oriented vaccination strategies focus on inducing a humoral immune response against F. In the quest for the development of a safe HRSV vaccine, the induction of a T cell immune response has received a lot less attention. T cell immunity directed against HRSV has not been associated unequivocally with protection against HRSV and CD4(+) T helper cell responses may even worsen disease due to HRSV. However, many studies support a protective role for CD8(+) T cells in clearance of HRSV from the lungs. In this review we highlight the clinical and experimental evidence in favor of a CD8(+) T lymphocyte-based vaccination strategy to protect against HRSV. First, we describe how T cell responses and T cell memory are induced in the lungs upon respiratory viral infection. HRSV has evolved mechanisms that hamper CD8(+) T cell priming and effector functions. We appraise the information on HRSV-specific CD8(+) T cell immunity gained from laboratory mouse studies, taking into account the advantages and limitations of this animal model and, where possible, the accordance with clinical evidence. Finally, we focus on recent efforts to develop T cell based vaccines against HRSV.

  9. Novel clinical features of recurrent human respiratory syncytial virus infections.

    PubMed

    Yui, Ikuko; Fujino, Motoko; Sawada, Akihito; Nakayama, Tetsuo

    2014-09-01

    Children and elderly individuals are often infected easily and repeatedly with human respiratory syncytial virus (HRSV); however, the features of recurrent infection in the same individual are defined poorly. To clarify the clinical significance of repeated HRSV infections in relation to subgroup epidemiology, this study performed prospective and longitudinal analyses in children with lower respiratory tract infections over 20 consecutive epidemics between 1985 and 2005 at a pediatric outpatient clinic in Kawasaki, Japan. HRSV infections were confirmed by 2 types of reverse-transcription PCR. Samples obtained from patients with repeated infections were subjected to sequence analysis and cloning analysis. A total of 1,312 lower respiratory tract infections observed in 1,010 patients were diagnosed as HRSV infections. Repeated HRSV infections occurred in 208 of the 1,010 patients. Analysis of the patients with repeated infections revealed that children were often infected multiple times even within a single short epidemic. Some patients were re-infected with strains having the same or virtually identical N gene sequences. In patients infected more than 4 times, cloning analysis revealed more frequent dual infections with both subgroups (23.8%). The HRSV-A subgroup caused subsequent homologous infections more frequently than did HRSV-B; furthermore, HRSV-A infections provided no protection from a second homologous infection. In contrast, HRSV-B infections offered significant protection against a second homologous infection. Statistical analysis revealed alleviation of symptoms with a reduced rate of dyspnoeic attacks only in the group re-infected with homologous HRSV-A strains. Thus, this study elucidates new clinical features of recurrent HRSV infection.

  10. New drugs and treatment for respiratory syncytial virus.

    PubMed

    Maggon, Krishan; Barik, Sailen

    2004-01-01

    The respiratory syncytial virus (RSV) is a global health problem affecting infants and the elderly and claiming more lives than AIDS in many parts of the world. Only two antibody drugs are approved for its prevention, and ribavarin, a relatively nonspecific antiviral, is used for treatment. In the mid-1990s, a number of pharmaceutical and biotech companies initiated research programs against RSV. Together, the academic and the industrial R&D covered the whole spectrum of antibodies, vaccines, synthetic small molecule antiviral and antisense technology, and at one point, accounted for at least 25 active R&D programs. However, coincident to the marketing of the monoclonal antibody palivizumab (Synagis) in 1998, a sharp decline in such projects ensued. Many companies recently cancelled RSV projects during a prioritisation of their R&D portfolios although the continuing medical need, large market size and sales projections clearly indicate that a safe and effective RSV drug or vaccine is likely to attain blockbuster status. Today RSV receives an insignificant fraction of the R&D budget compared with AIDS, for example. This article reviews the present status of the anti-RSV regimen, covers drugs in the market and in development, and attempts to link basic research to industrial drug development, animal models of RSV, clinical trials, current clinical management, and present and future market projections. It is hoped that the unmet medical need of the victims of RSV will encourage continued involvement of the pharmaceutical and biotechnology industry in developing safe and effective prevention and treatments for RSV.

  11. Evaluation of five methods for respiratory syncytial virus detection.

    PubMed Central

    Halstead, D C; Todd, S; Fritch, G

    1990-01-01

    A total of 117 nasal aspirates were cultured for respiratory syncytial virus (RSV) and tested for RSV antigen by a direct fluorescent-antibody (DFA) test (Bartels Immunodiagnostic Supplies, Inc., Bellevue, Wash.), the Directigen enzyme immunoassay (EIA; Becton Dickinson Microbiology Systems, Cockeysville, Md.), the TestPack EIA (Abbott Laboratories, North Chicago, Ill.), and RSV EIA (Abbott). Agreement of two of five methods or a positive RSV culture were required to validate a result. A total of 57 of 117 (48.7%) specimens were culture positive in HEp-2 cells, A549 cells, or both. A total of 5 of 117 (4.3%) additional specimens met the criteria of a positive specimen; i.e., 62 of 117 (53.0%) specimens were positive. Results obtained from 77 of 117 (65.8%) specimens were concordant for all five methods. The sensitivities, specificities, and positive and negative predictive values for the culture and DFA methods were 91.9, 100, 100, and 91.7% and 91.9, 96.4, 96.6, and 91.4%, respectively. The sensitivities, specificities, and positive and negative predictive values for the three EIA procedures, Directigen, TestPack, and RSV EIA, were 75.8, 80.0, 81.0, and 74.6%; 93.6, 100, 100, and 93.2%; and 71.0, 100, 100, and 75.3%, respectively. New self-contained EIA configurations and the DFA method offer attractive alternatives to the culture method. Technical simplicity, rapid turnaround time, performance, and cost must all be considered when selecting a system for RSV detection. PMID:2191003

  12. Respiratory viruses from hospitalized children with severe pneumonia in the Philippines

    PubMed Central

    2012-01-01

    Background Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined. Methods The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively. Result Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated. Conclusion Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries. PMID:23092190

  13. Respiratory viruses from hospitalized children with severe pneumonia in the Philippines.

    PubMed

    Suzuki, Akira; Lupisan, Socorro; Furuse, Yuki; Fuji, Naoko; Saito, Mariko; Tamaki, Raita; Galang, Hazel; Sombrero, Lydia; Mondoy, Melisa; Aniceto, Rapunzel; Olveda, Remigio; Oshitani, Hitoshi

    2012-10-23

    Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined. The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively. Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated. Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries.

  14. Detection of Common Respiratory Viruses and Mycoplasma pneumoniae in Patient-Occupied Rooms in Pediatric Wards

    PubMed Central

    Wan, Gwo-Hwa; Huang, Chung-Guei; Chung, Fen-Fang; Lin, Tzou-Yien; Tsao, Kuo-Chien; Huang, Yhu-Chering

    2016-01-01

    Abstract Few studies have assessed viral contamination in the rooms of hospital wards. This cross-sectional study evaluated the air and objects in patient-occupied rooms in pediatric wards for the presence of common respiratory viruses and Mycoplasma pneumoniae. Air samplers were placed at a short (60–80 cm) and long (320 cm) distance from the head of the beds of 58 pediatric patients, who were subsequently confirmed to be infected with enterovirus (n = 17), respiratory syncytial virus (RSV) (n = 13), influenza A virus (n = 13), adenovirus (n = 9), or M pneumoniae (n = 6). Swab samples were collected from the surfaces of 5 different types of objects in the patients’ rooms. All air and swab samples were analyzed via real-time quantitative polymerase chain reaction assay for the presence of the above pathogens. All pathogens except enterovirus were detected in the air, on the objects, or in both locations in the patients’ rooms. The detection rates of influenza A virus, adenovirus, and M pneumoniae for the long distance air sampling were 15%, 67%, and 17%, respectively. Both adenovirus and M pneumoniae were detected at very high rates, with high concentrations, on all sampled objects. The respiratory pathogens RSV, influenza A virus, adenovirus, and M pneumoniae were detected in the air and/or on the objects in the pediatric ward rooms. Appropriate infection control measures should be strictly implemented when caring for such patients. PMID:27057827

  15. Increased detection of respiratory syncytial virus, influenza viruses, parainfluenza viruses, and adenoviruses with real-time PCR in samples from patients with respiratory symptoms.

    PubMed

    van de Pol, Alma C; van Loon, Anton M; Wolfs, Tom F W; Jansen, Nicolaas J G; Nijhuis, Monique; Breteler, Els Klein; Schuurman, Rob; Rossen, John W A

    2007-07-01

    Respiratory samples (n = 267) from hospitalized patients with respiratory symptoms were tested by real-time PCR, viral culture, and direct immunofluorescence for respiratory syncytial virus, influenza virus, parainfluenza viruses, and adenoviruses. Compared with conventional diagnostic tests, real-time PCR increased the diagnostic yields for these viruses from 24% to 43% and from 3.5% to 36% for children and adults, respectively.

  16. [Application of the polymerase chain reaction for detecting respiratory syncytial virus].

    PubMed

    Sarmiento, L; Chacón, D; Valdivia, A; Savón, C; Goyenechea, A

    1997-01-01

    The polymerase chain reaction (PCR) was developed in order to identify the respiratory syncytial virus by using the reference strain. The high sensitivity and specificity obtained show the PCR utility for detecting the RSV genoma and its application on the diagnosis.

  17. Presentation of severe combined immunodeficiency with respiratory syncytial virus and pneumocystis co-infection.

    PubMed

    Domínguez-Pinilla, Nerea; Allende-Martínez, Luis; Corral Sánchez, María Dolores; Arocena, Jaime de Inocencio; González-Granado, Luis Ignacio

    2015-04-01

    Severe combined immunodeficiency can cause severe, life-threatening viral, bacterial and fungal infections at an early age. We report a case of a 4-month-old boy with co-infection by respiratory syncytial virus and Pneumocystis jiroveci infection that led to recognition of severe combined immunodeficiency.

  18. Pericarditis mediated by respiratory syncytial virus in a hematopoietic stem cell transplant patient.

    PubMed

    Rubach, M P; Pavlisko, E N; Perfect, J R

    2013-08-01

    We describe a case of pericarditis and large pericardial effusion in a 63-year-old African-American man undergoing autologous hematopoietic stem cell transplant for multiple myeloma. Pericardial tissue biopsy demonstrated fibrinous pericarditis, and immunohistochemistry stains were positive for respiratory syncytial virus. The patient improved with oral ribavirin and intravenous immune globulin infusions. © 2013 John Wiley & Sons A/S.

  19. Exhaled nitric oxide in acute respiratory syncytial virus bronchiolitis.

    PubMed

    Gadish, Tal; Soferman, Ruth; Merimovitch, Tamar; Fireman, Elizabeth; Sivan, Yakov

    2010-08-01

    To investigate fractional exhaled nitric oxide (FeNO) levels in infants during acute respiratory syncytial virus (RSV) bronchiolitis and during convalescence. Prospective cohort study. Comparison of FeNO levels between infants with laboratory-confirmed acute RSV bronchiolitis and 2 control groups: healthy infants and infants with recurrent wheezing. The Department of Pediatric Emergency Medicine and the Pediatric Pulmonary Clinic of the Tel Aviv Medical Center from November 2008 to July 2009. The FeNO levels were measured at referral and at 2 visits over 4 months after convalescence. The FeNO level was measured using the multiple-breath exhalation technique. Forty-four infants with acute RSV bronchiolitis (mean [SD] age, 6.8 [7.3] months), 21 infants with recurrent wheezing (mean [SD] age, 10.8 [7.59] months), and 32 age-matched healthy controls (mean [SD] age, 6.8 [9.1] months). Follow-up data were available for 22 children (55%) for the first follow-up visit and for 11 children (25%) for the second follow-up visit. Acute RSV bronchiolitis. The FeNO levels during acute RSV bronchiolitis vs controls and FeNO levels during follow-up vs acute-stage disease. Mean FeNO levels for RSV-positive infants were significantly lower compared with healthy controls and infants with recurrent wheezing: mean (SD), 1.89 (1.76) parts per billion (ppb), 7.28 (4.96) ppb, and 4.86 (7.49) ppb, respectively (P<.001). The FeNO levels at the 2- and 4-month follow-up visits increased to 7.74 (5.13) ppb and 11.37 (6.29) ppb, respectively (P=.001). The FeNO levels are temporarily reduced during acute RSV bronchiolitis and increase during convalescence to normal levels and higher. The mechanisms for this suppression and its relation to future wheezing and asthma need to be studied.

  20. ISG15 Is Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation

    PubMed Central

    González-Sanz, Rubén; Mata, Manuel; Bermejo-Martín, Jesús; Álvarez, Amparo; Cortijo, Julio; Melero, José A.

    2016-01-01

    ABSTRACT Human respiratory syncytial virus (RSV), for which neither a vaccine nor an effective therapeutic treatment is currently available, is the leading cause of severe lower respiratory tract infections in children. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that is highly increased during viral infections and has been reported to have an antiviral or a proviral activity, depending on the virus. Previous studies from our laboratory demonstrated strong ISG15 upregulation during RSV infection in vitro. In this study, an in-depth analysis of the role of ISG15 in RSV infection is presented. ISG15 overexpression and small interfering RNA (siRNA)-silencing experiments, along with ISG15 knockout (ISG15−/−) cells, revealed an anti-RSV effect of the molecule. Conjugation inhibition assays demonstrated that ISG15 exerts its antiviral activity via protein ISGylation. This antiviral activity requires high levels of ISG15 to be present in the cells before RSV infection. Finally, ISG15 is also upregulated in human respiratory pseudostratified epithelia and in nasopharyngeal washes from infants infected with RSV, pointing to a possible antiviral role of the molecule in vivo. These results advance our understanding of the innate immune response elicited by RSV and open new possibilities to control infections by the virus. IMPORTANCE At present, no vaccine or effective treatment for human respiratory syncytial virus (RSV) is available. This study shows that interferon-stimulated gene 15 (ISG15) lowers RSV growth through protein ISGylation. In addition, ISG15 accumulation highly correlates with the RSV load in nasopharyngeal washes from children, indicating that ISG15 may also have an antiviral role in vivo. These results improve our understanding of the innate immune response to RSV and identify ISG15 as a potential target for virus control. PMID:26763998

  1. Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children.

    PubMed

    Gomez, Margarita; Mufson, Maurice A; Dubovsky, Filip; Knightly, Conor; Zeng, Wen; Losonsky, Genevieve

    2009-07-01

    A live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine was evaluated in healthy respiratory syncytial virus/parainfluenza virus type 3 seropositive children aged 1 to 9 years. Three cohorts of 40 children were randomized 1:1 to receive 10, 10, or 10 median tissue culture infectious dose50 MEDI-534 vaccine or placebo. The vaccine's safety profile was similar to placebo, no viral shedding was detected, and the vaccine was minimally immunogenic.

  2. Pneumonia Virus of Mice Severe Respiratory Virus Infection in a Natural Host

    PubMed Central

    Rosenberg, Helene F.; Domachowske, Joseph B.

    2008-01-01

    Pneumonia virus of mice (PVM; family Paramyxoviridae, genus Pneumovirus) is a natural mouse pathogen that is closely related to the human and bovine respiratory syncytial viruses. Among the prominent features of this infection, robust replication of PVM takes place in bronchial epithelial cells in response to a minimal virus inoculum. Virus replication in situ results in local production of proinflammatory cytokines (MIP-1α, MIP-2, MCP-1 and IFNγ) and granulocyte recruitment to the lung. If left unchecked, PVM infection and the ensuing inflammatory response ultimately lead to pulmonary edema, respiratory compromise and death. In this review, we consider the recent studies using the PVM model that have provided important insights into the role of the inflammatory response in the pathogenesis of severe respiratory virus infection. We also highlight several works that have elucidated acquired immune responses to this pathogen, including T cell responses and the development of humoral immunity. Finally, we consider several immunomodulatory strategies that have been used successfully to reduce morbidity and mortality when administered to PVM infected, symptomatic mice, and thus hold promise as realistic therapeutic strategies for severe respiratory virus infections in human subjects. PMID:18471897

  3. Molecular Characterization of Human Respiratory Syncytial Virus in the Philippines, 2012-2013

    PubMed Central

    Malasao, Rungnapa; Okamoto, Michiko; Chaimongkol, Natthawan; Imamura, Tadatsugu; Tohma, Kentaro; Dapat, Isolde; Dapat, Clyde; Suzuki, Akira; Saito, Mayuko; Saito, Mariko; Tamaki, Raita; Pedrera-Rico, Gay Anne Granada; Aniceto, Rapunzel; Quicho, Reynaldo Frederick Negosa; Segubre-Mercado, Edelwisa; Lupisan, Socorro; Oshitani, Hitoshi

    2015-01-01

    Human respiratory syncytial virus (HRSV) is a major cause of acute lower respiratory tract infections in infants and children worldwide. We performed molecular analysis of HRSV among infants and children with clinical diagnosis of severe pneumonia in four study sites in the Philippines, including Biliran, Leyte, Palawan, and Metro Manila from June 2012 to July 2013. Nasopharyngeal swabs were collected and screened for HRSV using real-time polymerase chain reaction (PCR). Positive samples were tested by conventional PCR and sequenced for the second hypervariable region (2nd HVR) of the G gene. Among a total of 1,505 samples, 423 samples were positive for HRSV (28.1%), of which 305 (72.1%) and 118 (27.9%) were identified as HRSV-A and HRSV-B, respectively. Two genotypes of HRSV-A, NA1 and ON1, were identified during the study period. The novel ON1 genotype with a 72-nucleotide duplication in 2nd HVR of the G gene increased rapidly and finally became the predominant genotype in 2013 with an evolutionary rate higher than the NA1 genotype. Moreover, in the ON1 genotype, we found positive selection at amino acid position 274 (p<0.05) and massive O- and N-glycosylation in the 2nd HVR of the G gene. Among HRSV-B, BA9 was the predominant genotype circulating in the Philippines. However, two sporadic cases of GB2 genotype were found, which might share a common ancestor with other Asian strains. These findings suggest that HRSV is an important cause of severe acute respiratory infection among children in the Philippines and revealed the emergence and subsequent predominance of the ON1 genotype and the sporadic detection of the GB2 genotype. Both genotypes were detected for the first time in the Philippines. PMID:26540236

  4. Molecular Characterization of Human Respiratory Syncytial Virus in the Philippines, 2012-2013.

    PubMed

    Malasao, Rungnapa; Okamoto, Michiko; Chaimongkol, Natthawan; Imamura, Tadatsugu; Tohma, Kentaro; Dapat, Isolde; Dapat, Clyde; Suzuki, Akira; Saito, Mayuko; Saito, Mariko; Tamaki, Raita; Pedrera-Rico, Gay Anne Granada; Aniceto, Rapunzel; Quicho, Reynaldo Frederick Negosa; Segubre-Mercado, Edelwisa; Lupisan, Socorro; Oshitani, Hitoshi

    2015-01-01

    Human respiratory syncytial virus (HRSV) is a major cause of acute lower respiratory tract infections in infants and children worldwide. We performed molecular analysis of HRSV among infants and children with clinical diagnosis of severe pneumonia in four study sites in the Philippines, including Biliran, Leyte, Palawan, and Metro Manila from June 2012 to July 2013. Nasopharyngeal swabs were collected and screened for HRSV using real-time polymerase chain reaction (PCR). Positive samples were tested by conventional PCR and sequenced for the second hypervariable region (2nd HVR) of the G gene. Among a total of 1,505 samples, 423 samples were positive for HRSV (28.1%), of which 305 (72.1%) and 118 (27.9%) were identified as HRSV-A and HRSV-B, respectively. Two genotypes of HRSV-A, NA1 and ON1, were identified during the study period. The novel ON1 genotype with a 72-nucleotide duplication in 2nd HVR of the G gene increased rapidly and finally became the predominant genotype in 2013 with an evolutionary rate higher than the NA1 genotype. Moreover, in the ON1 genotype, we found positive selection at amino acid position 274 (p<0.05) and massive O- and N-glycosylation in the 2nd HVR of the G gene. Among HRSV-B, BA9 was the predominant genotype circulating in the Philippines. However, two sporadic cases of GB2 genotype were found, which might share a common ancestor with other Asian strains. These findings suggest that HRSV is an important cause of severe acute respiratory infection among children in the Philippines and revealed the emergence and subsequent predominance of the ON1 genotype and the sporadic detection of the GB2 genotype. Both genotypes were detected for the first time in the Philippines.

  5. Respiratory syncytial virus infection in children admitted to hospital but ventilated mechanically for other reasons.

    PubMed

    von Renesse, Anja; Schildgen, Oliver; Klinkenberg, Dennis; Müller, Andreas; von Moers, Arpad; Simon, Arne

    2009-01-01

    One thousand five hundred sixty-eight RSV infections were documented prospectively in 1,541 pediatric patients. Of these, 20 (1.3%) had acquired the RSV infection while treated by mechanical ventilation for reasons other than the actual RSV infection (group ventilated mechanically). The clinical characteristics of children who were infected with respiratory syncytial virus (RSV) infection while ventilated mechanically for other reasons are described and compared with a matched control group. Sixty percent of the group ventilated mechanically had at least one additional risk factor for a severe course of infection (prematurity 50%, chronic lung disease 20%, congenital heart disease 35%, immunodeficiency 20%). The median age at diagnosis in the group ventilated mechanically was 4.2 months. The matched pairs analysis (group ventilated mechanically vs. control group) revealed a higher proportion of patients with hypoxemia and apnoea in the group ventilated mechanically; more patients in the control group showed symptoms of airway obstruction (wheezing). At least one chest radiography was performed in 95% of the patients (n = 19) in the group ventilated mechanically versus 45% (n = 9) in the control group (P = 0.001). The frequency of pneumonia was 40% in the group ventilated mechanically and 20% in the control group. Despite existing consensus recommendations, only two patients (10%) of the group ventilated mechanically had received palivizumab previously. Significantly more patients in the group ventilated mechanically received antibiotic treatment (85% vs. 45%, P = 0.008), and attributable mortality was higher in the group ventilated mechanically (15% [n = 3] vs. 0% in the control group, P = 0.231). Children treated by long term mechanical ventilation may acquire RSV infection by transmission by droplets or caregivers and face an increased risk of a severe course of RSV infection. The low rate of immunoprophylaxis in this particular risk group should be improved.

  6. Healthcare costs within a year of respiratory syncytial virus among Medicaid infants.

    PubMed

    Palmer, Liisa; Hall, Caroline B; Katkin, Julie P; Shi, Nianwen; Masaquel, Anthony S; McLaurin, Kimmie K; Mahadevia, Parthiv J

    2010-08-01

    Limited research exists on the economic impact of respiratory syncytial virus lower respiratory infection (RSV LRI) among vulnerable infant populations. This study evaluated healthcare costs of full-term and late-preterm Medicaid infants with RSV LRI within 1 year of infection. Medicaid administrative claims were used to conduct a retrospective study of infants born 2003-2005. Full-term and late-preterm infants <1 year old were assigned to groups based on RSV LRI and unspecified bronchiolitis/pneumonia (UBP) diagnosis codes and stratified by setting of diagnosis. Infants without evidence of RSV LRI/UBP were selected as a comparison group. Economic and clinical outcomes were analyzed descriptively using propensity score weighting, and logged ordinary least squares models were used to examine relationship between RSV and costs incurred within 1 year of infection. RSV LRI and UBP infants, regardless of gestational age or healthcare setting, were more likely to experience respiratory diagnoses of wheezing and infantile asthma versus comparisons. Adjusted and weighted healthcare costs were significantly higher for all groups of RSV LRI and UBP infants relative to comparison infants (P < 0.001). Among late-preterm infants with inpatient and outpatient RSV, marginal costs compared with controls were $17,465 and $2,158, respectively. Costs for RSV LRI and UBP Medicaid infants are substantial. While much of the costs result from initial RSV episodes, higher post-episode costs and rates of respiratory events, procedures, and medications in RSV and UBP infants versus comparisons indicate long-term economic impact from infection and the impact is greater among late-preterm compared to full-term infants.

  7. Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus

    PubMed Central

    Bottau, Paolo; Faldella, Giacomo

    2015-01-01

    Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus. PMID:26064963

  8. Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus.

    PubMed

    Vandini, Silvia; Bottau, Paolo; Faldella, Giacomo; Lanari, Marcello

    2015-01-01

    Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus.

  9. Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants.

    PubMed

    You, Dahui; Saravia, Jordy; Siefker, David; Shrestha, Bishwas; Cormier, Stephania A

    2015-10-07

    The infant immune response to respiratory syncytial virus (RSV) remains incompletely understood. Here we review the use of a neonatal mouse model of RSV infection to mimic severe infection in human infants. We describe numerous age-specific responses, organized by cell type, observed in RSV-infected neonatal mice and draw comparisons (when possible) to human infants.

  10. Virus infection facilitates the development of severe pneumonia in transplant patients with hematologic malignancies

    PubMed Central

    Xu, Duorong; Wu, Jim; Pan, Yujia; Yan, JinSong; Liu, Min; Liu, Quentin

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for patients with hematologic malignancies. Severe pneumonia is associated with high mortality rate in HSCT recipients. Viral co-infection indicates a poor prognosis of HSCT recipients. In this study, a total of 68 allogeneic HSCT recipients were included. Cytomegalovirus (CMV) and Respiratory syncytial virus (RSV) infection was assessed by testing peripheral blood and oropharynx swabs, respectively, collected in the first 180 days after transplantation. We analysed the correlation of CMV and RSV co-infection with severe pneumonia and mortality. The incidence of CMV and RSV co-infection was 26.5% (18/68). Severe pneumonia was diagnosed in 61% (11/18) cases with co-infection compared to only 10% (5/50) cases with mono-infection or no infection. The analysis of potential risk factors for severe pneumonia showed that CMV and RSV co-infection was significantly associated with severe pneumonia (p < 0.001). The 5 patients who died of severe pneumonia were all co-infected with CMV and RSV. In conclusion, CMV and RSV co-infection appears to be an important factor and facilitates the development of severe pneumonia in allogeneic HSCT patients with hematologic malignancies. PMID:27340772

  11. Randomised controlled trial and health economic evaluation of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64-year-olds.

    PubMed

    Nicholson, Karl G; Abrams, Keith R; Batham, Sally; Medina, Marie Jo; Warren, Fiona C; Barer, Mike; Bermingham, Alison; Clark, Tristan W; Latimer, Nicholas; Fraser, Maria; Perera, Nelun; Rajakumar, K; Zambon, Maria

    2014-05-01

    Western industrialised nations face a large increase in the number of older people. People over the age of 60 years account for almost half of the 16.8 million hospital admissions in England from 2009 to 2010. During 2009-10, respiratory infections accounted for approximately 1 in 30 hospital admissions and 1 in 20 of the 51.5 million bed-days. To determine the diagnostic accuracy and clinical effectiveness and cost-effectiveness of rapid molecular and near-patient diagnostic tests for influenza, respiratory syncytial virus (RSV) and Streptococcus pneumoniae infections in comparison with traditional laboratory culture. We carried out a randomised controlled trial (RCT) to evaluate impact on prescribing and clinical outcomes of point-of-care tests (POCTs) for influenza A and B and pneumococcal infection, reverse transcriptase-polymerase chain reaction (RT-PCR) tests for influenza A and B and RSV A and B, and conventional culture for these pathogens. We evaluated diagnostic accuracy of POCTs for influenza and pneumococcal infection, RT-PCR for influenza and sputum culture for S. pneumoniae using samples collected during the RCT. We did a systematic review and meta-analysis of POCTs for influenza A and B. We evaluated ease and speed of use of each test, process outcomes and cost-effectiveness. There was no evidence of association between diagnostic group and prescribing or clinical outcomes. Using PCR as 'gold standard', Quidel Influenza A + B POCT detected 24.4% [95% confidence interval (CI) 16.0% to 34.6%] of influenza infections (specificity 99.7%, 95% CI 99.2% to 99.9%); viral culture detected 21.6% (95% CI 13.5% to 31.6%; specificity 99.8%, 95% CI 99.4% to 100%). Using blood culture as 'gold standard', BinaxNOW pneumococcal POCT detected 57.1% (95% CI 18.4% to 90.1%) of pneumococcal infections (specificity 92.5%; 95% CI 90.6% to 94.1%); sputum culture detected 100% (95% CI 2.5% to 100%; specificity 97.2%, 95% CI 94.3% to 98.9%). Overall, pooled estimates of

  12. Concurrent detection of other respiratory viruses in children shedding viable human respiratory syncytial virus.

    PubMed

    Gagliardi, T B; Paula, F E; Iwamoto, M A; Proença-Modena, J L; Santos, A E; Camara, A A; Cervi, M C; Cintra, O A L; Arruda, E

    2013-10-01

    Human respiratory syncytial virus (HRSV) is an important cause of respiratory disease. The majority of studies addressing the importance of virus co-infections to the HRSV-disease have been based on the detection of HRSV by RT-PCR, which may not distinguish current replication from prolonged shedding of remnant RNA from previous HRSV infections. To assess whether co-detections of other common respiratory viruses are associated with increased severity of HRSV illnesses from patients who were shedding viable-HRSV, nasopharyngeal aspirates from children younger than 5 years who sought medical care for respiratory infections in Ribeirão Preto (Brazil) were tested for HRSV by immunofluorescence, RT-PCR and virus isolation in cell culture. All samples with viable-HRSV were tested further by PCR for other respiratory viruses. HRSV-disease severity was assessed by a clinical score scale. A total of 266 samples from 247 children were collected and 111 (42%) were HRSV-positive. HRSV was isolated from 70 (63%), and 52 (74%) of them were positive for at least one additional virus. HRSV-positive diseases were more severe than HRSV-negative ones, but there was no difference in disease severity between patients with viable-HRSV and those HRSV-positives by RT-PCR. Co-detection of other viruses did not correlate with increased disease severity. HRSV isolation in cell culture does not seem to be superior to RT-PCR to distinguish infections associated with HRSV replication in studies of clinical impact of HRSV. A high rate of co-detection of other respiratory viruses was found in samples with viable-HRSV, but this was not associated with more severe HRSV infection. Copyright © 2013 Wiley Periodicals, Inc.

  13. Burden of Severe Respiratory Syncytial Virus Disease Among 33–35 Weeks’ Gestational Age Infants Born During Multiple Respiratory Syncytial Virus Seasons

    PubMed Central

    Carbonell-Estrany, Xavier; Blanken, Maarten; Lanari, Marcello; Sheridan-Pereira, Margaret; Rodgers-Gray, Barry; Fullarton, John; Rouffiac, Elisabeth; Vo, Pamela; Notario, Gerard; Campbell, Fiona; Paes, Bosco

    2017-01-01

    Background: Moderate-late preterm infants, 33–35 weeks’ gestational age (wGA), are at increased risk for respiratory syncytial virus hospitalization (RSVH). The objective of this study is to quantify the burden of RSVH in moderate-late preterm infants. Methods: A pooled analysis was conducted on RSVH from 7 prospective, observational studies in the Northern Hemisphere from 2000 to 2014. Infants’ 330–356 wGA without comorbidity born during the respiratory syncytial virus season who did not receive respiratory syncytial virus immunoprophylaxis were enrolled. Data for the first confirmed RSVH during the season (+1 month) were analyzed. Incidence and hospitalization rate per 100 patient-seasons, intensive care unit admission and length of stay (LOS), oxygen support, mechanical ventilation and overall hospital LOS were assessed. Results: The pooled analysis comprised 7,820 infants; 267 experienced a confirmed RSVH at a median age of 8.4 weeks. The crude pooled RSVH incidence rate was 3.41% and the rate per 100 patient-seasons was 4.52. Median hospital LOS was 5.7 days. A total of 22.2% of infants required intensive care unit admission for a median LOS of 8.3 days. A total of 70.4% received supplemental oxygen support for a median of 4.9 days, and 12.7% required mechanical ventilation for a median of 4.8 days. Conclusions: The burden of RSVH in moderate-late, 33–35 weeks’ wGA preterm infants without comorbidities born during the viral season in Northern Hemisphere countries is substantial. Severe cases required prolonged and invasive supportive therapy. PMID:27755464

  14. Pneumonia

    MedlinePlus

    ... is often caused by viruses, such as the influenza virus (flu) and adenovirus . Other viruses, such as respiratory ... especially which bug is causing the illness. With influenza pneumonia, for ... exposure to the flu virus. But with walking pneumonia, a person may not ...

  15. Pneumonia

    MedlinePlus

    Pneumonia Overview By Mayo Clinic Staff Pneumonia is an infection that inflames the air sacs in one or both lungs. The air sacs may fill with fluid or pus ( ... organisms, including bacteria, viruses and fungi, can cause pneumonia. Pneumonia can range in seriousness from mild to ...

  16. Evidence of respiratory syncytial virus and parainfluenza-3 virus in Mexican sheep.

    PubMed

    Contreras-Luna, M J; Ramírez-Martínez, L A; Sarmiento Silva, R E; Cruz Lazo, C; Pérez Torres, A; Sánchez-Betancourt, J I

    2017-03-01

    This is a first report in Mexico of the presence of antibodies against respiratory syncytial virus (RSV) and parainfluenza-3 virus in Mexican sheep in different productive stages. We determine the association of serological positivity with age and production system, and obtain molecular evidence of infection by both virus. RSV prevalence in adult sheep was 47% (49/105) at the tropic and 64% (63/99) at the uplands. A significant difference in RSV seropositivity between animals from the tropic and the uplands was observed (P < 0.05). Seropositivity correlated with production system (P = 0.003, OR = 2.042), with a risk of showing antibodies was 2.042 times higher in sheep under an extensive production system. A significant difference in PI3V seropositivity between animals from either provenance (P = 0.017, OR = 0.475) were also found, with a risk of showing antibodies 0.475 times higher in sheep under an extensive production system. Genetic material from RSV and PI3V was identified by RT-PCR in nasal swab samples from clinically healthy lambs and confirmed by sequencing and phylogenetic analysis. Serological results show that sheep are susceptible to infection by both viruses, and molecular results suggest that the identified antibodies are result of natural infections and reinfections.

  17. Analysis of proteins synthesized in respiratory syncytial virus-infected cells.

    PubMed Central

    Dubovi, E J

    1982-01-01

    The spectrum of respiratory syncytial virus-encoded proteins was examined in infected cell extracts by standard polyacrylamide gel electrophoresis and by two-dimensional gel analysis. Polyacrylamide gel electrophoresis analysis of a variety of respiratory syncytial virus-infected, actinomycin D-treated cell lines revealed the presence of as many as nine virus-encoded proteins. Seven of these nine proteins were immunoprecipitated by anti-respiratory syncytial serum. Only one major band of [3H]glucosamine was detected in infected cell extracts (Vp86), whereas the reported major virion glycoprotein (Vp48-53) was difficult to detect in infected cells when carbohydrate labels were employed. Two-dimensional gel analysis easily identified seven viral proteins, and one other was tentatively identified. The reported major virion glycoprotein again was not consistently detected. The results of this study confirm the existence of a virus-coded glycoprotein (Vp86) in infected cell extracts. The existence of this glycoprotein in the purified virion has been in dispute, but the apparent low methionine content of this protein may be the reason for this controversy. Images PMID:7086963

  18. High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants.

    PubMed

    Vissers, Marloes; Ahout, Inge M; van den Kieboom, Corné H; van der Gaast-de Jongh, Christa E; Groh, Laszlo; Cremers, Amelieke J; de Groot, Ronald; de Jonge, Marien I; Ferwerda, Gerben

    2016-03-17

    Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infections in infants. A small percentage of the infected infants develops a severe infection, while most of these severely ill patients were previously healthy. It remains unclear why these children develop severe RSV infections. In this study, we investigate whether pneumococcal nasopharyngeal carriage patterns correlate with mucosal inflammation and severity of disease. In total, 105 infants hospitalized with RSV infection were included and recovery samples were taken from 42 patients. The presence and density of Streptococcus pneumoniae was determined by RT qPCR to study its relation to viral load, inflammation (MMP-9 and IL-6) and severity of RSV disease. We show that pneumococcal presence or absence in the nasopharynx does not correlate with viral load, inflammation or severity of disease. However, when pneumococcus is present in patients, a higher nasopharyngeal pneumococcal density was correlated with a higher RSV load, higher MMP-9 levels and a less severe course of disease. Our results show correlations between S. pneumoniae density and viral load, inflammation and disease severity, suggesting that pneumococcal density may be an indicator for severity in paediatric RSV disease.

  19. Antibiotic use in children is not influenced by the result of rapid antigen detection test for the respiratory syncytial virus.

    PubMed

    Thibeault, Roseline; Gilca, Rodica; Côté, Stéphanie; De Serres, Gaston; Boivin, Guy; Déry, Pierre

    2007-07-01

    Rapid antigen detection test (RADT) for respiratory syncytial virus (RSV) is widely used in children hospitalized with acute respiratory tract infection (ARTI), but its influence on antibiotic (AB) use is uncertain. To evaluate if confirmation of RSV infection by RADT modified AB use and elucidate others factors associated with the continuation of antibiotics. Charts of children hospitalized with viral ARTI aged 0-35 months were reviewed. Modification of antibiotics according to RSV RADT results was compared using Kaplan-Meier estimates and multivariate Cox regression. Of children receiving antibiotics when the RSV RADT result was available, RSV RADT was positive in 144 and negative in 54. Positive RSV RADT results did not lead to modification of antibiotic use. Factors independently associated with cessation of intravenous antibiotics were age > or = 3 months (HR 2.44 [1.41-4.21]) and absence of pneumonia (HR 1.50 [1.03-2.19]). Absence of otitis was associated with cessation of oral antibiotics (HR 9.16 [95% CI, 2.35-35.76]). Confirmed presence of RSV by RADT did not influence antibiotic use in young children with ARTI. Except with pneumonia, the risk of bacterial superinfection of RSV infected children is minimal and confirmation of RSV infection should prompt treating physicians to interrupt antibiotics.

  20. Association between Respiratory Syncytial Virus Activity and Pneumococcal Disease in Infants: A Time Series Analysis of US Hospitalization Data

    PubMed Central

    Weinberger, Daniel M.; Klugman, Keith P.; Steiner, Claudia A.; Simonsen, Lone; Viboud, Cécile

    2015-01-01

    Background The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV. Methods and Findings We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993–2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1–2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1–2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (−18.0%, 95% CI: −22.6%, −13.1%, for 2004/2005–2008/2009 versus 1997/1998–1999/2000). This study used aggregated hospitalization data, and studies with

  1. Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data.

    PubMed

    Weinberger, Daniel M; Klugman, Keith P; Steiner, Claudia A; Simonsen, Lone; Viboud, Cécile

    2015-01-01

    The importance of bacterial infections following respiratory syncytial virus (RSV) remains unclear. We evaluated whether variations in RSV epidemic timing and magnitude are associated with variations in pneumococcal disease epidemics and whether changes in pneumococcal disease following the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) were associated with changes in the rate of hospitalizations coded as RSV. We used data from the State Inpatient Databases (Agency for Healthcare Research and Quality), including >700,000 RSV hospitalizations and >16,000 pneumococcal pneumonia hospitalizations in 36 states (1992/1993-2008/2009). Harmonic regression was used to estimate the timing of the average seasonal peak of RSV, pneumococcal pneumonia, and pneumococcal septicemia. We then estimated the association between the incidence of pneumococcal disease in children and the activity of RSV and influenza (where there is a well-established association) using Poisson regression models that controlled for shared seasonal variations. Finally, we estimated changes in the rate of hospitalizations coded as RSV following the introduction of PCV7. RSV and pneumococcal pneumonia shared a distinctive spatiotemporal pattern (correlation of peak timing: ρ = 0.70, 95% CI: 0.45, 0.84). RSV was associated with a significant increase in the incidence of pneumococcal pneumonia in children aged <1 y (attributable percent [AP]: 20.3%, 95% CI: 17.4%, 25.1%) and among children aged 1-2 y (AP: 10.1%, 95% CI: 7.6%, 13.9%). Influenza was also associated with an increase in pneumococcal pneumonia among children aged 1-2 y (AP: 3.2%, 95% CI: 1.7%, 4.7%). Finally, we observed a significant decline in RSV-coded hospitalizations in children aged <1 y following PCV7 introduction (-18.0%, 95% CI: -22.6%, -13.1%, for 2004/2005-2008/2009 versus 1997/1998-1999/2000). This study used aggregated hospitalization data, and studies with individual-level, laboratory-confirmed data could

  2. Enzyme-linked immunosorbent assay for detection of respiratory syncytial virus infection: application to clinical samples.

    PubMed Central

    McIntosh, K; Hendry, R M; Fahnestock, M L; Pierik, L T

    1982-01-01

    An enzyme-linked immunosorbent assay (ELISA) for respiratory syncytial virus antigens was applied to the rapid diagnosis of acute infections in children and was compared with viral culture and immunofluorescence tests. The ELISA test employed commercially available reagents and was run on a day-to-day basis as specimens were received in the laboratory. Sensitivity and specificity by ELISA were 82 and 95%, respectively, compared with culture. In the same specimens, the sensitivity and specificity by immunofluorescence were 86 and 96%, respectively. Nasopharyngeal aspirates were proven to be a better source of viral antigen than were nasopharyngeal swabs. ELISA-positive samples remained positive even when left unrefrigerated for a week or mailed to the laboratory in plastic containers. Respiratory syncytial virus ELISA, like culture, became negative as the disease progressed and showed no superiority over culture for diagnosis late in the illness. PMID:6749895

  3. Community-acquired pneumonia in Chile: the clinical relevance in the detection of viruses and atypical bacteria.

    PubMed

    Luchsinger, Vivian; Ruiz, Mauricio; Zunino, Enna; Martínez, María Angélica; Machado, Clarisse; Piedra, Pedro A; Fasce, Rodrigo; Ulloa, María Teresa; Fink, Maria Cristina; Lara, Pamela; Gebauer, Mónica; Chávez, Fernando; Avendaño, Luis F

    2013-11-01

    Adult community-acquired pneumonia (CAP) is a relevant worldwide cause of morbidity and mortality, however the aetiology often remains uncertain and the therapy is empirical. We applied conventional and molecular diagnostics to identify viruses and atypical bacteria associated with CAP in Chile. We used sputum and blood cultures, IgG/IgM serology and molecular diagnostic techniques (PCR, reverse transcriptase PCR) for detection of classical and atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumoniae) and respiratory viruses (adenovirus, respiratory syncytial virus (RSV), human metapneumovirus, influenza virus, parainfluenzavirus, rhinovirus, coronavirus) in adults >18 years old presenting with CAP in Santiago from February 2005 to September 2007. Severity was qualified at admission by Fine's pneumonia severity index. Overall detection in 356 enrolled adults were 92 (26%) cases of a single bacterial pathogen, 80 (22%) cases of a single viral pathogen, 60 (17%) cases with mixed bacterial and viral infection and 124 (35%) cases with no identified pathogen. Streptococcus pneumoniae and RSV were the most common bacterial and viral pathogens identified. Infectious agent detection by PCR provided greater sensitivity than conventional techniques. To our surprise, no relationship was observed between clinical severity and sole or coinfections. The use of molecular diagnostics expanded the detection of viruses and atypical bacteria in adults with CAP, as unique or coinfections. Clinical severity and outcome were independent of the aetiological agents detected.

  4. Mammalian Cell-Derived Respiratory Syncytial Virus-Like Particles Protect the Lower as well as the Upper Respiratory Tract.

    PubMed

    Walpita, Pramila; Johns, Lisa M; Tandon, Ravi; Moore, Martin L

    2015-01-01

    Globally, Respiratory Syncytial Virus (RSV) is a leading cause of bronchiolitis and pneumonia in children less than one year of age and in USA alone, between 85,000 and 144,000 infants are hospitalized every year. To date, there is no licensed vaccine. We have evaluated vaccine potential of mammalian cell-derived native RSV virus-like particles (RSV VLPs) composed of the two surface glycoproteins G and F, and the matrix protein M. Results of in vitro testing showed that the VLPs were functionally assembled and immunoreactive, and that the recombinantly expressed F protein was cleaved intracellularly similarly to the virus-synthesized F protein to produce the F1 and F2 subunits; the presence of the F1 fragment is critical for vaccine development since all the neutralizing epitopes present in the F protein are embedded in this fragment. Additional in vitro testing in human macrophage cell line THP-1 showed that both virus and the VLPs were sensed by TLR-4 and induced a Th1-biased cytokine response. Cotton rats vaccinated with RSV VLPs adjuvanted with alum and monophosphoryl lipid A induced potent neutralizing antibody response, and conferred protection in the lower as well as the upper respiratory tract based on substantial virus clearance from these sites. To the best of our knowledge, this is the first VLP/virosome vaccine study reporting protection of the lower as well as the upper respiratory tract: Prevention from replication in the nose is an important consideration if the target population is infants < 6 months of age. This is because continued virus replication in the nose results in nasal congestion and babies at this age are obligate nose breathers. In conclusion, these results taken together suggest that our VLPs show promise to be a safe and effective vaccine for RSV.

  5. Inhibition of respiratory syncytial virus replication and virus-induced p38 kinase activity by berberine.

    PubMed

    Shin, Han-Bo; Choi, Myung-Soo; Yi, Chae-Min; Lee, Jun; Kim, Nam-Jung; Inn, Kyung-Soo

    2015-07-01

    Respiratory syncytial virus (RSV) causes severe lower respiratory tract infection and poses a major public health threat worldwide. No effective vaccines or therapeutics are currently available; berberine, an isoquinoline alkaloid from various medicinal plants, has been shown to exert antiviral and several other biological effects. Recent studies have shown that p38 mitogen-activated protein kinase (MAPK) activity is implicated in infection by and replication of viruses such as RSV and the influenza virus. Because berberine has previously been implicated in modulating the activity of p38 MAPK, its effects on RSV infection and RSV-mediated p38 MAPK activation were examined. Replication of RSV in epithelial cells was significantly reduced by treatment with berberine. Berberine treatment caused decrease in viral protein and mRNA syntheses. Similar to previously reported findings, RSV infection caused phosphorylation of p38 MAPK at a very early time point of infection, and phosphorylation was dramatically reduced by berberine treatment. In addition, production of interleukin-6 mRNA upon RSV infection was significantly suppressed by treatment with berberine, suggesting the anti-inflammatory role of berberine during RSV infection. Taken together, we showed that berberine, a natural compound already proven to be safe for human consumption, suppresses the replication of RSV. In addition, the current study suggests that inhibition of RSV-mediated early p38 MAPK activation, which has been implicated as an early step in viral infection, as a potential molecular mechanism. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. A respiratory syncytial virus (RSV) vaccine based on parainfluenza virus 5 (PIV5)

    PubMed Central

    Phan, Shannon I.; Chen, Zhenhai; Xu, Pei; Li, Zhuo; Gao, Xiudan; Foster, Stephanie L.; Teng, Michael N.; Tripp, Ralph A.; Sakamoto, Kaori; He, Biao

    2014-01-01

    Human respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease and hospitalizations in infants and young children. It also causes significant morbidity and mortality in elderly and immune compromised individuals. No licensed vaccine currently exists. Parainfluenza virus 5 (PIV5) is a paramyxovirus that causes no known human illness and has been used as a platform for vector-based vaccine development. To evaluate the efficacy of PIV5 as a RSV vaccine vector, we generated two recombinant PIV5 viruses - one expressing the fusion (F) protein and the other expressing the attachment glycoprotein (G) of RSV strain A2 (RSV A2). The vaccine strains were used separately for single-dose vaccinations in BALB/c mice. The results showed that both vaccines induced RSV antigen-specific antibody responses, with IgG2a/IgG1 ratios similar to those seen in wild-type RSV A2 infection. After challenging the vaccinated mice with RSV A2, histopathology of lung sections showed that the vaccines did not exacerbate lung lesions relative to RSV A2-immunized mice. Importantly, both F and G vaccines induced protective immunity. Therefore, PIV5 presents an attractive platform for vector-based vaccines against RSV infection. PMID:24717150

  7. Post-extubation stridor in Respiratory Syncytial Virus bronchiolitis: Is there a role for prophylactic dexamethasone?

    PubMed Central

    Kappen, Teus H.; Calis, Job C.; van Woensel, Job; Raymakers-Janssen, Paulien A. M.; Bont, Louis J.; Hennus, Marije P.

    2017-01-01

    Aim The purpose of this study was to determine the incidence of reintubation due to upper airway obstruction in a homogeneous group of ventilated infants with Respiratory Syncytial Virus bronchiolitis. Our secondary objective was to determine whether prophylactic administration of dexamethasone prior to extubation was associated with decreased risk of reintubation. Methods This retrospective observational study in two Pediatric Intensive Care Units in 2 university hospitals in The Netherlands included two hundred patients younger than 13 months admitted with respiratory insufficiency caused by Respiratory Syncytial Virus bronchiolitis, requiring invasive mechanical ventilation. A logistic regression analysis with propensity score method was used to adjust for possible confounding. Results Reintubation due to post-extubation stridor occurred in 17 (8.5%) of 200 patients. After propensity score matching, administration of dexamethasone prior to extubation was associated with a significantly (p = 0.0011) decreased risk of reintubation due to post-extubation stridor compared to patients not receiving prophylactic dexamethasone (absolute risk reduction 13%, 95% CI 5.3–21%). Conclusion Reintubation due to post-extubation stridor is an important complication of ventilation for Respiratory Syncytial Virus bronchiolitis. Dexamethasone administered prior to extubation probably reduces the risk of post-extubation stridor necessitating reintubation in these infants. The results of this study support initiation of a placebo-controlled trial to confirm the beneficial effect of prophylactic dexamethasone. PMID:28207796

  8. Post-extubation stridor in Respiratory Syncytial Virus bronchiolitis: Is there a role for prophylactic dexamethasone?

    PubMed

    Veldhoen, Esther S; Smulders, Charlotte A; Kappen, Teus H; Calis, Job C; van Woensel, Job; Raymakers-Janssen, Paulien A M; Bont, Louis J; Hennus, Marije P

    2017-01-01

    The purpose of this study was to determine the incidence of reintubation due to upper airway obstruction in a homogeneous group of ventilated infants with Respiratory Syncytial Virus bronchiolitis. Our secondary objective was to determine whether prophylactic administration of dexamethasone prior to extubation was associated with decreased risk of reintubation. This retrospective observational study in two Pediatric Intensive Care Units in 2 university hospitals in The Netherlands included two hundred patients younger than 13 months admitted with respiratory insufficiency caused by Respiratory Syncytial Virus bronchiolitis, requiring invasive mechanical ventilation. A logistic regression analysis with propensity score method was used to adjust for possible confounding. Reintubation due to post-extubation stridor occurred in 17 (8.5%) of 200 patients. After propensity score matching, administration of dexamethasone prior to extubation was associated with a significantly (p = 0.0011) decreased risk of reintubation due to post-extubation stridor compared to patients not receiving prophylactic dexamethasone (absolute risk reduction 13%, 95% CI 5.3-21%). Reintubation due to post-extubation stridor is an important complication of ventilation for Respiratory Syncytial Virus bronchiolitis. Dexamethasone administered prior to extubation probably reduces the risk of post-extubation stridor necessitating reintubation in these infants. The results of this study support initiation of a placebo-controlled trial to confirm the beneficial effect of prophylactic dexamethasone.

  9. Renal transplant with bronchiolitis obliterans organizing pneumonia (BOOP) attributable to tacrolimus and herpes simplex virus (HSV) pneumonia.

    PubMed

    Cunha, Burke A; Syed, Uzma; Mickail, Nardeen

    2012-05-01

    Solid organ transplants (SOTs) may be complicated by a wide variety of infectious and noninfectious pulmonary disorders. Transplant patients receive immunosuppressive drugs to prevent rejection, but these drugs also predispose them to infection. Because immunosuppressive therapy impairs T-lymphocyte function, ie, cell-mediated immunity, such therapy, not surprisingly, predisposes patients to intracellular pulmonary pathogens. Community-acquired pneumonia (CAP) in patients with SOT usually involves one of the common typical or atypical bacterial CAP pathogens infecting immunocompetent hosts. The most frequent intracellular CAP pathogens in SOTs during immunosuppressive therapy are viral, eg, cytomegalovirus (CMV), respiratory syncytial virus (RSV), and herpes simplex virus (HSV). In addition, intracellular fungal pathogens are also common in patients with SOTs during immunosuppressive therapy, eg, Pneumocystis (carinii) jiroveci pneumonia (PCP). In addition, a variety of noninfectious disorders are not uncommon in patients with SOTs, including bronchiolitis obliterans organizing pneumonia (BOOP). Bronchiolitis obliterans organizing pneumonia may be associated with a variety of infectious agents, or may be attributable to drugs, including some immunosuppressive agents. The clinical approach to CAP in patients with SOTs may be based on the appearance of the chest x-ray (CXR) or chest computed tomography scan, combined with the degree of hypoxemia (ie, the A-a gradient). Patients with SOTs and with a normal or nearly normal CXR and a high degree of hypoxemia (A-a gradient, >35) most often have an early viral pneumonia, eg, CMV or early PCP. If the CXR reveals bilateral patchy interstitial infiltrates and severe hypoxemia, the differential diagnosis is limited to moderate or severe viral pneumonia or PCP. Patients with SOTs and presenting with diffuse infiltrates and mild to moderate hypoxemia (A-a gradient, <35) are usually prone to noninfectious disorders, eg

  10. Immunohistochemical detection of antigens of distemper, adenovirus and parainfluenza viruses in domestic dogs with pneumonia.

    PubMed

    Damián, M; Morales, E; Salas, G; Trigo, F J

    2005-11-01

    The lungs of 35 dogs that died in Mexico from acute or subacute pneumonia were examined immunohistochemically for canine distemper virus (CDV), canine adenovirus (CAV) and canine parainfluenza virus (CpiV), to determine their frequency and occurrence and possible associations. CDV was identified in 27 (77%) cases, CAV in 20 (57%) and CpiV in 18 (51%). The most frequent dual association was that between CDV and CpiV (five cases; 14%). All three viruses, however, were identified in the same lung in 10 cases. Immunolabelling occurred in alveolar macrophages, monocytes, pneumocytes, epithelial cells and syncytial cells. It was concluded that immunohistochemistry is a useful diagnostic tool in canine respiratory disease to complement histopathological examination.

  11. Structure of a Major Antigenic Site on the Respiratory Syncytial Virus Fusion Glycoprotein in Complex with Neutralizing Antibody 101F

    SciTech Connect

    McLellan, Jason S.; Chen, Man; Chang, Jung-San; Yang, Yongping; Kim, Albert; Graham, Barney S.; Kwong, Peter D.

    2010-11-19

    Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in infants and elderly people. Currently there is no effective vaccine against RSV, but passive prophylaxis with neutralizing antibodies reduces hospitalizations. To investigate the mechanism of antibody-mediated RSV neutralization, we undertook structure-function studies of monoclonal antibody 101F, which binds a linear epitope in the RSV fusion glycoprotein. Crystal structures of the 101F antigen-binding fragment in complex with peptides from the fusion glycoprotein defined both the extent of the linear epitope and the interactions of residues that are mutated in antibody escape variants. The structure allowed for modeling of 101F in complex with trimers of the fusion glycoprotein, and the resulting models suggested that 101F may contact additional surfaces located outside the linear epitope. This hypothesis was supported by surface plasmon resonance experiments that demonstrated 101F bound the peptide epitope {approx}16,000-fold more weakly than the fusion glycoprotein. The modeling also showed no substantial clashes between 101F and the fusion glycoprotein in either the pre- or postfusion state, and cell-based assays indicated that 101F neutralization was not associated with blocking virus attachment. Collectively, these results provide a structural basis for RSV neutralization by antibodies that target a major antigenic site on the fusion glycoprotein.

  12. C5 Modulates Airway Hyperreactivity and Pulmonary Eosinophilia during Enhanced Respiratory Syncytial Virus Disease by Decreasing C3a Receptor Expression▿

    PubMed Central

    Melendi, Guillermina A.; Hoffman, Scott J.; Karron, Ruth A.; Irusta, Pablo M.; Laham, Federico R.; Humbles, Alison; Schofield, Brian; Pan, Chien-Hsiung; Rabold, Richard; Thumar, Bhagvanji; Thumar, Adeep; Gerard, Norma P.; Mitzner, Wayne; Barnum, Scott R.; Gerard, Craig; Kleeberger, Steven R.; Polack, Fernando P.

    2007-01-01

    Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses. PMID:17079327

  13. Cellular reactivity to respiratory syncytial virus in human colostrum and breast milk.

    PubMed

    Scott, R; Scott, M; Toms, G L

    1985-09-01

    Colostrum and breast-milk samples were taken from 23 mothers between 2 days and 7 weeks postpartum and were examined for the presence of cellular reactivity to respiratory syncytial (RS) virus using a lymphocyte transformation assay. Positive responses were detected in nine of the 23 (39%) samples taken at 2-5 days postpartum, but this reactivity was undetectable at 3 weeks. Positive responses developed in a further three mothers during the 3-7-week period of lactation, suggesting a response to virus infection. Colostral whey was found to suppress the cellular response to RS virus and inhibition was related to the level of specific IgA antibody to RS virus present in the whey. The role of colostral cellular reactivity in protection of breast-fed infants from RS virus bronchiolitis is discussed.

  14. The Viral Transcription Group Determines the HLA Class I Cellular Immune Response Against Human Respiratory Syncytial Virus*

    PubMed Central

    Johnstone, Carolina; Lorente, Elena; Barriga, Alejandro; Barnea, Eilon; Infantes, Susana; Lemonnier, François A.; David, Chella S.; Admon, Arie; López, Daniel

    2015-01-01

    The cytotoxic T-lymphocyte-mediated killing of virus-infected cells requires previous recognition of short viral antigenic peptides bound to human leukocyte antigen class I molecules that are exposed on the surface of infected cells. The cytotoxic T-lymphocyte response is critical for the clearance of human respiratory syncytial virus infection. In this study, naturally processed viral human leukocyte antigen class I ligands were identified with mass spectrometry analysis of complex human leukocyte antigen-bound peptide pools isolated from large amounts of human respiratory syncytial virus-infected cells. Acute antiviral T-cell response characterization showed that viral transcription determines both the immunoprevalence and immunodominance of the human leukocyte antigen class I response to human respiratory syncytial virus. These findings have clear implications for antiviral vaccine design. PMID:25635267

  15. The viral transcription group determines the HLA class I cellular immune response against human respiratory syncytial virus.

    PubMed

    Johnstone, Carolina; Lorente, Elena; Barriga, Alejandro; Barnea, Eilon; Infantes, Susana; Lemonnier, François A; David, Chella S; Admon, Arie; López, Daniel

    2015-04-01

    The cytotoxic T-lymphocyte-mediated killing of virus-infected cells requires previous recognition of short viral antigenic peptides bound to human leukocyte antigen class I molecules that are exposed on the surface of infected cells. The cytotoxic T-lymphocyte response is critical for the clearance of human respiratory syncytial virus infection. In this study, naturally processed viral human leukocyte antigen class I ligands were identified with mass spectrometry analysis of complex human leukocyte antigen-bound peptide pools isolated from large amounts of human respiratory syncytial virus-infected cells. Acute antiviral T-cell response characterization showed that viral transcription determines both the immunoprevalence and immunodominance of the human leukocyte antigen class I response to human respiratory syncytial virus. These findings have clear implications for antiviral vaccine design.

  16. Respiratory Syncytial Virus and Other Respiratory Viral Infections in Older Adults With Moderate to Severe Influenza-like Illness

    PubMed Central

    Falsey, Ann R.; McElhaney, Janet E.; Beran, Jiri; van Essen, Gerrit A.; Duval, Xavier; Esen, Meral; Galtier, Florence; Gervais, Pierre; Hwang, Shinn-Jang; Kremsner, Peter; Launay, Odile; Leroux-Roels, Geert; McNeil, Shelly A.; Nowakowski, Andrzej; Richardus, Jan Hendrik; Ruiz-Palacios, Guillermo; St Rose, Suzanne; Devaster, Jeanne-Marie; Oostvogels, Lidia; Durviaux, Serge; Taylor, Sylvia

    2014-01-01

    Background. Few studies have prospectively assessed viral etiologies of acute respiratory infections in community-based elderly individuals. We assessed viral respiratory pathogens in individuals ≥65 years with influenza-like illness (ILI). Methods. Multiplex reverse-transcriptase polymerase chain reaction identified viral pathogens in nasal/throat swabs from 556 episodes of moderate-to-severe ILI, defined as ILI with pneumonia, hospitalization, or maximum daily influenza symptom severity score (ISS) >2. Cases were selected from a randomized trial of an adjuvanted vs nonadjuvanted influenza vaccine conducted in elderly adults from 15 countries. Results. Respiratory syncytial virus (RSV) was detected in 7.4% (41/556) moderate-to-severe ILI episodes in elderly adults. Most (39/41) were single infections. There was a significant association between country and RSV detection (P = .004). RSV prevalence was 7.1% (2/28) in ILI with pneumonia, 12.5% (8/64) in ILI with hospitalization, and 6.7% (32/480) in ILI with maximum ISS > 2. Any virus was detected in 320/556 (57.6%) ILI episodes: influenza A (104/556, 18.7%), rhinovirus/enterovirus (82/556, 14.7%), coronavirus and human metapneumovirus (each 32/556, 5.6%). Conclusions. This first global study providing data on RSV disease in ≥65 year-olds confirms that RSV is an important respiratory pathogen in the elderly. Preventative measures such as vaccination could decrease severe respiratory illnesses and complications in the elderly. PMID:24482398

  17. Clinical characterization of influenza A and human respiratory syncytial virus among patients with influenza like illness.

    PubMed

    Saxena, Swati; Singh, Dharamveer; Zia, Amreen; Umrao, Jyoti; Srivastava, Naveen; Pandey, Ankita; Singh, Sushma; Bhattacharya, Piyali; Kumari, Reema; Kushwaha, Ramawadh; Dhole, T N

    2017-01-01

    Influenza A and Respiratory Syncytial Virus (RSV) has been recognized as a major cause of acute respiratory tract infection. H1N1 is one of the subtypes of influenza A, pandemic worldwide in July 2009, causing 18,449 deaths globally. To investigate the prevalence and clinical manifestation of the influenza A, H1N1pdm09, and RSV. Throat/nasal swab collected from the patients of all age group either outpatients/inpatients having respiratory illness from 2 to 5 days. The clinical data were recorded in a predesigned questionnaire. RNA was extracted and analyzed by real time PCR at a tertiary care center, 2009-2014. Total 4,352 samples tested for influenza A and H1N1. Out of 4,352, 32.2% (median positivity 21%; range 16-41% during 6 years) were positive for influenza A and 19% were H1N1 (median positivity 16.7%; range 8.7-23% during 6 years). Total 1653 samples were analyzed for RSV from 2011 to 2014, 12% were RSV positive (median positivity 11.35%; range 10-16.3% during 4 years). Pharyngitis, dyspnea were frequent symptoms in influenza A and H1N1 (P < 0.005) whereas bronchiolitis and pneumonia were commonly present in RSV (P < 0.005). The positivity of influenza A and H1N1 was higher in age-group 21-30, whereas RSV in infant and children. H1N1 and RSV were co-circulated and have common clinical symptoms particularly in lower age group. Therefore, laboratory confirmation is necessary for further disease prognosis. Age was an important risk factor that affects the positivity of influenza A, H1N1, and RSV. Different clinical manifestation of H1N1 and RSV will be helpful for early and accurate diagnosis. J. Med. Virol. 89:49-54, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. l-carbocisteine inhibits respiratory syncytial virus infection in human tracheal epithelial cells.

    PubMed

    Asada, Masanori; Yoshida, Motoki; Hatachi, Yukimasa; Sasaki, Takahiko; Yasuda, Hiroyasu; Deng, Xue; Nishimura, Hidekazu; Kubo, Hiroshi; Nagatomi, Ryoichi; Yamaya, Mutsuo

    2012-01-15

    To examine the effects of l-carbocisteine on airway infection with respiratory syncytial (RS) virus, human tracheal epithelial cells were pretreated with l-carbocisteine and infected with RS virus. Viral titer, virus RNA, and pro-inflammatory cytokine secretion, including interleukin (IL)-1 and IL-6, increased with time after infection. l-carbocisteine reduced the viral titer in the supernatant fluids, the amount of RS virus RNA, RS virus infection susceptibility, and the concentration of pro-inflammatory cytokines induced by virus infection. l-carbocisteine reduced the expression of intercellular adhesion molecule (ICAM)-1, an RS virus receptor, on the cells. However, l-carbocisteine had no effects on the expression of heparan sulfate, a glycosaminoglycan that binds to the RS virus attachment protein, or on the amount of intracellular activated-RhoA, isoform A of the Ras-homologous family, that binds to the RS virus fusion protein. These findings suggest that l-carbocisteine may inhibit RS virus infection by reducing the expression of ICAM-1. It may also modulate airway inflammation during RS virus infection.

  19. Age-specific epidemic waves of influenza and respiratory syncytial virus in a subtropical city.

    PubMed

    Yang, Lin; Chan, Kwok Hung; Suen, Lorna K P; Chan, King Pan; Wang, Xiling; Cao, Peihua; He, Daihai; Peiris, J S Malik; Wong, Chit Ming

    2015-05-18

    Both influenza and respiratory syncytial virus (RSV) are active throughout the year in subtropical or tropical regions, but few studies have reported on age-specific seasonal patterns of these viruses. We examined the age-specific epidemic curves of laboratory-confirmed cases of influenza A (subtyped into seasonal A(H1N1), A(H3N2), and pandemic virus A(H1N1)pdm09), influenza B and respiratory syncytial virus (RSV), in subtropical city Hong Kong from 2004 to 2013. We found that different types and subtypes of influenza showed similar two-peak patterns across age groups, with one peak in winter and another in spring/summer. Age differences were found in epidemic onset time and duration, but none could reach statistical significance (p > 0.05). Age synchrony was found in epidemic peak time for both cool and warm seasons. RSV showed less clear seasonal patterns and non-synchronized epidemic curves across age. In conclusion, age synchrony was found in influenza seasonal epidemics and the 2009 pandemic, but not in RSV. None of the age groups consistently appear as the driving force for seasonal epidemics of influenza and RSV in Hong Kong.

  20. Bacteremia in Children Hospitalized with Respiratory Syncytial Virus Infection

    PubMed Central

    Pardo-Seco, Jacobo; Gómez-Carballa, Alberto; Martinón-Torres, Nazareth; Martinón-Sánchez, José María; Justicia-Grande, Antonio; Rivero-Calle, Irene; Pinnock, Elli; Salas, Antonio; Fink, Colin

    2016-01-01

    Background The risk of bacteremia is considered low in children with acute bronchiolitis. However the rate of occult bacteremia in infants with RSV infection is not well established. The aim was to determine the actual rate and predictive factors of bacteremia in children admitted to hospital due to confirmed RSV acute respiratory illness (ARI), using both conventional culture and molecular techniques. Methods A prospective multicenter study (GENDRES-network) was conducted between 2011–2013 in children under the age of two admitted to hospital because of an ARI. Among those RSV-positive, bacterial presence in blood was assessed using PCR for Meningococcus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, in addition to conventional cultures. Results 66 children with positive RSV respiratory illness were included. In 10.6% patients, bacterial presence was detected: H. influenzae (n = 4) and S. pneumoniae (n = 2). In those patients with bacteremia, there was a previous suspicion of bacterial superinfection and had received empirical antibiotic treatment 6 out of 7 (85.7%) patients. There were significant differences in terms of severity between children with positive bacterial PCR and those with negative results: PICU admission (100% vs. 50%, P-value = 0.015); respiratory support necessity (100% vs. 18.6%, P-value < 0.001); Wood-Downes score (mean = 8.7 vs. 4.8 points, P-value < 0.001); GENVIP scale (mean = 17 vs. 10.1, P-value < 0.001); and length of hospitalization (mean = 12.1 vs. 7.5 days, P-value = 0.007). Conclusion Bacteremia is not frequent in infants hospitalized with RSV respiratory infection, however, it should be considered in the most severe cases. PMID:26872131

  1. Efficacy of a virus-vectored vaccine against human and bovine respiratory syncytial virus infections.

    PubMed

    Taylor, Geraldine; Thom, Michelle; Capone, Stefania; Pierantoni, Angiolo; Guzman, Efrain; Herbert, Rebecca; Scarselli, Elisa; Napolitano, Federico; Giuliani, Alessandro; Folgori, Antonella; Colloca, Stefano; Cortese, Riccardo; Nicosia, Alfredo; Vitelli, Alessandra

    2015-08-12

    Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract disease in children and the elderly for which there is still no effective vaccine. We have previously shown that PanAd3-RSV, which is a chimpanzee adenovirus-vectored vaccine candidate that expresses a secreted form of the HRSV F protein together with the N and M2-1 proteins of HRSV, is immunogenic in rodents and nonhuman primates, and protects mice and cotton rats from HRSV challenge. Because the extent to which protection demonstrated in rodent models will translate to humans is unclear, we have exploited the calf model of bovine RSV (BRSV) infection, which mimics HRSV disease in children more closely than do experimental models of unnatural laboratory hosts, to evaluate the safety and efficacy of the PanAd3-RSV vaccine. We show that PanAd3-RSV alone and in combination with a modified vaccinia Ankara expressing the same HRSV antigens (MVA-RSV) induced neutralizing antibodies and cellular immunity in young seronegative calves and protected against upper and lower respiratory tract infection and pulmonary disease induced by heterologous BRSV challenge. There was no evidence either of enhanced pulmonary pathology or of enhanced respiratory disease in vaccinated calves after BRSV challenge. These findings support the continued evaluation of the vectored RSV vaccines in man.

  2. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials.

    PubMed

    Broadbent, Lindsay; Groves, Helen; Shields, Michael D; Power, Ultan F

    2015-07-01

    As the most important viral cause of severe respiratory disease in infants and increasing recognition as important in the elderly and immunocompromised, respiratory syncytial virus (RSV) is responsible for a massive health burden worldwide. Prophylactic antibodies were successfully developed against RSV. However, their use is restricted to a small group of infants considered at high risk of severe RSV disease. There is still no specific therapeutics or vaccines to combat RSV. As such, it remains a major unmet medical need for most individuals. The World Health Organisations International Clinical Trials Registry Platform (WHO ICTRP) and PubMed were used to identify and review all RSV vaccine, prophylactic and therapeutic candidates currently in clinical trials. This review presents an expert commentary on all RSV-specific prophylactic and therapeutic candidates that have entered clinical trials since 2008.

  3. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials

    PubMed Central

    Broadbent, Lindsay; Groves, Helen; Shields, Michael D; Power, Ultan F

    2015-01-01

    As the most important viral cause of severe respiratory disease in infants and increasing recognition as important in the elderly and immunocompromised, respiratory syncytial virus (RSV) is responsible for a massive health burden worldwide. Prophylactic antibodies were successfully developed against RSV. However, their use is restricted to a small group of infants considered at high risk of severe RSV disease. There is still no specific therapeutics or vaccines to combat RSV. As such, it remains a major unmet medical need for most individuals. The World Health Organisations International Clinical Trials Registry Platform (WHO ICTRP) and PubMed were used to identify and review all RSV vaccine, prophylactic and therapeutic candidates currently in clinical trials. This review presents an expert commentary on all RSV-specific prophylactic and therapeutic candidates that have entered clinical trials since 2008. PMID:25847510

  4. Vaccination against respiratory syncytial virus in pregnancy: a suitable tool to combat global infant morbidity and mortality?

    PubMed

    Saso, Anja; Kampmann, Beate

    2016-08-01

    Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia in early childhood (ie, younger than 2 years), responsible for high infant morbidity and mortality worldwide. It is widely accepted that an effective vaccine against RSV would have a major impact on child health globally. Despite the setbacks of the clinical trials in the 1960s, there has been a recent and significant revival of interest in vaccines against RSV, with several promising candidates undergoing evaluation. In this Review, we describe the epidemiological and immunological background to RSV infection and subsequently focus on the promising pipeline of RSV vaccine development. We discuss the potential for implementation of a safe and immunogenic RSV vaccine within the context of global health and with regards to a range of strategies, including vaccination of women during pregnancy, which is likely to emerge as a beneficial and feasible public health tool. This approach would provide interim protection to vulnerable, RSV-naive infants and other high risk groups, in which the burden of admission to hospital and death is greatest. Extending research and implementation from resource-rich to resource-poor settings is required to enhance our understanding of RSV immunity and inform vaccine development and delivery strategies for all settings. We summarise key outstanding issues for researchers and policy makers to understand the interplay of biological and non-biological factors affecting design and distribution of a successful RSV vaccine globally. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Rapid antigen detection test for respiratory syncytial virus diagnosis as a diagnostic tool.

    PubMed

    Mesquita, Flávio da Silva; Oliveira, Danielle Bruna Leal de; Crema, Daniela; Pinez, Célia Miranda Nunes; Colmanetti, Thaís Cristina; Thomazelli, Luciano Matsumia; Gilio, Alfredo Elias; Vieira, Sandra Elisabeth; Martinez, Marina Baquerizo; Botosso, Viviane Fongaro; Durigon, Edison Luiz

    The aim of this study was to evaluate the QuickVue(®) RSV Test Kit (QUIDEL Corp, CA, USA) as a screening tool for respiratory syncytial virus in children with acute respiratory disease in comparison with the indirect immunofluorescence assay as gold standard. In Brazil, rapid antigen detection tests for respiratory syncytial virus are not routinely utilized as a diagnostic tool, except for the diagnosis of dengue and influenza. The authors retrospectively analyzed 486 nasopharyngeal aspirate samples from children under age 5 with acute respiratory infection, between December 2013 and August 2014, the samples were analyzed by indirect immunofluorescence assay and QuickVue(®) RSV Test kit. Samples with discordant results were analyzed by real time PCR and nucleotide sequencing. From 313 positive samples by immunofluorescence assays, 282 (90%) were also positive by the rapid antigen detection test, two were positive only by rapid antigen detection test, 33 were positive only by immunofluorescence assays, and 171 were positive by both methods. The 35 samples with discordant results were analyzed by real time PCR; the two samples positive only by rapid antigen detection test and the five positive only by immunofluorescence assays were also positive by real time PCR. There was no relation between the negativity by QuickVue(®) RSV Test and viral load or specific strain. The QuickVue(®) RSV Test showed sensitivity of 90%, specificity of 98.8%, predictive positive value of 99.3%, and negative predictive value of 94.6%, with accuracy of 93.2% and agreement κ index of 0.85 in comparison to immunofluorescence assay. This study demonstrated that the QuickVue(®) RSV Test Kit can be effective in early detection of Respiratory syncytial virus in nasopharyngeal aspirate and is reliable for use as a diagnostic tool in pediatrics. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  6. In vitro and in vivo fitness of respiratory syncytial virus monoclonal antibody escape mutants.

    PubMed

    Zhao, Xiaodong; Liu, Enmei; Chen, Fu-Ping; Sullender, Wayne M

    2006-12-01

    Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

  7. In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants▿

    PubMed Central

    Zhao, Xiaodong; Liu, Enmei; Chen, Fu-Ping; Sullender, Wayne M.

    2006-01-01

    Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts. PMID:17005645

  8. Attenuated temperature-sensitive respiratory syncytial virus mutants generated by cold adaptation.

    PubMed

    Randolph, V B; Kandis, M; Stemler-Higgins, P; Kennelly, M S; McMullen, Y M; Speelman, D J; Weeks-Levy, C

    1994-09-01

    Two strains of respiratory syncytial virus (RSV), RSV 2B and RSV 3A (representing subgroup B and A virus respectively) were cold-adapted by passaging in Vero cells for up to 42 weeks at successively lower temperatures down to 20 degrees C. Successful cold adaptation of the virus population was dependent on the amount of time the cultures were maintained at the various low temperatures, as well as on the strain of virus used. Temperature-sensitive (TS) mutants appeared in the cold passaged virus populations; however, the majority of the virus variants remained predominantly non-TS. Four RSV 2B and three RSV 3A TS mutants were selected for further characterization. These seven TS mutants retained their fusion phenotype and two major neutralizing antibody epitopes, and displayed varying levels of temperature sensitivity. Six of the seven mutants had a cold-adapted (CA) phenotype. All of the RSV 2B mutants were highly attenuated in cotton rats and two of the mutants elicited relatively high levels of neutralizing antibody and were able to protect rats against virus challenge. The RSV 3A TS mutants grew well in the nose but poorly in the cotton rat lungs, as did the parental 3A virus. All 3A mutants elicited high titers of neutralizing antibody and provided complete protection against virus challenge. These mutants showed varying levels of temperature sensitivity in vitro and attenuation in vivo and represent potential vaccine candidates.

  9. Mathematical modelling of respiratory syncytial virus (RSV): vaccination strategies and budget applications.

    PubMed

    Acedo, L; Díez-Domingo, J; Moraño, J-A; Villanueva, R-J

    2010-06-01

    We propose an age-structured mathematical model for respiratory syncytial virus in which children aged <1 year are especially considered. Real data on hospitalized children in the Spanish region of Valencia were used in order to determine some seasonal parameters of the model. Weekly predictions of the number of children aged <1 year that will be hospitalized in the following years in Valencia are presented using this model. Results are applied to estimate the regional cost of paediatric hospitalizations and to perform a cost-effectiveness analysis of possible vaccination strategies.

  10. Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy.

    PubMed

    Beeler, Judy A; Eichelberger, Maryna C

    2013-02-01

    Respiratory viral infections in infants and young children frequently cause illness that can easily progress to hospitalization and death. There are currently no licensed vaccines to prevent respiratory viral disease in children younger than 6 months, reflecting safety concerns and the difficulty in inducing effective immune responses in infants. This review discusses vaccines that have been developed, or are currently being developed, against influenza and respiratory syncytial virus, with a focus on studies performed to demonstrate their safety and efficacy, and the impact of immunologic immaturity and maternal antibodies on the infant response to vaccines.

  11. Replacement of previously circulating respiratory syncytial virus subtype B strains with the BA genotype in South Africa.

    PubMed

    van Niekerk, Stephanie; Venter, Marietjie

    2011-09-01

    Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in infants, the immunocompromised, and the elderly in both developed and developing countries. Reinfections are common, and G protein variability is one mechanism to overcome herd immunity. This is illustrated by the appearance of the BA genotype with a 60-nucleotide duplication dominating the subtype B genotypes in epidemics worldwide. To investigate the evolution of subtype B in South Africa since 2002, the genetic variability of the G protein was analyzed in all recent strains isolated over 4 years (2006 to 2009) in South African hospitals. Bayesian analysis revealed a replacement of all subtype B genotypes previously identified in South Africa with the BA genotype since 2006, while subtype A genotypes identified in previous years are still circulating. Compared to BA strains from other countries, the evolutionary rate of the South African BA genotype was shown to be 2.305 × 10(-3) nucleotide substitutions/site/year and drift was evident. The most recent common ancestor (MRCA) of the South African BA viruses was determined to date back to 1996. All South African BA isolates clustered with the BA-IV subgenotype, and the appearance of new subgenotypes within this branch may occur if drift continues. Sequencing of the complete G protein of selected South African strains revealed an additional 6-nucleotide deletion. Acquisition of the 60-nucleotide duplication appeared to have improved the fitness of this virus, and more recent subtype B strains may need to be included in experimental vaccines to evaluate their efficacy in the current setting of evolved circulating strains.

  12. Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus

    PubMed Central

    van Woensel, J B M; van Aalderen, W M C; de Weerd, W; Jansen, N; van Gestel, J P J; Markhorst, D; van Vught, A J; Bos, A; Kimpen, J

    2003-01-01

    Background: A study was undertaken to evaluate the efficacy of dexamethasone in patients mechanically ventilated for lower respiratory infection caused by respiratory syncytial virus (RSV-LRTI). Methods: In a multicentre randomised controlled trial patients were randomised to receive either intravenous dexamethasone (0.15 mg/kg 6 hourly for 48 hours) or placebo. End points were the duration of mechanical ventilation, length of stay (LOS) in the pediatric intensive care unit (PICU) and in hospital, and the duration of supplemental oxygen administration. Results: Thirty seven patients received dexamethasone and 45 received placebo. There was no significant difference in any of the end points between the two groups. In a post hoc analysis patients were stratified into those with mild gas exchange anomalies (PaO2/FiO2 >200 mm Hg and/or mean airway pressure ⩽ 10 cm H2O, bronchiolitis group) and those with severe gas exchange anomalies (PaO2/FiO2 ⩽200 mm Hg and mean airway pressure >10 cm H2O, pneumonia group). In the 39 patients with bronchiolitis the duration of mechanical ventilation was 4.3 days shorter in the dexamethasone group than in the placebo group (4.9 v 9.2 days, 95% CI -7.8 to -0.8, p=0.02) and the duration of supplemental oxygen was 3.6 days shorter (7.7 v 11.3 days, 95% CI -8.0 to -0.1, p=0.048). No differences in end points were found in the pneumonia group. Conclusions: Dexamethasone had no beneficial effect in patients mechanically ventilated for RSV-LRTI but was found to have a beneficial effect in patients with bronchiolitis. PMID:12728156

  13. Detection of Respiratory Viruses and Atypical Bacteria in Children's Tonsils and Adenoids▿

    PubMed Central

    Drago, Lorenzo; Esposito, Susanna; De Vecchi, Elena; Marchisio, Paola; Blasi, Francesco; Baggi, Elena; Capaccio, Pasquale; Pignataro, Lorenzo

    2008-01-01

    The tonsils and adenoids of 44 children were analyzed for the detection of respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Viruses were detected in 47.7% of the children and 37.3% of the specimens, with adenovirus and parainfluenza viruses being the most frequently detected microorganisms. PMID:17989193

  14. Detection of respiratory viruses and atypical bacteria in children's tonsils and adenoids.

    PubMed

    Drago, Lorenzo; Esposito, Susanna; De Vecchi, Elena; Marchisio, Paola; Blasi, Francesco; Baggi, Elena; Capaccio, Pasquale; Pignataro, Lorenzo

    2008-01-01

    The tonsils and adenoids of 44 children were analyzed for the detection of respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Viruses were detected in 47.7% of the children and 37.3% of the specimens, with adenovirus and parainfluenza viruses being the most frequently detected microorganisms.

  15. Simultaneous influenza and respiratory syncytial virus infection in human respiratory tract

    NASA Astrophysics Data System (ADS)

    Pinky, Lubna Jahan Rashid; Dobrovolny, Hana

    2015-03-01

    Studies have shown that simultaneous infection of the respiratory tract with at least two viruses is not uncommon in hospitalized patients, although it is not clear whether these infections are more or less severe than single infections. We use mathematical models to study the dynamics of simultaneous influenza (flu) and respiratory syncytial virus (RSV) infection, two of the more common respiratory viruses, in an effort to understand simultaneous infections. We examine the roles of initial viral inoculum, relative starting time, and cell regeneration on the severity of the infection. We also study the effect of antiviral treatment on the course of the infection. This study shows that, unless treated with antivirals, flu always takes over the infection no matter how small the initial dose and how delayed it starts with respect to RSV.

  16. [Monitoring respiratory syncytial virus through the Spanish influenza surveillance system, 2006-2014].

    PubMed

    Jiménez-Jorge, Silvia; Delgado-Sanz, Concepción; de Mateo, Salvador; Pozo, Francisco; Casas, Inmaculada; Larrauri, Amparo

    2016-02-01

    The aim of the study is to analyze the information on respiratory syncytial virus (RSV) obtained through the Spanish Influenza Surveillance System (SISS) and to study its usefulness as supplementary information for the characterization of influenza epidemics. The temporal patterns of both RSV and influenza viruses were analyzed by patterns comparing the weekly viral detection rates from 2006 to 2014. In general, the RSV circulation was characterized by showing a peak between 52-1 weeks, and circulated from 2 to 8 weeks before/prior to influenza viruses. RSV information obtained from the SISS is useful for the characterization of influenza epidemics in Spain. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  17. Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy.

    PubMed

    Walsh, Kevin B; Teijaro, John R; Brock, Linda G; Fremgen, Daniel M; Collins, Peter L; Rosen, Hugh; Oldstone, Michael B A

    2014-06-01

    The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8(+) T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8(+) T cell response, resulting in diminished pulmonary disease and enhanced survival. A dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.

  18. Recombinant measles viruses expressing respiratory syncytial virus proteins induced virus-specific CTL responses in cotton rats.

    PubMed

    Yamaji, Yoshiaki; Nakayama, Tetsuo

    2014-07-31

    Respiratory syncytial virus (RSV) is a common cause of serious lower respiratory tract illnesses in infants. Natural infections with RSV provide limited protection against reinfection because of inefficient immunological responses that do not induce long-term memory. RSV natural infection has been shown to induce unbalanced immune response. The effective clearance of RSV is known to require the induction of a balanced Th1/Th2 immune response, which involves the induction of cytotoxic T lymphocytes (CTL). In our previous study, recombinant AIK-C measles vaccine strains MVAIK/RSV/F and MVAIK/RSV/G were developed, which expressed the RSV fusion (F) protein or glycoprotein (G). These recombinant viruses elicited antibody responses against RSV in cotton rats, and no infectious virus was recovered, but small amounts of infiltration of inflammatory cells were observed in the lungs following RSV challenge. In the present study, recombinant AIK-C measles vaccine strains MVAIK/RSV/M2-1 and MVAIK/RSV/NP were developed, expressing RSV M2-1 or Nucleoprotein (NP), respectively. These viruses exhibited temperature-sensitivity (ts), which was derived from AIK-C, and expressed respective RSV antigens. The intramuscular inoculation of cotton rats with the recombinant measles virus led to the induction of CD8(+) IFN-γ(+) cells. No infectious virus was recovered from a lung homogenate following the challenge. A Histological examination of the lungs revealed a significant reduction in inflammatory reactions without alveolar damage. These results support the recombinant measles viruses being effective vaccine candidates against RSV that induce RSV-specific CTL responses with or without the development of an antibody response.

  19. Strategic priorities for respiratory syncytial virus (RSV) vaccine development

    PubMed Central

    Anderson, L.J.; Dormitzer, P.R.; Nokes, D.J.; Rappuoli, R.; Roca, A.; Graham, B.S.

    2013-01-01

    Although RSV has been a high priority for vaccine development, efforts to develop a safe and effective vaccine have yet to lead to a licensed product. Clinical and epidemiologic features of RSV disease suggest there are at least 4 distinct target populations for vaccines, the RSV naïve young infant, the RSV naïve child ≥6 months of age, pregnant women (to provide passive protection to newborns), and the elderly. These target populations raise different safety and efficacy concerns and may require different vaccination strategies. The highest priority target population is the RSV naïve child. The occurrence of serious adverse events associated with the first vaccine candidate for young children, formalin inactivated RSV (FI-RSV), has focused vaccine development for the young RSV naïve child on live virus vaccines. Enhanced disease is not a concern for persons previously primed by a live virus infection. A variety of live-attenuated viruses have been developed with none yet achieving licensure. New live-attenuated RSV vaccines are being developed and evaluated that maybe sufficiently safe and efficacious to move to licensure. A variety of subunit vaccines are being developed and evaluated primarily for adults in whom enhanced disease is not a concern. An attenuated parainfluenza virus 3 vector expressing the RSV F protein was evaluated in RSV naïve children. Most of these candidate vaccines have used the RSV F protein in various vaccine platforms including virus-like particles, nanoparticles, formulated with adjuvants, and expressed by DNA or virus vectors. The other surface glycoprotein, the G protein, has also been used in candidate vaccines. We now have tools to make and evaluate a wide range of promising vaccines. Costly clinical trials in the target population are needed to evaluate and select candidate vaccines for advancement to efficacy trials. Better data on RSV-associated mortality in developing countries, better estimates of the risk of long term

  20. Strategic priorities for respiratory syncytial virus (RSV) vaccine development.

    PubMed

    Anderson, L J; Dormitzer, P R; Nokes, D J; Rappuoli, R; Roca, A; Graham, B S

    2013-04-18

    Although RSV has been a high priority for vaccine development, efforts to develop a safe and effective vaccine have yet to lead to a licensed product. Clinical and epidemiologic features of RSV disease suggest there are at least 4 distinct target populations for vaccines, the RSV naïve young infant, the RSV naïve child ≥ 6 months of age, pregnant women (to provide passive protection to newborns), and the elderly. These target populations raise different safety and efficacy concerns and may require different vaccination strategies. The highest priority target population is the RSV naïve child. The occurrence of serious adverse events associated with the first vaccine candidate for young children, formalin inactivated RSV (FI-RSV), has focused vaccine development for the young RSV naïve child on live virus vaccines. Enhanced disease is not a concern for persons previously primed by a live virus infection. A variety of live-attenuated viruses have been developed with none yet achieving licensure. New live-attenuated RSV vaccines are being developed and evaluated that maybe sufficiently safe and efficacious to move to licensure. A variety of subunit vaccines are being developed and evaluated primarily for adults in whom enhanced disease is not a concern. An attenuated parainfluenza virus 3 vector expressing the RSV F protein was evaluated in RSV naïve children. Most of these candidate vaccines have used the RSV F protein in various vaccine platforms including virus-like particles, nanoparticles, formulated with adjuvants, and expressed by DNA or virus vectors. The other surface glycoprotein, the G protein, has also been used in candidate vaccines. We now have tools to make and evaluate a wide range of promising vaccines. Costly clinical trials in the target population are needed to evaluate and select candidate vaccines for advancement to efficacy trials. Better data on RSV-associated mortality in developing countries, better estimates of the risk of long term

  1. Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses.

    PubMed

    Bajimaya, Shringkhala; Frankl, Tünde; Hayashi, Tsuyoshi; Takimoto, Toru

    2017-10-01

    Cholesterol-rich lipid raft microdomains in the plasma membrane are considered to play a major role in the enveloped virus lifecycle. However, the functional role of cholesterol in assembly, infectivity and stability of respiratory RNA viruses is not fully understood. We previously reported that depletion of cellular cholesterol by cholesterol-reducing agents decreased production of human parainfluenza virus type 1 (hPIV1) particles by inhibiting virus assembly. In this study, we analyzed the role of cholesterol on influenza A virus (IAV) and respiratory syncytial virus (RSV) production. Unlike hPIV1, treatment of human airway cells with the agents did not decrease virus particle production. However, the released virions were less homogeneous in density and unstable. Addition of exogenous cholesterol to the released virions restored virus stability and infectivity. Collectively, these data indicate a critical role of cholesterol in maintaining IAV and RSV membrane structure that is essential for sustaining viral stability and infectivity. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Long-Term Shedding of Influenza Virus, Parainfluenza Virus, Respiratory Syncytial Virus and Nosocomial Epidemiology in Patients with Hematological Disorders.

    PubMed

    Lehners, Nicola; Tabatabai, Julia; Prifert, Christiane; Wedde, Marianne; Puthenparambil, Joe; Weissbrich, Benedikt; Biere, Barbara; Schweiger, Brunhilde; Egerer, Gerlinde; Schnitzler, Paul

    2016-01-01

    Respiratory viruses are a cause of upper respiratory tract infections (URTI), but can be associated with severe lower respiratory tract infections (LRTI) in immunocompromised patients. The objective of this study was to investigate the genetic variability of influenza virus, parainfluenza virus and respiratory syncytial virus (RSV) and the duration of viral shedding in hematological patients. Nasopharyngeal swabs from hematological patients were screened for influenza, parainfluenza and RSV on admission as well as on development of respiratory symptoms. Consecutive swabs were collected until viral clearance. Out of 672 tested patients, a total of 111 patients (17%) were infected with one of the investigated viral agents: 40 with influenza, 13 with parainfluenza and 64 with RSV; six patients had influenza/RSV or parainfluenza/RSV co-infections. The majority of infected patients (n = 75/111) underwent stem cell transplantation (42 autologous, 48 allogeneic, 15 autologous and allogeneic). LRTI was observed in 48 patients, of whom 15 patients developed severe LRTI, and 13 patients with respiratory tract infection died. Phylogenetic analysis revealed a variety of influenza A(H1N1)pdm09, A(H3N2), influenza B, parainfluenza 3 and RSV A, B viruses. RSV A was detected in 54 patients, RSV B in ten patients. The newly emerging RSV A genotype ON1 predominated in the study cohort and was found in 48 (75%) of 64 RSV-infected patients. Furthermore, two distinct clusters were detected for RSV A genotype ON1, identical RSV G gene sequences in these patients are consistent with nosocomial transmission. Long-term viral shedding for more than 30 days was significantly associated with prior allogeneic transplantation (p = 0.01) and was most pronounced in patients with RSV infection (n = 16) with a median duration of viral shedding for 80 days (range 35-334 days). Long-term shedding of respiratory viruses might be a catalyzer of nosocomial transmission and must be considered for

  3. Exploratory Spatial Analysis of in vitro Respiratory Syncytial Virus Co-infections

    PubMed Central

    Simeonov, Ivan; Gong, Xiaoyan; Kim, Oekyung; Poss, Mary; Chiaromonte, Francesca; Fricks, John

    2010-01-01

    The cell response to virus infection and virus perturbation of that response is dynamic and is reflected by changes in cell susceptibility to infection. In this study, we evaluated the response of human epithelial cells to sequential infections with human respiratory syncytial virus strains A2 and B to determine if a primary infection with one strain will impact the ability of cells to be infected with the second as a function of virus strain and time elapsed between the two exposures. Infected cells were visualized with fluorescent markers, and location of all cells in the tissue culture well were identified using imaging software. We employed tools from spatial statistics to investigate the likelihood of a cell being infected given its proximity to a cell infected with either the homologous or heterologous virus. We used point processes, K-functions, and simulation procedures designed to account for specific features of our data when assessing spatial associations. Our results suggest that intrinsic cell properties increase susceptibility of cells to infection, more so for RSV-B than for RSV-A. Further, we provide evidence that the primary infection can decrease susceptibility of cells to the heterologous challenge virus but only at the 16 h time point evaluated in this study. Our research effort highlights the merits of integrating empirical and statistical approaches to gain greater insight on in vitro dynamics of virus-host interactions. PMID:21994640

  4. Detection of bovine respiratory syncytial virus infections in young dairy and beef cattle in Poland.

    PubMed

    Urban-Chmiel, Renata; Wernicki, Andrzej; Puchalski, Andrzej; Dec, Marta; Stęgierska, Diana; Grooms, Daniel L; Barbu, Nicolas I

    2015-03-01

    Bovine respiratory syncytial virus (BRSV) is a major contributor to bovine respiratory disease complex in dairy and beef calves, especially during the first year of life. There is a lack of comprehensive information about the prevalence of infection in cattle herds in Poland as well as in European countries outside the European Union. The aim of this study was to estimate the prevalence of BRSV infections in young beef and dairy cattle in southeastern Poland, a region that has direct contact with non-EU countries. Animals & methods: Nasal swabs and sera (n = 120) were obtained from young cattle aged 6-12 months from 45 farms in eastern and southeastern Poland. BRSV antigen detection in the nasal swabs was carried out using a rapid immunomigration assay used in diagnosing human respiratory syncytial virus (hRSV) infections in humans, while antibodies to BRSV were detected in the sera by ELISA antibody detection. The study confirmed the presence of BRSV infections in young cattle under 12 months of age from both dairy and beef herds. BRSV was detected in 27 of the 45 herds (60%) sampled. Findings from this study indicate a high prevalence of BRSV infections in cattle in Poland, which may have a significant influence on health status and animal performance. The prevalence of infection is similar to that in other parts of Poland and other countries in Europe. Development of strategies to reduce BRSV infections is needed to improve health and productivity.

  5. Recombinant Sendai viruses expressing fusion proteins with two furin cleavage sites mimic the syncytial and receptor-independent infection properties of respiratory syncytial virus.

    PubMed

    Rawling, Joanna; Cano, Olga; Garcin, Dominique; Kolakofsky, Daniel; Melero, José A

    2011-03-01

    Cell entry by paramyxoviruses requires fusion between viral and cellular membranes. Paramyxovirus infection also gives rise to the formation of multinuclear, fused cells (syncytia). Both types of fusion are mediated by the viral fusion (F) protein, which requires proteolytic processing at a basic cleavage site in order to be active for fusion. In common with most paramyxoviruses, fusion mediated by Sendai virus F protein (F(SeV)) requires coexpression of the homologous attachment (hemagglutinin-neuraminidase [HN]) protein, which binds to cell surface sialic acid receptors. In contrast, respiratory syncytial virus fusion protein (F(RSV)) is capable of fusing membranes in the absence of the viral attachment (G) protein. Moreover, F(RSV) is unique among paramyxovirus fusion proteins since F(RSV) possesses two multibasic cleavage sites, which are separated by an intervening region of 27 amino acids. We have previously shown that insertion of both F(RSV) cleavage sites in F(SeV) decreases dependency on the HN attachment protein for syncytium formation in transfected cells. We now describe recombinant Sendai viruses (rSeV) that express mutant F proteins containing one or both F(RSV) cleavage sites. All cleavage-site mutant viruses displayed reduced thermostability, with double-cleavage-site mutants exhibiting a hyperfusogenic phenotype in infected cells. Furthermore, insertion of both F(RSV) cleavage sites in F(SeV) reduced dependency on the interaction of HN with sialic acid for infection, thus mimicking the unique ability of RSV to fuse and infect cells in the absence of a separate attachment protein.

  6. Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection.

    PubMed

    Jordan, Robert; Shao, Matt; Mackman, Richard L; Perron, Michel; Cihlar, Tomas; Lewis, Sandy A; Eisenberg, Eugene J; Carey, Anne; Strickley, Robert G; Chien, Jason W; Anderson, Mark L; McEligot, Heather A; Behrens, Nicole E; Gershwin, Laurel J

    2015-08-01

    Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. Effective treatment for RSV infection is a significant unmet medical need. While new RSV therapeutics are now in development, there are very few animal models that mimic the pathogenesis of human RSV, making it difficult to evaluate new disease interventions. Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory infection that is similar to human RSV infection, providing a relevant model for testing novel therapeutic agents. In this model, viral load is readily detected in nasal secretions by quantitative real-time PCR (qRT-PCR), and cumulative symptom scoring together with histopathology evaluations of infected tissue allow for the assessment of disease severity. The bovine RSV model was used to evaluate the antiviral activity of an RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in two randomized, blind, placebo-controlled studies in bRSV-infected calves. Intravenous administration of GS1 at 4 mg/kg of body weight/day for 7 days starting 24 h or 72 h postinoculation provided clear therapeutic benefit by reducing the viral load, disease symptom score, respiration rate, and lung pathology associated with bRSV infection. These data support the use of the bovine RSV model for evaluation of experimental therapeutics for treatment of RSV.

  7. Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants.

    PubMed

    Papin, James F; Wolf, Roman F; Kosanke, Stanley D; Jenkins, Justin D; Moore, Sara N; Anderson, Michael P; Welliver, Robert C

    2013-04-15

    Respiratory syncytial virus (RSV) infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in >300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons (Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for ≥14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a much-needed model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines.

  8. Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

    PubMed Central

    Papin, James F.; Wolf, Roman F.; Kosanke, Stanley D.; Jenkins, Justin D.; Moore, Sara N.; Anderson, Michael P.

    2013-01-01

    Respiratory syncytial virus (RSV) infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in >300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons (Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for ≥14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a much-needed model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines. PMID:23418091

  9. STUDIES ON PNEUMONIA VIRUS OF MICE (PVM)

    PubMed Central

    Horsfall, Frank L.; Curnen, Edward C.

    1946-01-01

    The results of neutralization tests with PVM and serum obtained from numerous animal species indicate that antibodies agaiust this virus were present in the blood of all mammalian species tested, as not in that of fowls, and that their incidence in various species was widely different. They indicate, also, that in certain species, particularly the cotton rat, there were marked seasonal variations in the incidence of such antibodies; in the late winter and spring the incidence was much higher than during the summer and fall seasons. Cotton rats and hamsters which did not possess neutralizing antibodies against PVM were susceptible to manifest pulmonary infection with this virus, irrespective of the effects of previous experiments upon them, whereas those which possessed such antibodies were immune. It is suggested that circulating antibodies against PVM were present as a result of preceding infection with a latent virus; either PVM or an agent closely related to it in antigenic composition. Appropriate non-specific stimuli, e.g. the intranasal injection of suspensions of normal chick embryos, induced the development of neutralizing antibodies against PVM with significantly greater frequency in each of three species than occurred in control animals. Materials derived from patients with primary atypical pneumonia yielded results almost identical to those obtained with normal chick embryo suspensions. It is suggested that such materials, like the other non-specific stimuli employed, were effective in evoking a specific antibody response, because they unbalanced an equilibrium which previously existed between animal host and latent pneumotropic virus. PMID:19871515

  10. INHIBITION OF RESPIRATORY SYNCYTIAL VIRUS (RSV)-INDUCED INFLAMMATION BY 3-NITROTYROSINE IN HUMAN BRONCHIAL EPITHELIAL CELLS

    EPA Science Inventory

    Inhibition of Respiratory Syncytial Virus (RSV)-Induced Inflammation by 3-Nitrotyrosine in Human Bronchial Epithelial Cells. J. M. Soukup, MPH 1, ZW. Li, MD 2 and YC. T. Huang, MD 1. 1 NHEERL, US Environmental Protection Agency, RTP, NC and 2 CEMALB, University of North Carolina,...

  11. INHIBITION OF RESPIRATORY SYNCYTIAL VIRUS (RSV)-INDUCED INFLAMMATION BY 3-NITROTYROSINE IN HUMAN BRONCHIAL EPITHELIAL CELLS

    EPA Science Inventory

    Inhibition of Respiratory Syncytial Virus (RSV)-Induced Inflammation by 3-Nitrotyrosine in Human Bronchial Epithelial Cells. J. M. Soukup, MPH 1, ZW. Li, MD 2 and YC. T. Huang, MD 1. 1 NHEERL, US Environmental Protection Agency, RTP, NC and 2 CEMALB, University of North Carolina,...

  12. Global gene expression profiling in infants with acute respiratory syncytial virus broncholitis demonstrates systemic activation of interferon signaling networks

    USDA-ARS?s Scientific Manuscript database

    Respiratory syncytial virus (RSV) is a leading cause of pediatric lower respiratory tract infections and has a high impact on pediatric emergency department utilization. Variation in host response may influence the pathogenesis and disease severity. We evaluated global gene expression profiles to be...

  13. Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines.

    PubMed

    Fuentes, Sandra; Arenas, Diego; Moore, Martin M; Golding, Hana; Khurana, Surender

    2017-01-23

    Respiratory Syncytial virus (RSV) is one of the leading causes of pneumonia among infants with no human vaccine or efficient curative treatments. Efforts are underway to develop new RSV vaccines and therapeutics. There is a dire need for animal models for preclinical evaluation and selection of products against RSV. Herein, we developed a whole body bioluminescence imaging to follow replication of RSV A2 virus strain expressing firefly luciferase (RSVA2-line19-FFL) in live BALB/c mice that can be used as an extremely sensitive readout for studying effects of antiviral and vaccines in living mice. Strong bioluminescence signal was detected in the nasal cavity and in the lungs following intranasal infection of mice with RSVA2-line19-FFL. The kinetics of viral replication in lungs quantified by daily live imaging strongly correlated with viral titers measured by ex-vivo plaque assay and by assessing viral RNA by qRT-PCR. Vaccination of mice with a pre-fusion F protein elicited high neutralizing antibody titers conferring strong protective immunity against virus replication in the nasal cavity and lungs. In contrast, post-challenge treatment of mice with the monoclonal antibody Palivizumab two days after infection reduced viral replication in the nasal cavity at day 4, but only modestly reduced virus loads in the lungs by day 5. In contrast to RSV bioluminescence, plaque assay did not detect viral titers in lungs on day 5 in Palivizumab-treated animals. This difference between viral loads measured by the two assays was found to be due to coating of virions with the Palivizumab that blocked infection of target cells in vitro and shows importance of live imaging in evaluation of RSV therapeutics. This recombinant RSV based live imaging animal model is convenient and valuable tool that can be used to study host dissemination of RSV and evaluation of antiviral compounds and vaccines against RSV.

  14. Respiratory Picornaviruses and Respiratory Syncytial Virus as Causative Agents of Acute Expiratory Wheezing in Children

    PubMed Central

    Lehtinen, Pasi; Vuorinen, Tytti; Österback, Riikka; van den Hoogen, Bernadette; Osterhaus, Albert D.M.E.; Ruuskanen, Olli

    2004-01-01

    We studied the viral etiology of acute expiratory wheezing (bronchiolitis, acute asthma) in 293 hospitalized children in a 2-year prospective study in Finland. A potential causative viral agent was detected in 88% of the cases. Eleven different viruses were represented. Respiratory syncytial virus (RSV) (27%), enteroviruses (25%), rhinovirus (24%), and nontypable rhino/enterovirus (16%) were found most frequently. In infants, RSV was found in 54% and respiratory picornaviruses (rhinovirus and enteroviruses) in 42% of the cases. In older children, respiratory picornaviruses dominated (65% of children ages 1-2 years and 82% of children ages >3 years). Human metapneumovirus was detected in 4% of all children and in 11% of infants. To prevent and treat acute expiratory wheezing illnesses in children, efforts should be focused on RSV, enterovirus, and rhinovirus infections. PMID:15207063

  15. Respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children.

    PubMed

    Jartti, Tuomas; Lehtinen, Pasi; Vuorinen, Tytti; Osterback, Riika; van den Hoogen, Bernadette; Osterhaus, Albert D M E; Ruuskanen, Olli

    2004-06-01

    We studied the viral etiology of acute expiratory wheezing (bronchiolitis, acute asthma) in 293 hospitalized children in a 2-year prospective study in Finland. A potential causative viral agent was detected in 88% of the cases. Eleven different viruses were represented. Respiratory syncytial virus (RSV) (27%), enteroviruses (25%), rhinovirus (24%), and nontypable rhino/enterovirus (16%) were found most frequently. In infants, RSV was found in 54% and respiratory picornaviruses (rhinovirus and enteroviruses) in 42% of the cases. In older children, respiratory picornaviruses dominated (65% of children ages 1-2 years and 82% of children ages > or =3 years). Human metapneumovirus was detected in 4% of all children and in 11% of infants. To prevent and treat acute expiratory wheezing illnesses in children, efforts should be focused on RSV, enterovirus, and rhinovirus infections.

  16. Respiratory syncytial virus infection in infants and correlation with meteorological factors and air pollutants

    PubMed Central

    2013-01-01

    Background Respiratory Syncytial Virus (RSV) is the most important cause of severe respiratory infections in infants with seasonal epidemics. Environmental factors (temperature, humidity, air pollution) could influence RSV epidemics through their effects on virus activity and diffusion. Methods We conducted a retrospective study on a paediatric population who referred to our Paediatric Emergency Unit in order to analyze the correlation between weekly incidence of RSV positive cases during winter season in Bologna and meteorological factors and air pollutants concentration. Results We observed a significant correlation between the incidence of RSV infections and the mean minimum temperature registered during the same week and the previous weeks. The weekly number of RSV positive cases was also correlated to the mean PM10 concentration of the week before. Conclusions RSV epidemic trend in Bologna (Italy) is related to the mean minimum temperature, and the mean PM10 concentration. PMID:23311474

  17. Antiviral immune responses and lung inflammation after respiratory syncytial virus infection.

    PubMed

    Openshaw, Peter J M

    2005-01-01

    Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease coincides not with the peak of viral replication but with the development of specific T and B cell responses. This immune response is apparently responsible for much of the disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. The inflammatory host response to viral infection may be relevant not only to childhood bronchiolitis, but also to obstructive lung diseases in adults.

  18. A respiratory syncytial virus isolate enables the testing of virucidal products.

    PubMed

    Thevenin, Thomas; Lobert, P E; Dewilde, A; Hober, D

    2012-04-01

    The respiratory syncytial virus (RSV) is known as a major cause of respiratory infections and nosocomial diseases. Testing this virus is rather difficult due to the problems encountered in producing it at a high titer without using any purification method. A RSV isolate which replicates to high level on a Hep-2 cell line with an infectious titer of at least 10(7)TCID(50)mL(-1) in culture supernatant fluids has been identified. Thanks to this isolate, the virucidal effects of two products, a hand rub solution and a surface disinfectant, were conveniently tested according to the EN 14476:2007-02 procedure. Copyright © 2011 Elsevier GmbH. All rights reserved.

  19. Enzyme-linked immunosorbent assay for detection of respiratory syncytial virus infection: development and description.

    PubMed Central

    Hendry, R M; McIntosh, K

    1982-01-01

    An indirect enzyme-linked immunosorbent assay for detection of respiratory syncytial virus (RSV) antigens was developed, using commercially available antisera. Horse anti-RSV and calf antiserum to bovine RSV were used as capture and detector antibodies, respectively. The assay could detect as few as 50 PFU of unpurified RSV per ml in infected cell culture supernatant fluids and as little as 10 ng of affinity-purified RSV antigen per ml. No cross-reactions were observed with heterologous virus types. Freeze-thaw treatment had no effect on RSV enzyme-linked immunosorbent assay titers, but viral transport medium inhibited RSV enzyme-linked immunosorbent assay titers from 10- to 100-fold. The assay can be easily performed in 24 h and is a sensitive and specific method for the detection of RSV antigens. PMID:6749894

  20. New respiratory virus (chicken pox, influenza and respiratory syncytial virus) vaccines: efficacy, necessity and policy for the tropical world at present.

    PubMed

    Wiwanitkit, Viroj

    2009-09-01

    Several respiratory viruses are documented in medicine. Several infectious diseases due to these viruses are current global public health problems. Prevention of respiratory viral infections becomes the focus of the public health ministries of many tropical countries. Presently, there are many new vaccines for respiratory viruses. These vaccines include chicken pox vaccine, influenza vaccine and respiratory syncytial virus vaccine. In this article, the author will briefly discuss on these quoted vaccines focusing on efficacy, necessity and policy for tropical world at present.

  1. Epidemiology and clinical characteristics of respiratory syncytial virus infections among children and adults in Mexico.

    PubMed

    Gamiño-Arroyo, Ana E; Moreno-Espinosa, Sarbelio; Llamosas-Gallardo, Beatriz; Ortiz-Hernández, Ana A; Guerrero, M Lourdes; Galindo-Fraga, Arturo; Galán-Herrera, Juan F; Prado-Galbarro, Francisco J; Beigel, John H; Ruiz-Palacios, Guillermo M; Noyola, Daniel E

    2017-01-01

    Respiratory syncytial virus (RSV) is a leading etiological agent of acute respiratory tract infections and hospitalizations in children. However, little information is available regarding RSV infections in Latin American countries, particularly among adult patients. To describe the epidemiology of RSV infection and to analyze the factors associated with severe infections in children and adults in Mexico. Patients ≥1 month old, who presented with an influenza-like illness (ILI) to six hospitals in Mexico, were eligible for participation in the study. Multiplex reverse-transcriptase polymerase chain reaction identified viral pathogens in nasal swabs from 5629 episodes of ILI. Patients in whom RSV was detected were included in this report. Respiratory syncytial virus was detected in 399 children and 171 adults. RSV A was detected in 413 cases and RSV B in 163, including six patients who had coinfection with both subtypes; 414 (72.6%) patients required hospital admission, including 96 (16.8%) patients that required admission to the intensive care unit. Coinfection with one or more respiratory pathogens other than RSV was detected in 159 cases. Young age (in children) and older age (in adults) as well as the presence of some underlying conditions were associated with more severe disease. This study confirms that RSV is an important respiratory pathogen in children in Mexico. In addition, a substantial number of cases in adults were also detected highlighting the relevance of this virus in all ages. It is important to identify subjects at high risk of complications who may benefit from current or future preventive interventions. © 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

  2. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.

    PubMed

    Phipps, Simon; Lam, Chuan En; Mahalingam, Suresh; Newhouse, Matthew; Ramirez, Ruben; Rosenberg, Helene F; Foster, Paul S; Matthaei, Klaus I

    2007-09-01

    Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssRNA) stimulation of the TLR-7-MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF)-7 and eosinophil-associated ribonucleases EAR-1 and EAR-2. Hypereosinophilia in the airways of infected mice also correlated with increased expression of IRF-7, IFN-beta, and NOS-2, and inhibition of NO production with the NOS-2 inhibitor L-NMA partially reversed the accelerated virus clearance promoted by eosinophils. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.

  3. Development of a real time reverse transcriptase polymerase chain reaction for the detection of bovine respiratory syncytial virus in clinical samples and its comparison with immunohistochemistry and immunofluorescence antibody testing.

    PubMed

    Willoughby, Kim; Thomson, Karen; Maley, Madeleine; Gilray, Janice; Scholes, Sandra; Howie, Fiona; Caldow, George; Nettleton, Peter F

    2008-01-01

    Bovine respiratory syncytial virus is an agent involved in calf pneumonia complex, a disease of significant economic importance. Accurate diagnosis of the agents involved on farm premises is important when formulating disease control measures, including vaccination. We have developed a real time reverse transcriptase polymerase chain reaction (rtRT-PCR) and compared it with the diagnostic tests currently available in the United Kingdom: immunohistochemistry (IHC) and immunofluorescence antibody test (IFAT). The rtRT-PCR had a detection limit of 10 gene copies and was 96% efficient. Recent UK isolates and clinical samples were tested; the rtRT-PCR was more sensitive than both conventional tests.

  4. Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus.

    PubMed

    Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye; Ko, Eun-Ju; Lee, Youri; Kwon, Young-Man; Kang, Sang-Moo

    2017-11-01

    Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. Copyright © 2017. Published by Elsevier Inc.

  5. Crucial roles of reactive chemical species in modification of respiratory syncytial virus by nitrogen gas plasma.

    PubMed

    Sakudo, Akikazu; Toyokawa, Yoichi; Imanishi, Yuichiro; Murakami, Tomoyuki

    2017-05-01

    The exact mechanisms by which nanoparticles, especially those composed of soft materials, are modified by gas plasma remain unclear. Here, we used respiratory syncytial virus (RSV), which has a diameter of 80-350nm, as a model system to identify important factors for gas plasma modification of nanoparticles composed of soft materials. Nitrogen gas plasma, generated by applying a short high-voltage pulse using a static induction (SI) thyristor power supply produced reactive chemical species (RCS) and caused virus inactivation. The plasma treatment altered the viral genomic RNA, while treatment with a relatively low concentration of hydrogen peroxide, which is a neutral chemical species among RCS, effectively inactivated the virus. Furthermore, a zero dimensional kinetic global model of the reaction scheme during gas plasma generation identified the production of various RCS, including neutral chemical species. Our findings suggest the nitrogen gas plasma generates RCS, including neutral species that damage the viral genomic RNA, leading to virus inactivation. Thus, RCS generated by gas plasma appears to be crucial for virus inactivation, suggesting this may constitute an important factor in terms of the efficient modification of nanoparticles composed of soft materials.

  6. Challenges to evaluating respiratory syncytial virus mortality in Bangladesh, 2004-2008.

    PubMed

    Stockman, Lauren J; Brooks, W Abdullah; Streatfield, Peter K; Rahman, Mustafizur; Goswami, Doli; Nahar, Kamrun; Rahman, Mohammed Z; Luby, Stephen P; Anderson, Larry J

    2013-01-01

    Acute lower respiratory illness is the most common cause of death among children, globally. Data are not available to make accurate estimates on the global mortality from respiratory syncytial virus (RSV), specifically. Respiratory samples collected from children under 5 years of age during 2004 to 2008 as part of population-based respiratory disease surveillance in an urban community in Dhaka, Bangladesh were tested for RSV, human metapneumovirus (HMPV), human parainfluenza virus (PIV) types 1, 2, and 3, influenza and adenovirus by RT-PCR. Verbal autopsy data were used to identify children who died from respiratory illness in a nearby rural community. Significance of the correlation between detections and community respiratory deaths was determined using Spearman's coefficient. RSV activity occurred during defined periods lasting approximately three months but with no clear seasonal pattern. There was no significant correlation between respiratory deaths and detection of any of the respiratory viruses studied. Outbreaks of respiratory viruses may not be associated with deaths in children in the study site; however, the few respiratory deaths observed and community-to-community variation in the timing of outbreaks may have obscured an association. An accurate assessment of respiratory virus-associated deaths will require detections and death data to come from the same location and a larger study population.

  7. Exogenous, TAP-independent lysosomal presentation of a respiratory syncytial virus CTL epitope.

    PubMed

    Johnstone, Carolina; Ramos, Manuel; García-Barreno, Blanca; López, Daniel; Melero, José A; Del Val, Margarita

    2012-11-01

    Respiratory syncytial virus causes lower respiratory tract infections in infancy and old age, affecting also immunocompromised patients. The viral fusion protein is an important vaccine candidate eliciting antibody and cell-mediated immune responses. CD8(+) cytotoxic T lymphocytes (CTLs) are known to have a role in both lung pathology and viral clearance. In BALB/c mice, the fusion protein epitope F249-258 is presented to CTLs by the murine major histocompatibility complex (MHC) class I molecule K(d). In cells infected with recombinant vaccinia viruses encoding the fusion protein, F249-258 is presented by MHC class I molecules through pathways that are independent of the transporters associated with antigen processing (TAP). We have now found that F249-258 can be generated from non-infectious virus from an exogenous source. Antigen processing follows a lysosomal pathway that appears to require autophagy. As a practical consequence, inactivated virus suffices for in vivo priming of virus-specific CTLs.

  8. Interference between respiratory syncytial virus and rhinovirus in respiratory tract infections in children.

    PubMed

    Karppinen, S; Toivonen, L; Schuez-Havupalo, L; Waris, M; Peltola, V

    2016-02-01

    An acute viral respiratory tract infection might prevent infections by other viruses because of the antiviral innate immune response. However, with the use of PCR methods, simultaneous detection of two or more respiratory viruses is frequent. We analysed the effect of respiratory syncytial virus (RSV) infection on the occurrence of simultaneous rhinovirus (RV) infection in children within a birth cohort study setting. We used PCR for virus detection in nasal swabs collected from children with an acute respiratory tract infection at the age of 0-24 months and from healthy control children, who were matched for age and date of sample collection. Of 226 children with RSV infections, 18 (8.0%) had co-infections with RV, whereas RV was detected in 31 (14%) of 226 control children (p 0.049 by chi-square test). Adjustment for sex, number of siblings and socio-economic status strengthened the negative association between RSV and RV (OR 0.46, 95% CI 0.24-0.90; p 0.02). The median durations of symptoms (cough, rhinorrhoea, or fever) were 11 days in children with single RSV infections and 14 days in children with RSV-RV co-infections (p 0.02). Our results suggest that the presence of RSV reduces the probability of RV infection, but that, if a co-infection occurs, both viruses cause clinical symptoms.

  9. Gene-gun DNA vaccination aggravates respiratory syncytial virus-induced pneumonitis.

    PubMed

    Bartholdy, Christina; Olszewska, Wieslawa; Stryhn, Anette; Thomsen, Allan Randrup; Openshaw, Peter J M

    2004-10-01

    A CD8+ T-cell memory response to respiratory syncytial virus (RSV) was generated by using a DNA vaccine construct encoding the dominant Kd-restricted epitope from the viral transcription anti-terminator protein M2 (M2(82-90)), linked covalently to human beta2-microglobulin (beta2m). Cutaneous gene-gun immunization of BALB/c mice with this construct induced an antigen-specific CD8+ T-cell memory. After intranasal RSV challenge, accelerated CD8+ T-cell responses were observed in pulmonary lymph nodes and virus clearance from the lungs was enhanced. The construct induced weaker CD8+ T-cell responses than those elicited with recombinant vaccinia virus expressing the complete RSV M2 protein, but stronger than those induced by a similar DNA construct without the beta2m gene. DNA vaccination led to enhanced pulmonary disease after RSV challenge, with increased weight loss and cell recruitment to the lung. Depletion of CD8+ T cells reduced, but did not abolish, enhancement of disease. Mice vaccinated with a construct encoding a class I-restricted lymphocytic choriomeningitis virus epitope and beta2m suffered more severe weight loss after RSV infection than unvaccinated RSV-infected mice, although RSV-specific CD8+ T-cell responses were not induced. Thus, in addition to specific CD8+ T cell-mediated immunopathology, gene-gun DNA vaccination causes non-specific enhancement of RSV disease without affecting virus clearance.

  10. Caveolae provide a specialized membrane environment for respiratory syncytial virus assembly

    PubMed Central

    Nguyen, Tra Huong; Leong, Daniel; Ravi, Laxmi Iyer; Tan, Boon Huan; Sandin, Sara; Sugrue, Richard J.

    2017-01-01

    ABSTRACT Respiratory syncytial virus (RSV) is an enveloped virus that assembles into filamentous virus particles on the surface of infected cells. Morphogenesis of RSV is dependent upon cholesterol-rich (lipid raft) membrane microdomains, but the specific role of individual raft molecules in RSV assembly is not well defined. Here, we show that RSV morphogenesis occurs within caveolar membranes and that both caveolin-1 and cavin-1 (also known as PTRF), the two major structural and functional components of caveolae, are actively recruited to and incorporated into the RSV envelope. The recruitment of caveolae occurred just prior to the initiation of RSV filament assembly, and was dependent upon an intact actin network as well as a direct physical interaction between caveolin-1 and the viral G protein. Moreover, cavin-1 protein levels were significantly increased in RSV-infected cells, leading to a virus-induced change in the stoichiometry and biophysical properties of the caveolar coat complex. Our data indicate that RSV exploits caveolae for its assembly, and we propose that the incorporation of caveolae into the virus contributes to defining the biological properties of the RSV envelope. PMID:28154158

  11. Alternative Mechanisms of Respiratory Syncytial Virus Clearance in Perforin Knockout Mice Lead to Enhanced Disease

    PubMed Central

    Aung, Sandra; Rutigliano, John A.; Graham, Barney S.

    2001-01-01

    Virus-specific cytotoxic T lymphocytes are key effectors for the clearance of virus-infected cells and are required for the normal clearance of respiratory syncytial virus (RSV) in mice. Although perforin/granzyme-mediated lysis of infected cells is thought to be the major molecular mechanism used by CD8+ cytotoxic T lymphocytes for elimination of virus, its role in RSV has not been reported. Here, we show that viral clearance in perforin knockout (PKO) mice is slightly delayed but that both PKO and wild-type mice clear virus by day 10, suggesting an alternative mechanism of RSV clearance. Effector T cells from the lungs of both groups of mice were shown to lyse Fas (CD95)-overexpressing target cells in greater numbers than target cells expressing low levels of Fas, suggesting that Fas ligand (CD95L)-mediated target cell lysis was occurring in vivo. This cell lysis was associated with a delay in RSV-induced disease in PKO mice compared to the time of disease onset for wild-type controls, which correlated with increased and prolonged production of gamma interferon and tumor necrosis factor alpha levels in PKO mice. We conclude that while perforin is not necessary for the clearance of primary RSV infection, the use of alternative CTL target cell killing mechanisms is less efficient and can lead to enhanced disease. PMID:11559824

  12. Influence of respiratory syncytial virus strain differences on pathogenesis and immunity.

    PubMed

    Melero, José A; Moore, Martin L

    2013-01-01

    Molecular epidemiology studies have provided convincing evidence of antigenic and sequence variability among respiratory syncytial virus (RSV) isolates. Circulating viruses have been classified into two antigenic groups (A and B) that correlate with well-delineated genetic groups. Most sequence and antigenic differences (both inter- and intra-groups) accumulate in two hypervariable segments of the G-protein gene. Sequences of the G gene have been used for phylogenetic analyses. These studies have shown a worldwide distribution of RSV strains with both local and global replacement of dominant viruses with time. Although data are still limited, there is evidence that strain variation may contribute to differences in pathogenicity. In addition, there is some but limited evidence that RSV variation may be, at least partially, immune (antibody) driven. However, there is the paradox in RSV that, in contrast to other viruses (e.g., influenza viruses) the epitopes recognized by the most effective RSV-neutralizing antibodies are highly conserved. In contrast, antibodies that recognize strain-specific epitopes are poorly neutralizing. It is likely that this apparent contradiction is due to the lack of a comprehensive knowledge of the duration and specificities of the human antibody response against RSV antigens. Since there are some data supporting a group- (or clade-) specific antibody response after a primary infection in humans, it may be wise to consider the incorporation of strains representative of groups A and B (or their antigens) in future RSV vaccine development.

  13. Therapeutic effects of garenoxacin in murine experimental secondary pneumonia by Streptococcus pneumoniae after influenza virus infection.

    PubMed

    Fukuda, Yoshiko; Furuya, Yuri; Nozaki, Yusuke; Takahata, Masahiro; Nomura, Nobuhiko; Mitsuyama, Junichi

    2014-02-01

    In a pneumococcal pneumonia murine model following influenza virus infection, garenoxacin was more effective than other fluoroquinolones and demonstrated high levels of bacterial eradication in the lung, low mortality, and potent histopathological improvements. Garenoxacin could potentially be used for the treatment of secondary pneumococcal pneumonia following influenza.

  14. Reduced activation and proliferation of human lymphocytes exposed to respiratory syncytial virus compared to cells exposed to influenza virus.

    PubMed

    Fleming, Elisa H; Ochoa, Eliana E; Nichols, Joan E; O'Banion, M Kerry; Salkind, Alan R; Roberts, Norbert J

    2017-08-30

    Both respiratory syncytial virus (RSV) and influenza A virus (IAV) may infect human peripheral blood mononuclear leukocytes (PBMC) during the immune response to viral challenge as the cells are recruited to the respiratory tract. The current studies demonstrated differences in PBMC responses to the two viruses very early after exposure, including reduced fos protein and CD69 expression and IL-2 production by RSV-exposed T lymphocytes. Exposure to RSV resulted in reduced lymphocyte proliferation despite evidence of a virus-specific T lymphocyte frequency equivalent to that for influenza virus. Reduced RSV-induced proliferation was not due to apoptosis, which was itself reduced relative to that of influenza virus-exposed T lymphocytes. The data indicate that differential immune responses to RSV and influenza virus are determined early after exposure of human PBMC and support the concept that the anamnestic immune response that might prevent clinically evident reinfection is attenuated very soon after exposure to RSV. Thus, candidate RSV vaccines should be expected to reduce but not prevent clinical illness upon subsequent infection by RSV. Furthermore, effective therapeutic agents for RSV are likely to be needed, especially for high-risk populations, even after vaccine development. © 2017 Wiley Periodicals, Inc.

  15. Ficus religiosa L. bark extracts inhibit human rhinovirus and respiratory syncytial virus infection in vitro.

    PubMed

    Cagno, Valeria; Civra, Andrea; Kumar, Ravi; Pradhan, Subhankar; Donalisio, Manuela; Sinha, Barij Nayan; Ghosh, Manik; Lembo, David

    2015-12-24

    Ficus religiosa L. is one of the most relevant members of the family of Moraceae. It is the most sacred tree of South Asia, and it is used in traditional Ayurvedic and Unani medicine to cure respiratory disorders like cough, wheezing and asthma. Some studies were performed to investigate the anti-asthmatic potential of F. religiosa bark, leaves and fruit extracts but none of them tested their antiviral activity against viruses responsible for the exacerbation of wheezing and asthma. The present study was undertaken to investigate the antiviral activity of F. religiosa L. extracts against respiratory viruses such as human respiratory syncytial virus (RSV) and human rhinovirus (HRV). The antiviral activity of F. religiosa L. was tested in vitro by plaque reduction and virus yield assays and the major mechanism of action was investigated by virus inactivation and time-of-addition assays. F. religiosa L. methanol bark extract was the most active against HRV with an EC50 of 5.52 µg/mL. This extract likely inhibited late steps of replicative cycle. Water bark extract was the most active against RSV with an EC50 between 2.23 and 4.37 µg/mL. Partial virus inactivation and interference with virus attachment were both found to contribute to the anti-RSV activity. Replication of both viruses was inhibited in viral yield reduction assays. The results of the present study demonstrate that F. religiosa L. is endowed with antiviral activity against RSV and HRV in vitro. Further work remains to be done to identify the active components and to assess the therapeutic potential in vivo. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors.

    PubMed

    Brüggmann, Dörthe; Köster, Corinna; Klingelhöfer, Doris; Bauer, Jan; Ohlendorf, Daniela; Bundschuh, Matthias; Groneberg, David A

    2017-07-26

    Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research. Retrospective, descriptive study. The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools. We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil. The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries. © Article author(s) (or their employer

  17. Respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors

    PubMed Central

    Brüggmann, Dörthe; Köster, Corinna; Klingelhöfer, Doris; Bauer, Jan; Ohlendorf, Daniela; Bundschuh, Matthias; Groneberg, David A

    2017-01-01

    Objective Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research. Design Retrospective, descriptive study. Setting The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools. Results We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil. Conclusions The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these

  18. Curcumin modified silver nanoparticles for highly efficient inhibition of respiratory syncytial virus infection

    NASA Astrophysics Data System (ADS)

    Yang, Xiao Xi; Li, Chun Mei; Huang, Cheng Zhi

    2016-01-01

    Interactions between nanoparticles and viruses have attracted increasing attention due to the antiviral activity of nanoparticles and the resulting possibility to be employed as biomedical interventions. In this contribution, we developed a very simple route to prepare uniform and stable silver nanoparticles (AgNPs) with antiviral properties by using curcumin, which is a member of the ginger family isolated from rhizomes of the perennial herb Curcuma longa and has a wide range of biological activities like antioxidant, antifungal, antibacterial and anti-inflammatory effects, and acts as reducing and capping agents in this synthetic route. The tissue culture infectious dose (TCID50) assay showed that the curcumin modified silver nanoparticles (cAgNPs) have a highly efficient inhibition effect against respiratory syncytial virus (RSV) infection, giving a decrease of viral titers about two orders of magnitude at the concentration of cAgNPs under which no toxicity was found to the host cells. Mechanism investigations showed that cAgNPs could prevent RSV from infecting the host cells by inactivating the virus directly, indicating that cAgNPs are a novel promising efficient virucide for RSV.Interactions between nanoparticles and viruses have attracted increasing attention due to the antiviral activity of nanoparticles and the resulting possibility to be employed as biomedical interventions. In this contribution, we developed a very simple route to prepare uniform and stable silver nanoparticles (AgNPs) with antiviral properties by using curcumin, which is a member of the ginger family isolated from rhizomes of the perennial herb Curcuma longa and has a wide range of biological activities like antioxidant, antifungal, antibacterial and anti-inflammatory effects, and acts as reducing and capping agents in this synthetic route. The tissue culture infectious dose (TCID50) assay showed that the curcumin modified silver nanoparticles (cAgNPs) have a highly efficient inhibition

  19. Induction and Antagonism of Antiviral Responses in Respiratory Syncytial Virus-Infected Pediatric Airway Epithelium

    PubMed Central

    Villenave, Rémi; Broadbent, Lindsay; Douglas, Isobel; Lyons, Jeremy D.; Coyle, Peter V.; Teng, Michael N.; Tripp, Ralph A.; Heaney, Liam G.; Shields, Michael D.

    2015-01-01

    ABSTRACT Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well-differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda 1 (IFN-λ1)/interleukin-29 (IL-29). In contrast, type I IFNs were not detected following RSV infection of WD-PBECs. IFN responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD-PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN-mediated antiviral responses in infected cells. Our data are consistent with RSV nonstructural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic. IMPORTANCE Most respiratory viruses target airway epithelium for infection and replication, which is central to causing disease. However, for most human viruses we have a poor understanding of their interactions with human airway epithelium. Respiratory syncytial virus (RSV) is the most important viral pathogen of young infants. To help understand RSV interactions with pediatric

  20. In silico analysis of amino acid variation in human respiratory syncytial virus: insights into immunodiagnostics.

    PubMed

    Souza, Claudemir; Zanchin, Nilson It; Krieger, Marco A; Ludwig, Adriana

    2017-10-01

    The highly contagious nature of human respiratory syncytial virus (HRSV) and the gravity of its infection in newborns and vulnerable adults pose a serious public health problem. Thus, a rapid and sensitive diagnostic test for viral detection that can be implemented upon the first appearance of symptoms is needed. The genetic variation of the virus must be considered for immunodiagnostic purposes. To analyse HRSV genetic variation and discuss the possible consequences for capture immunoassay development. We performed a wide analysis of N, F and G protein variation based on the HRSV sequences currently available in the GenBank database. We also evaluated their similarity with homologous proteins from other viruses. The mean amino acid divergences for the N, F, and G proteins between HRSV-A and HRSV-B were determined to be approximately 4%, 10% and 47%, respectively. Due to their high conservation, assays based on the full-length N and F proteins may not distinguish HRSV from human metapneumovirus and other Mononegavirales viruses, and the full-length G protein would most likely produce false negative results due to its high divergence. We have identified specific regions in each of these three proteins that have higher potential to produce specific results, and their combined utilisation should be considered for immunoassay development.

  1. Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection.

    PubMed

    González, Andrea E; Lay, Margarita K; Jara, Evelyn L; Espinoza, Janyra A; Gómez, Roberto S; Soto, Jorge; Rivera, Claudia A; Abarca, Katia; Bueno, Susan M; Riedel, Claudia A; Kalergis, Alexis M

    2016-12-02

    Human Respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are the two major etiological viral agents of lower respiratory tract diseases, affecting mainly infants, young children and the elderly. Although the infection of both viruses trigger an antiviral immune response that mediate viral clearance and disease resolution in immunocompetent individuals, the promotion of long-term immunity appears to be deficient and reinfection are common throughout life. A possible explanation for this phenomenon is that hRSV and hMPV, can induce aberrant T cell responses, which leads to exacerbated lung inflammation and poor T and B cell memory immunity. The modulation of immune response exerted by both viruses include different strategies such as, impairment of immunological synapse mediated by viral proteins or soluble factors, and the induction of pro-inflammatory cytokines by epithelial cells, among others. All these viral strategies contribute to the alteration of the adaptive immunity in order to increase the susceptibility to reinfections. In this review, we discuss current research related to the mechanisms underlying the impairment of T and B cell immune responses induced by hRSV and hMPV infection. In addition, we described the role each virulence factor involved in immune modulation caused by these viruses.

  2. Reliable Detection of Respiratory Syncytial Virus Infection in Children for Adequate Hospital Infection Control Management

    PubMed Central

    Abels, Susanne; Nadal, David; Stroehle, Angelika; Bossart, Walter

    2001-01-01

    By using a rapid test for respiratory syncytial virus (RSV) detection (Abbott TestPack RSV), a number of patients were observed, showing repeatedly positive results over a period of up to 10 weeks. A prospective study was initiated to compare the rapid test with an antigen capture enzyme immunoassay (EIA) and a nested reverse transcriptase PCR (RT-PCR) protocol for detection of RSV serotypes A and B. Only respiratory samples from children exhibiting the prolonged presence of RSV (≥5 days) as determined by the rapid test were considered. A total of 134 specimens from 24 children was investigated by antigen capture EIA and nested RT-PCR. Using RT-PCR as the reference method, we determined the RSV rapid test to have a specificity of 63% and a sensitivity of 66% and the antigen capture EIA to have a specificity of 96% and a sensitivity of 69% for acute-phase samples and the homologous virus serotype A. In 7 (29%) of 24 patients, the positive results of the RSV rapid test could not be confirmed by either nested RT-PCR or antigen capture EIA. In these seven patients a variety of other respiratory viruses were detected. For general screening the RSV rapid test was found to be a reasonable tool to get quick results. However, its lack of specificity in some patients requires confirmation by additional tests to rule out false-positive results and/or detection of other respiratory viruses. PMID:11526141

  3. Different NF-κB activation characteristics of human respiratory syncytial virus subgroups A and B.

    PubMed

    Wu, Weining; Macdonald, Andrew; Hiscox, Julian A; Barr, John N

    2012-03-01

    Human respiratory syncytial virus (HRSV) is a member of the family Paramyxoviridae, and is responsible for serious respiratory illness in infants, the elderly and the immunocompromised. HRSV exists as two distinct lineages known as subgroups A and B, which represent two lines of divergent evolution with extensive genetic and serologic differences. While both subgroup A and B viruses contribute to overall HRSV disease, subgroup A isolates are associated with both increased frequency and morbidity of infections, and reasons for this are unclear. HRSV disease is characterized by virus-mediated cell destruction in combination with extensive inflammatory and immune modulatory responses, and for HRSV subgroup A isolates, several of these signaling pathways are regulated through activation of the transcription factor NF-κB. In contrast, the NF-κB activation characteristics of HRSV subgroup B infection remain untested. Here, we performed a quantitative and comparative analysis of NF-κB activation in response to infection of both continuous and primary cell cultures with HRSV subgroup A and B isolates. Our results showed the model HRSV subgroup A isolate consistently induced increased NF-κB activation compared to its HRSV subgroup B counterpart. The differential NF-κB activation characteristics of HRSV subgroup A and B viruses may contribute to differences in their pathogenesis.

  4. Respiratory Syncytial Virus Assembles into Structured Filamentous Virion Particles Independently of Host Cytoskeleton and Related Proteins

    PubMed Central

    Shaikh, Fyza Y.; Utley, Thomas J.; Craven, Ryan E.; Rogers, Meredith C.; Lapierre, Lynne A.; Goldenring, James R.; Crowe, James E.

    2012-01-01

    Respiratory syncytial virus (RSV) is a single-stranded RNA virus that assembles into viral filaments at the cell surface. Virus assembly often depends on the ability of a virus to use host proteins to accomplish viral tasks. Since the fusion protein cytoplasmic tail (FCT) is critical for viral filamentous assembly, we hypothesized that host proteins important for viral assembly may be recruited by the FCT. Using a yeast two-hybrid screen, we found that filamin A interacted with FCT, and mammalian cell experiments showed it localized to viral filaments but did not affect viral replication. Furthermore, we found that a number of actin-associated proteins also were excluded from viral filaments. Actin or tubulin cytoskeletal rearrangement was not necessary for F trafficking to the cell surface or for viral assembly into filaments, but was necessary for optimal viral replication and may be important for anchoring viral filaments. These findings suggest that RSV assembly into filaments occurs independently of actin polymerization and that viral proteins are the principal drivers for the mechanical tasks involved with formation of complex, structured RSV filaments at the host cell plasma membrane. PMID:22808269

  5. Latency and persistence of respiratory syncytial virus despite T cell immunity.

    PubMed

    Schwarze, Jurgen; O'Donnell, Diarmund R; Rohwedder, Angela; Openshaw, Peter J M

    2004-04-01

    Respiratory syncytial virus (RSV) causes bronchiolitis in infants, which is associated with recurrent wheezing in later childhood. There is mounting evidence that the virus becomes latent or persists in vivo, but little is known about the mechanisms of its latency, persistence, and immune evasion. We therefore infected BALB/c mice intranasally with human RSV, analyzed sequential tissue samples by direct culture and polymerase chain reaction for viral and messenger RNA, and monitored antiviral immune responses. Virus could not be detected in bronchoalveolar lavage samples beyond Day 14, but viral genomic and messenger RNA was present in lung homogenates for 100 days or more; combined depletion of CD4 and CD8 T cells allowed infective virus to be recovered. Neutralizing antibody and memory cytotoxic T cell responses were intact in mice with latent infections, and latent viral genome contained an authentic nonmutated M2 82-91 K(d) cytotoxic T lymphocyte epitope. A mutation of this epitope, detected in one clone, did not assist evasion. We suggest that RSV latency depends on persistence in privileged sites rather than on viral mutation.

  6. Synthetic Biodegradable Microparticle and Nanoparticle Vaccines against the Respiratory Syncytial Virus

    PubMed Central

    Jorquera, Patricia A.; Tripp, Ralph A.

    2016-01-01

    Synthetic biodegradable microparticle and nanoparticle platform technology provides the opportunity to design particles varying in composition, size, shape and surface properties for application in vaccine development. The use of particle vaccine formulations allows improvement of antigen stability and immunogenicity while allowing targeted delivery and slow release. This technology has been design to develop novel vaccines against the respiratory syncytial virus (RSV), the leading cause of lower respiratory tract infection in infants. In the last decade, several nano- and micro-sized RSV vaccine candidates have been developed and tested in animal models showing promising results. This review provides an overview of recent advances in prophylactic particle vaccines for RSV and the multiple factors that can affect vaccine efficacy. PMID:27918420

  7. Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state

    PubMed Central

    Rossey, Iebe; Gilman, Morgan S. A.; Kabeche, Stephanie C.; Sedeyn, Koen; Wrapp, Daniel; Kanekiyo, Masaru; Chen, Man; Mas, Vicente; Spitaels, Jan; Melero, José A.; Graham, Barney S.; Schepens, Bert; McLellan, Jason S.; Saelens, Xavier

    2017-01-01

    Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV. PMID:28194013

  8. Structural, antigenic and immunogenic features of respiratory syncytial virus glycoproteins relevant for vaccine development

    PubMed Central

    Melero, José A.; Mas, Vicente; McLellan, Jason S.

    2016-01-01

    Extraordinary progress in the structure and immunobiology of the human respiratory syncytial virus glycoproteins has been accomplished during the last few years. Determination of the fusion (F) glycoprotein structure folded in either the prefusion or the postfusion conformation was an inspiring breakthrough not only to understand the structural changes associated with the membrane fusion process but additionally to appreciate the antigenic intricacies of the F molecule. Furthermore, these developments have opened new avenues for structure-based designs of promising hRSV vaccine candidates. Finally, recent advances in our knowledge of the attachment (G) glycoprotein and its interaction with cell-surface receptors have revitalized interest in this molecule as a vaccine, as well as its role in hRSV immunobiology. PMID:27692522

  9. Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery.

    PubMed

    Heylen, Elisabeth; Neyts, Johan; Jochmans, Dirk

    2017-03-01

    The development of antiviral strategies to prevent or treat respiratory syncytial virus (RSV) infections is of great importance, especially considering the fact that RSV is one of the most important causes of pediatric respiratory infections. However, despite intense efforts, there is no antiviral or vaccine approved for the prevention or treatment of RSV infections. Several inhibitors, targeting different RSV proteins have been discovered over the past decade. We here review the most important chemical series as well as recent developments in understanding which viral proteins and/or host cell factors are good targets for inhibition of viral replication. In addition, we highlight the current in vitro and in vivo model systems of the disease. A number of molecules are currently in (advanced) preclinical or clinical development. Significant breakthroughs in the field may be expected in the upcoming years.

  10. Spontaneous Pneumothorax With Subcutaneous Emphysema: A Rare Complication of Respiratory Syncytial Virus Infection

    PubMed Central

    Silva, Carmen; Almeida, Ana Filipe; Ferraz, Catarina; Nunes, Teresa; Guedes Vaz, Luisa

    2016-01-01

    Viral bronchiolitis is the most common lower respiratory tract infection in infants and children under the age of 2. Respiratory syncytial virus (RSV) is the infecting agent in more than 50% of the cases. Usually the clinical course is uneventful and complications are uncommon. Secondary air leaks are a recognized rare complication of bronchiolitis, although the real incidence remains unknown. We report a case of a 21-month-old female that developed a spontaneous pneumothorax (PNO) with subcutaneous emphysema (SE) late in the course of RSV acute bronchiolitis. Additional investigation ruled out any underlying disease predisposing to spontaneous PNO. Physicians, especially those who work with small children, must be aware of this uncommon complication of bronchiolitis that may appear late in the course of the disease despite an initial clinical improvement. PMID:26858803

  11. Spontaneous Pneumothorax With Subcutaneous Emphysema: A Rare Complication of Respiratory Syncytial Virus Infection.

    PubMed

    Silva, Carmen; Almeida, Ana Filipe; Ferraz, Catarina; Nunes, Teresa; Guedes Vaz, Luisa

    2016-03-01

    Viral bronchiolitis is the most common lower respiratory tract infection in infants and children under the age of 2. Respiratory syncytial virus (RSV) is the infecting agent in more than 50% of the cases. Usually the clinical course is uneventful and complications are uncommon. Secondary air leaks are a recognized rare complication of bronchiolitis, although the real incidence remains unknown. We report a case of a 21-month-old female that developed a spontaneous pneumothorax (PNO) with subcutaneous emphysema (SE) late in the course of RSV acute bronchiolitis. Additional investigation ruled out any underlying disease predisposing to spontaneous PNO. Physicians, especially those who work with small children, must be aware of this uncommon complication of bronchiolitis that may appear late in the course of the disease despite an initial clinical improvement.

  12. Displacement of predominant respiratory syncytial virus genotypes in Malaysia between 1989 and 2011.

    PubMed

    Khor, Chee-Sieng; Sam, I-Ching; Hooi, Poh-Sim; Chan, Yoke-Fun

    2013-03-01

    From 1989 to 2011 in Kuala Lumpur, Malaysia, multiple genotypes from both respiratory syncytial virus (RSV) subgroups were found co-circulating each year. RSV-A subgroup predominated in 12 out of 17years with the remaining years predominated by RSV-B subgroup. Local RSV strains exhibited temporal clustering with RSV strains reported in previous epidemiological studies. Every few years, the existing predominant genotype was replaced by a new genotype. The RSV-A genotypes GA2, GA5 and GA7 were replaced by NA1 and NA2, while BA became the predominant RSV-B genotype. A unique local cluster, BA12, was seen in 2009, and the recently-described ON1 genotype with 72-nt duplication emerged in 2011. Our findings will have important implications for future vaccine intervention. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Respiratory syncytial virus (RSV) outbreak in the NICU: description of eight cases.

    PubMed

    Kilani, Ramzi A

    2002-04-01

    Respiratory syncytial virus (RSV) has been recognized as a major nosocomial hazard on pediatric wards. Because of maternally acquired antibodies, symptomatic RSV infection is rare in term neonates. During an outbreak of RSV in our neonatal ICU, 12 infants (gestational age = 34 +/- 5 weeks) remained RSV negative. In contrast, eight preterm infants (gestational age = 28 +/- 2 weeks) became RSV positive. Four infants became very sick with RSV and required mechanical ventilation and support. Acute respiratory distress syndrome (ARDS) developed in two of them resulting in death of one of them. Control measures were effective in controlling the outbreak. We conclude that during an RSV outbreak in the neonatal ICU, the attack rate is higher in preterm infants born at lower gestational age resulting in significant mortality and morbidity.

  14. Evidence for a causal relationship between respiratory syncytial virus infection and asthma.

    PubMed

    Wu, Pingsheng; Hartert, Tina V

    2011-09-01

    Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.

  15. Circulating Strains of Human Respiratory Syncytial Virus in Central and South America

    PubMed Central

    Sovero, Merly; Garcia, Josefina; Kochel, Tadeusz; Laguna-Torres, V. Alberto; Gomez, Jorge; Chicaiza, Wilson; Barrantes, Melvin; Sanchez, Felix; Jimenez, Mirna; Comach, Guillermo; de Rivera, Ivette Lorenzana; Arango, Ana E.; Agudo, Roberto; Halsey, Eric S.

    2011-01-01

    Human respiratory syncytial virus (HRSV) is a major cause of viral lower respiratory tract infections among infants and young children. HRSV strains vary genetically and antigenically and have been classified into two broad subgroups, A and B (HRSV-A and HRSV-B, respectively). To date, little is known about the circulating strains of HRSV in Latin America. We have evaluated the genetic diversity of 96 HRSV strains by sequencing a variable region of the G protein gene of isolates collected from 2007 to 2009 in Central and South America. Our results show the presence of the two antigenic subgroups of HRSV during this period with the majority belonging to the genotype HRSV-A2. PMID:21829605

  16. Evaluation of antiviral efficacy against human respiratory syncytial virus using cotton rat and mouse models.

    PubMed

    Van den Berg, Joke; Kwanten, Leen; Roymans, Dirk

    2013-01-01

    Infection with human respiratory syncytial virus (hRSV) causes a wide spectrum of respiratory disease in infants, young children, and elderly persons. No vaccine is available today and hRSV treatment options are limited. As a consequence, the treatment of hRSV infection remains largely supportive and new therapeutic options are needed to treat severe lower respiratory tract hRSV disease. Several animal models have been developed to study hRSV disease and evaluate novel therapies or preventive measures such as vaccines. However, each of these models reproduces different aspects of hRSV disease, and therefore, an appropriate model should be selected on the basis of the scientific question under investigation. In this chapter, we describe how cotton rats and Balb/c mice are used in our laboratory to test the in vivo efficacy of small-molecule inhibitors against hRSV.

  17. A rapid, simple, and accurate plaque assay for human respiratory syncytial virus (HRSV).

    PubMed

    Kim, Kyung Sook; Kim, Ah Ra; Piao, Ying; Lee, Ju-Hie; Quan, Fu-Shi

    2017-03-31

    Plaque assays of human respiratory syncytial virus (HRSV) are time-consuming, requiring 4 to 7 days for plaque formation and several hours for dye staining. Here, we describe a simple method by which RSV plaques can be visualized and counted with the naked eye only 2 days after infection of HEp-2 cells. In this assay, the infected cells are stained with monoclonal antibodies and the plaques are developed using diaminobenzidine (DAB). We tested the accuracy of this new plaque assay by comparing the results obtained on days 1, 2, 3, 4, 5, and 6 post-infection. The whole procedure is significantly simpler than the traditional method, with an immunostaining process of around 1.5h. Our method is rapid, accurate, and simple; thus, it has the potential to significantly contribute to studies related to RSV disease.

  18. Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells.

    PubMed

    Oliveira, Andressa P; Simabuco, Fernando M; Tamura, Rodrigo E; Guerrero, Manuel C; Ribeiro, Paulo G G; Libermann, Towia A; Zerbini, Luiz F; Ventura, Armando M

    2013-10-01

    Characterization of Human Respiratory Syncytial Virus (HRSV) protein interactions with host cell components is crucial to devise antiviral strategies. Viral nucleoprotein, phosphoprotein and matrix protein genes were optimized for human codon usage and cloned into expression vectors. HEK-293T cells were transfected with these vectors, viral proteins were immunoprecipitated, and co-immunoprecipitated cellular proteins were identified through mass spectrometry. Cell proteins identified with higher confidence scores were probed in the immunoprecipitation using specific antibodies. The results indicate that nucleoprotein interacts with arginine methyl-transferase, methylosome protein and Hsp70. Phosphoprotein interacts with Hsp70 and tropomysin, and matrix with tropomysin and nucleophosmin. Additionally, we performed immunoprecipitation of these cellular proteins in cells infected with HRSV, followed by detection of co-immunoprecipitated viral proteins. The results indicate that these interactions also occur in the context of viral infection, and their potential contribution for a HRSV replication model is discussed.

  19. Links between respiratory syncytial virus bronchiolitis and childhood asthma: clinical and research approaches.

    PubMed

    Openshaw, Peter J; Dean, Gillian S; Culley, Fiona J

    2003-02-01

    This review examines the relationship between severe pulmonary disease caused by respiratory syncytial virus (RSV) infection in infancy and later development of asthma or reactive airway disease (RAD). RSV infection accounts for 70% or greater of all cases of infantile bronchiolitis and has been linked to subsequent asthma or RAD, either directly or through a shared common predisposition. Several studies suggest that RSV bronchiolitis is an important factor in the development of asthma and possibly atopy, although the association is lost by the age of 13 years. The mechanism is as yet unclear, but murine models of RSV disease have identified many plausible causal explanations. Further study is necessary to determine the relative roles of RSV infection and genetic predisposition in explaining the association between RSV infection and asthma/RAD.

  20. Role of CCL11 in eosinophilic lung disease during respiratory syncytial virus infection.

    PubMed

    Matthews, Stephen P; Tregoning, John S; Coyle, Anthony J; Hussell, Tracy; Openshaw, Peter J M

    2005-02-01

    Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.

  1. The innate immune system of the perinatal lung and responses to respiratory syncytial virus infection.

    PubMed

    Derscheid, R J; Ackermann, M R

    2013-09-01

    The response of the preterm and newborn lung to airborne pathogens, particles, and other insults is initially dependent on innate immune responses since adaptive responses may not fully mature and require weeks for sufficient responses to antigenic stimuli. Foreign material and microbial agents trigger soluble, cell surface, and cytoplasmic receptors that activate signaling cascades that invoke release of surfactant proteins, defensins, interferons, lactoferrin, oxidative products, and other innate immune substances that have antimicrobial activity, which can also influence adaptive responses. For viral infections such as respiratory syncytial virus (RSV), the pulmonary innate immune responses has an essential role in defense as there are no fully effective vaccines or therapies for RSV infections of humans and reinfections are common. Understanding the innate immune response by the preterm and newborn lung may lead to preventive strategies and more effective therapeutic regimens.

  2. Severe respiratory syncytial virus (RSV) infection in infants with neuromuscular diseases and immune deficiency syndromes.

    PubMed

    Resch, Bernhard; Manzoni, Paolo; Lanari, Marcello

    2009-09-01

    Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in infants and children. There is growing evidence of severe RSV disease in infants with neuromuscular diseases and immune deficiency syndromes. Factors predisposing to a more severe course of RSV disease in neuromuscular diseases include the impaired ability to clear secretions from the airways due to ineffective cough, respiratory muscle weakness, high prevalence of gastro-oesophageal reflux and swallowing dysfunction which leads to aspiration. Similarly, pulmonary disease is a common presenting feature and complication of T-cell immunodeficiency. Infants with severe congenital and acquired immune deficiency syndromes may demonstrate prolonged viral shedding in RSV LRTI and are reported to have increased morbidity and mortality associated with RSV infection. Although not indicated in most guideline statements, palivizumab prophylaxis for these uncommon underlying conditions is under consideration by clinicians. Prospective studies are needed to determine the burden of RSV disease in these children.

  3. Risk Factors for Respiratory Failure Associated with Respiratory Syncytial Virus Infection in Adults

    PubMed Central

    Duncan, Coley B.; Walsh, Edward E.; Peterson, Derick R.; Lee, F.Eun-Hyung; Falsey, Ann R.

    2010-01-01

    Risk factors associated with respiratory failure during respiratory syncytial virus (RSV) infection have not been assessed in adults. We identified RSV by quantitative reverse transcription polymerase chain reaction in 58 adults during the 2007–2008 winter. Clinical variables and respiratory secretion viral loads were compared in 26 outpatients and 32 inpatients. Cardiopulmonary diseases were more common among inpatients than outpatients (91% vs 31%, P = .0001), whereas mean RSV load was similar. Nasal viral load was higher in ventilated vs nonventilated hospitalized patients (log10 3.7 ± 1.7 plaque-forming units (PFUs)/mL vs 2.4 ± 1.1 PFUs/mL, P = .02), and high viral load was independently associated with respiratory failure. PMID:19758094

  4. Recent Advances in Diagnosis, Prevention, and Treatment of Human Respiratory Syncytial Virus

    PubMed Central

    Bawage, Swapnil Subhash; Tiwari, Pooja Munnilal; Singh, Shree Ram

    2013-01-01

    Human respiratory syncytial virus (RSV) is a common cause of respiratory infection in infants and the elderly, leading to significant morbidity and mortality. The interdisciplinary fields, especially biotechnology and nanotechnology, have facilitated the development of modern detection systems for RSV. Many anti-RSV compounds like fusion inhibitors and RNAi molecules have been successful in laboratory and clinical trials. But, currently, there are no effective drugs for RSV infection even after decades of research. Effective diagnosis can result in effective treatment, but the progress in both of these facets must be concurrent. The development in prevention and treatment measures for RSV is at appreciable pace, but the implementation into clinical practice still seems a challenge. This review attempts to present the promising diverse research approaches and advancements in the area of diagnosis, prevention, and treatment that contribute to RSV management. PMID:24382964

  5. Prevailing genotype distribution and characteristics of human respiratory syncytial virus in northeastern China.

    PubMed

    Zheng, Yuxuan; Liu, Li; Wang, Shaohua; Li, Zhaolong; Hou, Min; Li, Jingliang; Yu, Xiao-Fang; Zhang, Wenyan; Hua, Shucheng

    2017-02-01

    Although human respiratory syncytial virus (RSV) is one of the most common viruses inducing respiratory tract infections in young children and the elderly, the genotype distribution and characteristics of RSV in northeastern China have not been investigated. Here, we identified 25 RSV-A and 8 RSV-B strains from 80 samples of patients with respiratory infections between February 2015 and May 2015. All 25 RSV-A viruses were classified as the ON1 genotype, which rapidly spread and became the dominant genotype in the world since being identified in Ontario (Canada) in December 2010. All eight RSV-B viruses belonged to the BA genotype with a 60-nucleotide duplication, seven of which formed two new genotypes, BA-CCA and BA-CCB. The remaining RSV-B virus clustered with one of the Hangzhou strains belonging to genotype BA11. Construction of a phylogenetic tree and amino acid substitution analysis showed that Changchun ON1 viruses exclusively constituted Lineages 3, 5 and 6, and contained several unique and newly identified amino acid substitutions, including E224G, R244K, L289I, Y297H, and L298P. Selective pressure was also evaluated, and various N and O-glycosylation sites were predicted. This study provides the first genetic analysis of RSV in northeastern China and may facilitate a better understanding of the evolution of this virus locally and globally. J. Med. Virol. 89:222-233, 2017. © 2016 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.

  6. Prevailing genotype distribution and characteristics of human respiratory syncytial virus in northeastern China

    PubMed Central

    Zheng, Yuxuan; Liu, Li; Wang, Shaohua; Li, Zhaolong; Hou, Min; Li, Jingliang; Yu, Xiao‐Fang

    2016-01-01

    Although human respiratory syncytial virus (RSV) is one of the most common viruses inducing respiratory tract infections in young children and the elderly, the genotype distribution and characteristics of RSV in northeastern China have not been investigated. Here, we identified 25 RSV‐A and 8 RSV‐B strains from 80 samples of patients with respiratory infections between February 2015 and May 2015. All 25 RSV‐A viruses were classified as the ON1 genotype, which rapidly spread and became the dominant genotype in the world since being identified in Ontario (Canada) in December 2010. All eight RSV‐B viruses belonged to the BA genotype with a 60‐nucleotide duplication, seven of which formed two new genotypes, BA‐CCA and BA‐CCB. The remaining RSV‐B virus clustered with one of the Hangzhou strains belonging to genotype BA11. Construction of a phylogenetic tree and amino acid substitution analysis showed that Changchun ON1 viruses exclusively constituted Lineages 3, 5 and 6, and contained several unique and newly identified amino acid substitutions, including E224G, R244K, L289I, Y297H, and L298P. Selective pressure was also evaluated, and various N and O‐glycosylation sites were predicted. This study provides the first genetic analysis of RSV in northeastern China and may facilitate a better understanding of the evolution of this virus locally and globally. J. Med. Virol. 89:222–233, 2017. © 2016 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc. PMID:27448044

  7. γδ T cells and the immune response to respiratory syncytial virus infection.

    PubMed

    McGill, Jodi L; Sacco, Randy E

    2016-11-15

    γδ T cells are a subset of nonconventional T cells that play a critical role in bridging the innate and adaptive arms of the immune system. γδ T cells are particularly abundant in ruminant species and may constitute up to 60% of the circulating lymphocyte pool in young cattle. The frequency of circulating γδ T cells is highest in neonatal calves and declines as the animal ages, suggesting these cells may be particularly important in the immune system of the very young. Bovine respiratory syncytial virus (BRSV) is a significant cause of respiratory infection in calves, and is most severe in animals under one year of age. BRSV is also a significant factor in the development of bovine respiratory disease complex (BRDC), the leading cause of morbidity and mortality in feedlot cattle. Human respiratory syncytial virus (RSV) is closely related to BRSV and a leading cause of lower respiratory tract infection in infants and children worldwide. BRSV infection in calves shares striking similarities with RSV infection in human infants. To date, there have been few studies defining the role of γδ T cells in the immune response to BRSV or RSV infection in animals or humans, respectively. However, emerging evidence suggests that γδ T cells may play a critical role in the early recognition of infection and in shaping the development of the adaptive immune response through inflammatory chemokine and cytokine production. Further, while it is clear that γδ T cells accumulate in the lungs during BRSV and RSV infection, their role in protection vs. immunopathology remains unclear. This review will summarize what is currently known about the role of γδ T cells in the immune response to BRSV and BRDC in cattle, and where appropriate, draw parallels to the role of γδ T cells in the human response to RSV infection.

  8. Molecular evolution of the fusion protein (F) gene in human respiratory syncytial virus subgroup B.

    PubMed

    Kimura, Hirokazu; Nagasawa, Koo; Kimura, Ryusuke; Tsukagoshi, Hiroyuki; Matsushima, Yuki; Fujita, Kiyotaka; Hirano, Eiko; Ishiwada, Naruhiko; Misaki, Takako; Oishi, Kazunori; Kuroda, Makoto; Ryo, Akihide

    2017-08-01

    In this study, we examined the molecular evolution of the fusion protein (F) gene in human respiratory syncytial virus subgroup B (HRSV-B). First, we performed time-scale evolution analyses using the Bayesian Markov chain Monte Carlo (MCMC) method. Next, we performed genetic distance, linear B-cell epitope prediction, N-glycosylation, positive/negative selection site, and Bayesian skyline plot analyses. We also constructed a structural model of the F protein and mapped the amino acid substitutions and the predicted B-cell epitopes. The MCMC-constructed phylogenetic tree indicated that the HRSV F gene diverged from the bovine respiratory syncytial virus gene approximately 580years ago and had a relatively low evolutionary rate (7.14×10(-4)substitutions/site/year). Furthermore, a common ancestor of HRSV-A and -B diverged approximately 290years ago, while HRSV-B diverged into three clusters for approximately 60years. The genetic similarity of the present strains was very high. Although a maximum of 11 amino acid substitutions were observed in the structural model of the F protein, only one strain possessed an amino acid substitution located within the palivizumab epitope. Four epitopes were predicted, although these did not correspond to the neutralization sites of the F protein including the palivizumab epitope. In addition, five N-glycosylation sites of the present HRSV-B strains were inferred. No positive selection sites were identified; however, many sites were found to be under negative selection. The effective population size of the gene has remained almost constant. On the basis of these results, it can be concluded that the HRSV-B F gene is highly conserved, as is the F protein of HRSV-A. Moreover, our prediction of B-cell epitopes does not show that the palivizumab reaction site may be recognized as an epitope during naturally occurring infections. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Epidemiological and genetic characteristics associated with the severity of acute viral bronchiolitis by respiratory syncytial virus.

    PubMed

    Alvarez, Alfonso Eduardo; Marson, Fernando Augusto de Lima; Bertuzzo, Carmen Sílvia; Arns, Clarice Weis; Ribeiro, José Dirceu

    2013-01-01

    to assess the epidemiological and genetic factors associated with severity of acute viral bronchiolitis (AVB) by respiratory syncytial virus (RSV). the key words "bronchiolitis", "risk factor", "genetics" and "respiratory syncytial virus", and all combinations among them were used to perform a search in the PubMed, SciELO, and Lilacs databases, of articles published after the year 2000 that included individuals younger than 2 years of age. a total of 1,259 articles were found, and their respective summaries were read. Of these, 81 were selected, which assessed risk factors for the severity of AVB, and were read in full; the 60 most relevant studies were included. The epidemiologic factors associated with AVB severity by RSV were prematurity, passive smoking, young age, lack of breastfeeding, chronic lung disease, congenital heart disease, male gender, ethnicity, viral coinfection, low weight at admission, maternal smoking during pregnancy, atopic dermatitis, mechanical ventilation in the neonatal period, maternal history of atopy and/or asthma during pregnancy, season of birth, low socioeconomic status, Down syndrome, environmental pollution, living at an altitude > 2,500 meters above sea level, and cesarean section birth. Conversely, some children with severe AVB did not present any of these risk factors. In this regard, recent studies have verified the influence of genetic factors on the severity of AVB by RSV. Polymorphisms of the TLRs, RANTES, JUN, IFNA5, NOS2, CX3CR1, ILs, and VDR genes have been shown to be associated with more severe evolution of AVB by RSV. the severity of AVB by RSV is a phenomenon that depends on the varying degrees of interaction among epidemiological, environmental, and genetic variables. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  10. Serologic Cross-Reactions between Nucleocapsid Proteins of Human Respiratory Syncytial Virus and Human Metapneumovirus

    PubMed Central

    Zhang, Yange; Pohl, Jan; Brooks, W. Abdullah

    2015-01-01

    Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) share virologic and epidemiologic features and cause clinically similar respiratory illness predominantly in young children. In a previous study of acute febrile respiratory illness in Bangladesh, we tested paired serum specimens from 852 children presenting fever and cough for diagnostic increases in titers of antibody to hRSV and hMPV by enzyme immunoassay (EIA). Unexpectedly, of 93 serum pairs that showed a ≥4-fold increase in titers of antibody to hRSV, 24 (25.8%) showed a concurrent increase in titers of antibody to hMPV; of 91 pairs showing an increase to hMPV, 13 (14.3%) showed a concurrent increase to hRSV. We speculated that common antigens shared by these viruses explain this finding. Since the nucleocapsid (N) proteins of these viruses show the greatest sequence homology, we tested hyperimmune antisera prepared for each virus against baculovirus-expressed recombinant N (recN) proteins for potential cross-reactivity. The antisera were reciprocally reactive with both proteins. To localize common antigenic regions, we first expressed the carboxy domain of the hMPV N protein that was the most highly conserved region within the hRSV N protein. Although reciprocally reactive with antisera by Western blotting, this truncated protein did not react with hMPV IgG-positive human sera by EIA. Using 5 synthetic peptides that spanned the amino-terminal portion of the hMPV N protein, we identified a single peptide that was cross-reactive with human sera positive for either virus. Antiserum prepared for this peptide was reactive with recN proteins of both viruses, indicating that a common immunoreactive site exists in this region. PMID:25740767

  11. [Detection and subgrouping of respiratory syncytial virus RNA by real-time RT-PCR].

    PubMed

    Yokoi, Hajime; Tanaka, Toshimitsu; Mizumura, Ayano; Kitahashi, Tomoko

    2012-09-01

    The TaqMan-based quantitative real-time RT-PCR assay we developed uses specific probes to identify respiratory syncytial virus (RSV) and to distinguish RSV subgroups A (RSV-A) and B (RSV-B). We selected conserved regions of the F gene as assay targets and designed new primers and TaqMan MGB probes to detect RSV-A and B. RSV-A and B control plasmids confirmed real-time reverse transcription polymerase chain reaction (RT-PCR) reactivity whose efficiency was 2.5 x 10(1) to 2.5 x 10(7) copies/tube. The assay detection limit was 10 to 10(2) times higher than that of the conventional RT-PCR assay and was equal to the nested PCR assay. No cross-reactions occurred against other respiratory viruses, including influenza virus, metapneumovirus, measles virus, coxsackievirus, enterovirus, echovirus, mumps virus, parainfluenza virus, and rhinovirus. Of 154 clinical specimens derived from subjects with acute respiratory infection and tested by using both real-time RT-PCR and nested PCR, 40 were RSV-positive in both assays. Of these, 25 were identified as RSV-A and 15 as RSV-B by both assays. There was 100% concordance in RSV subgroup identification between real-time RT-PCR and nested PCR assays. These results indicate that our real-time RT-PCR assay can be used for rapid detection, quantitative analysis and subgrouping of RSV-A and RSV-B.

  12. New Host Factors Important for Respiratory Syncytial Virus (RSV) Replication Revealed by a Novel Microfluidics Screen for Interactors of Matrix (M) Protein*

    PubMed Central

    Kipper, Sarit; Hamad, Samar; Caly, Leon; Avrahami, Dorit; Bacharach, Eran; Jans, David A.; Gerber, Doron; Bajorek, Monika

    2015-01-01

    Although human respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in infants and elderly worldwide, there is no licensed RSV vaccine or effective drug treatment available. The RSV Matrix protein plays key roles in virus life cycle, being found in the nucleus early in infection in a transcriptional inhibitory role, and later localizing in viral inclusion bodies before coordinating viral assembly and budding at the plasma membrane. In this study, we used a novel, high throughput microfluidics platform and custom human open reading frame library to identify novel host cell binding partners of RSV matrix. Novel interactors identified included proteins involved in host transcription regulation, the innate immunity response, cytoskeletal regulation, membrane remodeling, and cellular trafficking. A number of these interactions were confirmed by immunoprecipitation and cellular colocalization approaches. Importantly, the physiological significance of matrix interaction with the actin-binding protein cofilin 1, caveolae protein Caveolin 2, and the zinc finger protein ZNF502 was confirmed. siRNA knockdown of the host protein levels resulted in reduced RSV virus production in infected cells. These results have important implications for future antiviral strategies aimed at targets of RSV matrix in the host cell. PMID:25556234

  13. New host factors important for respiratory syncytial virus (RSV) replication revealed by a novel microfluidics screen for interactors of matrix (M) protein.

    PubMed

    Kipper, Sarit; Hamad, Samar; Caly, Leon; Avrahami, Dorit; Bacharach, Eran; Jans, David A; Gerber, Doron; Bajorek, Monika

    2015-03-01

    Although human respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in infants and elderly worldwide, there is no licensed RSV vaccine or effective drug treatment available. The RSV Matrix protein plays key roles in virus life cycle, being found in the nucleus early in infection in a transcriptional inhibitory role, and later localizing in viral inclusion bodies before coordinating viral assembly and budding at the plasma membrane. In this study, we used a novel, high throughput microfluidics platform and custom human open reading frame library to identify novel host cell binding partners of RSV matrix. Novel interactors identified included proteins involved in host transcription regulation, the innate immunity response, cytoskeletal regulation, membrane remodeling, and cellular trafficking. A number of these interactions were confirmed by immunoprecipitation and cellular colocalization approaches. Importantly, the physiological significance of matrix interaction with the actin-binding protein cofilin 1, caveolae protein Caveolin 2, and the zinc finger protein ZNF502 was confirmed. siRNA knockdown of the host protein levels resulted in reduced RSV virus production in infected cells. These results have important implications for future antiviral strategies aimed at targets of RSV matrix in the host cell.

  14. Phosphorylation of human respiratory syncytial virus P protein at serine 54 regulates viral uncoating

    SciTech Connect

    Asenjo, Ana; Gonzalez-Armas, Juan C.; Villanueva, Nieves

    2008-10-10

    The human respiratory syncytial virus (HRSV) structural P protein, phosphorylated at serine (S) and threonine (T) residues, is a co-factor of viral RNA polymerase. The phosphorylation of S54 is controlled by the coordinated action of two cellular enzymes: a lithium-sensitive kinase, probably glycogen synthetase kinase (GSK-3) {beta} and protein phosphatase 2A (PP2A). Inhibition of lithium-sensitive kinase, soon after infection, blocks the viral growth cycle by inhibiting synthesis and/or accumulation of viral RNAs, proteins and extracellular particles. P protein phosphorylation at S54 is required to liberate viral ribonucleoproteins (RNPs) from M protein, during the uncoating process. Kinase inhibition, late in infection, produces a decrease in genomic RNA and infectious viral particles. LiCl, intranasally applied to mice infected with HRSV A2 strain, reduces the number of mice with virus in their lungs and the virus titre. Administration of LiCl to humans via aerosol should prevent HRSV infection, without secondary effects.

  15. Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity

    PubMed Central

    Hendricks, Matthew R.; Lashua, Lauren P.; Fischer, Douglas K.; Flitter, Becca A.; Eichinger, Katherine M.; Durbin, Joan E.; Sarkar, Saumendra N.; Coyne, Carolyn B.; Empey, Kerry M.; Bomberger, Jennifer M.

    2016-01-01

    Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients’ acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation. PMID:26729873

  16. c-Jun N-terminal kinase activity is required for efficient respiratory syncytial virus production.

    PubMed

    Caly, Leon; Li, Hong-Mei; Bogoyevitch, Marie A; Jans, David A

    2017-01-29

    Respiratory syncytial virus (RSV) is a major cause of respiratory infections in infants and the elderly, leading to more deaths than influenza each year worldwide. With no RSV antiviral or efficacious vaccine currently available, improved understanding of the host-RSV interaction is urgently required. Here we examine the contribution to RSV infection of the host stress-regulated c-Jun N-terminal kinase (JNK), for the first time. Peak JNK1/2 phosphoactivation is observed at ∼24 h post-infection, correlating with the time of virus assembly. The release of infectious RSV virions from infected cells was significantly reduced by either JNK1/2 siRNA knockdown or treatment with the JNK-specific inhibitor, JNK-IN-VIII. High resolution microscopy confirmed RSV accumulation in the host cell cytoplasm. The results implicate JNK1/2 as a key host factor for RSV virus production, raising the possibility of agents targeting JNK activity as potential anti-RSV therapeutics.

  17. Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity.

    PubMed

    Hendricks, Matthew R; Lashua, Lauren P; Fischer, Douglas K; Flitter, Becca A; Eichinger, Katherine M; Durbin, Joan E; Sarkar, Saumendra N; Coyne, Carolyn B; Empey, Kerry M; Bomberger, Jennifer M

    2016-02-09

    Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation.

  18. Secretion of respiratory syncytial virus inhibitors and antibody in human milk throughout lactation.

    PubMed

    Toms, G L; Gardner, P S; Pullan, C R; Scott, M; Taylor, C

    1980-01-01

    Neutralising inhibitors to respiratory syncytial (RS) virus have been demonstrated in the whey of most samples of human milk tested. Although high titres were secreted in colostra of some mothers (1/10-1/2,560; median 1/40) inhibitor levels in milk collected after the first week of lactation were uniformly low (median 1/10). High neutralising titres correlated with high colostral levels of specific antiviral IgA but, unlike neutralising activity, IgA antiviral antibody persisted in the milk of only four of 18 mothers. Similarly, antiviral IgG and IgM antibodies were not generally detected after the first post-partum week. Differences in antibody secretion among mothers did not correlate with differences in total protein or total immunoglobulin secretion, and appeared to reflect maternal immune status. In one mother a marked rise in specific antiviral IgA and IgG secretions during the second and third months of lactation suggested a response to virus infection. The relevance of maternal immunity and colostral and milk antiviral antibody to protection of breast-fed babies from RS-virus bronchiolitis is discussed.

  19. Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons

    PubMed Central

    Makris, Spyridon; Bajorek, Monika; Culley, Fiona J.; Goritzka, Michelle; Johansson, Cecilia

    2016-01-01

    Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections. Immunity to RSV is initiated upon detection of the virus by pattern recognition receptors, such as RIG-I-like receptors. RIG-I-like receptors signal via MAVS to induce the synthesis of proinflammatory mediators, including type I interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. Alveolar macrophages (AMs) are amongst the first cells to encounter invading viruses and the ones producing type I IFNs. However, it is unclear whether IFNs act to prevent AMs from serving as vehicles for viral replication. In this study, primary AMs from MAVS (Mavs-/-)- or type I IFN receptor (Ifnar1-/-)-deficient mice were exposed to RSV ex vivo. Wild-type (wt) AMs but not Mavs-/- and Ifnar1-/- AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/- and Ifnar1-/- AMs accumulated more RSV proteins than wt AMs, but the infection was abortive. Thus, RIG-I-like receptor-MAVS and IFNAR signalling are important for the induction of proinflammatory mediators from AMs upon RSV infection, but this signalling is not central for controlling viral replication. The ability to restrict viral replication makes AMs ideal sensors of RSV infection and important initiators of immune responses in the lung. PMID:27423203

  20. Recognizing the importance of respiratory syncytial virus in chronic obstructive pulmonary disease.

    PubMed

    Ramaswamy, Murali; Groskreutz, Dayna J; Look, Dwight C

    2009-02-01

    Acute exacerbations of chronic obstructive pulmonary disease (COPD) are responsible for a large proportion of the health care dollar expenditure, morbidity, and mortality related to COPD. Respiratory infections are the most common cause of acute exacerbations, but recent evidence indicates that the importance of respiratory syncytial virus (RSV) infection in COPD is under-appreciated. Improved detection of RSV using techniques based on the polymerase chain reaction accounts for much of the increased recognition of the importance of this virus in COPD patients. Furthermore, COPD patients may be more susceptible to RSV infection, possibly due to RSV-or immune response-induced pulmonary effects that are altered by age, environmental exposures, genetics, COPD itself, or a combination of these. However, although RSV infection occurs throughout life, viral and host factors that place COPD patients at increased risk are unclear. The complexities of RSV effects in COPD present opportunities for research with the goal of developing approaches to selectively modify damaging viral effects (e.g., altered airway function), while retaining beneficial immunity (e.g., clearance of virus) in COPD patients. This review explores the role RSV plays in acute exacerbations of COPD, the potential for RSV disease in chronic stable COPD, and newer concepts in RSV diagnosis, epidemiology, and host defense.

  1. Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors.

    PubMed

    Grandin, Clément; Hourani, Marianne-Lucas; Janin, Yves L; Dauzonne, Daniel; Munier-Lehmann, Hélène; Paturet, Adeline; Taborik, Fabrice; Vabret, Astrid; Contamin, Hugues; Tangy, Frédéric; Vidalain, Pierre-Olivier

    2016-01-01

    There is imperious need for efficient therapies against ubiquitous and life-threatening respiratory viruses, foremost among them being the human respiratory syncytial virus (hRSV). Several research groups who performed functional screens for broad-spectrum antivirals identified compounds targeting the de novo pyrimidine biosynthesis pathway. Despite their strong antiviral activity in vitro, whether such antimetabolites are effective in vivo remains highly controversial. Here, we evaluated two potent pyrimidine biosynthesis inhibitors developed in our laboratory, IPPA17-A04 and GAC50, in a model of mild hRSV-infection in cynomolgus macaques. In this model, hRSV replication is restricted to the epithelium of the upper respiratory tract, and is compatible with a topical treatment by intranasal sprays. The local administration of palivizumab, a neutralizing anti-hRSV antibody used in clinics, significantly reduced virus replication. In contrast, pyrimidine biosynthesis inhibitors did not show any inhibitory effect on hRSV growth when delivered topically as experimented in our model. Our results should help to better define the potential applications of this class of antimetabolites in the treatment of viral infections. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Respiratory syncytial virus shedding by children hospitalized with lower respiratory tract infection.

    PubMed

    Takeyama, Aya; Hashimoto, Koichi; Sato, Masatoki; Kawashima, Ryoko; Kawasaki, Yukihiko; Hosoya, Mitsuaki

    2016-06-01

    Children with respiratory syncytial virus (RSV) infection shed virus for variable periods. The aim of this study was to quantify the viral load in nasopharyngeal aspirates of children with RSV throughout their hospitalization. This study included 37 children who were admitted with a diagnosis of RSV infection based on a positive rapid diagnostic test. Nasopharyngeal aspirates were collected from patients every day, from admission to discharge. Viral detection and quantification were performed using quantitative real-time PCR. Of the 37 patients, RSV-A was detected in 29 and RSV-B in 6. Two patients were PCR-negative for any type of RSV. RSV-A was detected in 12 of 16 patients (75%) 6 days after admission. These patients shed detectable virus from days 1 to 12, and for a significantly longer period (mean 5.7 days) than RSV-B (mean 3.8 days) patients. Half of the RSV-A patients were also positive on day 14 following onset. RSV-A was detected in patients <12 months of age for significantly longer periods after onset than in patients ≥12 months of age. RSV-A viral load was negatively correlated with days from admission and days from onset. Because RSV shedding was frequently prolonged, the hospitalized children may have contracted RSV as a nosocomial infection. To prevent nosocomial RSV infections in hospital wards, healthcare workers must take appropriate infection control measures and provide adequate guidance on hand washing to the family of the patient.

  3. An attraction-repulsion point process model for respiratory syncytial virus infections.

    PubMed

    Goldstein, Joshua; Haran, Murali; Simeonov, Ivan; Fricks, John; Chiaromonte, Francesca

    2015-06-01

    How is the progression of a virus influenced by properties intrinsic to individual cells? We address this question by studying the susceptibility of cells infected with two strains of the human respiratory syncytial virus (RSV-A and RSV-B) in an in vitro experiment. Spatial patterns of infected cells give us insight into how local conditions influence susceptibility to the virus. We observe a complicated attraction and repulsion behavior, a tendency for infected cells to lump together or remain apart. We develop a new spatial point process model to describe this behavior. Inference on spatial point processes is difficult because the likelihood functions of these models contain intractable normalizing constants; we adapt an MCMC algorithm called double Metropolis-Hastings to overcome this computational challenge. Our methods are computationally efficient even for large point patterns consisting of over 10,000 points. We illustrate the application of our model and inferential approach to simulated data examples and fit our model to various RSV experiments. Because our model parameters are easy to interpret, we are able to draw meaningful scientific conclusions from the fitted models.

  4. Premature infants have impaired airway antiviral IFNγ responses to human metapneumovirus compared to respiratory syncytial virus

    PubMed Central

    Pancham, Krishna; Perez, Geovanny F.; Huseni, Shehlanoor; Jain, Amisha; Kurdi, Bassem; Rodriguez-Martinez, Carlos E.; Preciado, Diego; Rose, Mary C.; Nino, Gustavo

    2017-01-01

    BACKGROUND It is unknown why human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) cause severe respiratory infection in children, particularly in premature infants. Our aim was to investigate if there are defective airway antiviral responses to these viruses in young children with history of prematurity. METHODS Nasal airway secretions were collected from 140 children ≤3 y old without detectable virus (n = 80) or with PCR-confirmed HMPV or RSV infection (n = 60). Nasal protein levels of IFNγ, CCL5/RANTES, IL-10, IL-4, and IL-17 were determined using a multiplex magnetic bead immunoassay. RESULTS Full-term children with HMPV and RSV infection had increased levels of nasal airway IFNγ, CCL5, and IL-10 along with an elevation in Th1 (IFNγ)/Th2 (IL-4) ratios, which is expected during antiviral responses. In contrast, HMPV-infected premature children (< 32 wk gestation) did not exhibit increased Th1/Th2 ratios or elevated nasal airway secretion of IFNγ, CCL5, and IL-10 relative to uninfected controls. CONCLUSION Our study is the first to demonstrate that premature infants have defective IFNγ, CCL5/RANTES, and IL-10 airway responses during HMPV infection and provides novel insights about the potential reason why HMPV causes severe respiratory disease in children with history of prematurity. PMID:26086642

  5. A study of the genetic variability of human respiratory syncytial virus in Croatia, 2006-2008.

    PubMed

    Forcic, Dubravko; Ivancic-Jelecki, Jelena; Mlinaric-Galinovic, Gordana; Vojnovic, Gordana; Babic-Erceg, Andrea; Tabain, Irena

    2012-12-01

    Human respiratory syncytial virus (HRSV) is a common etiological agent of acute lower respiratory tract disease in infants. The molecular epidemiology of HRSV in Croatia over four consecutive seasons (from 2006 to 2008) was investigated. A total of 72 HRSV samples were chosen from 696 screened cases in a pediatric clinic in Zagreb. Molecular characterization of HRSV revealed the predominance of HRSV group B viruses in the first two epidemic seasons and HRSV group A viruses in the next two seasons. According to the phylogenetic analysis, NA1 and BA9 were the predominant circulating HRSV genotypes detected during the study. Overall, 82.9% of all HRSV A strains belonged to the NA1 genotype. The HRSV B genotype BA9, detected in two consecutive seasons (2006 and 2007), was the predominant circulating HRSV B genotype, accounting for 80.6% of all HRSV B strains. This study provides data on the circulation pattern of HRSV genotypes in Croatia and their molecular characterization.

  6. IL-9 regulates pathology during primary and memory responses to respiratory syncytial virus infection.

    PubMed

    Dodd, Jonathan S; Lum, Eda; Goulding, John; Muir, Roshell; Van Snick, Jacques; Openshaw, Peter J M

    2009-12-01

    IL-9 is a cytokine of great current interest associated with allergic/Th2 responses. High levels of IL-9 are present in bronchial secretions from infants with respiratory syncytial virus (RSV) bronchiolitis. To test its effects in RSV disease with a Th2 profile, BALB/c mice were vaccinated with recombinant vaccinia virus expressing the RSV G protein. On RSV challenge, immunized mice developed augmented disease characterized by enhanced pulmonary Th2 and local IL-9 production peaking on days 7-10 of RSV infection. Depletion with anti-IL-9 Ab at vaccination or RSV challenge enhanced viral clearance. Depletion only at challenge had no effect on disease severity, whereas depletion at immunization and challenge enhanced Th1 responses, inhibited virus-specific IgG1 production, and enhanced disease severity. By contrast, depletion of IL-9 at immunization boosted IgG2a and inhibited the Th2 response and disease during subsequent infection without a concomitant increase in type 1 cytokines. Adoptive transfer of secondary memory CD4 T cells from the spleens of IL-9-depleted mice into naive recipients replicated many of the effects of depletion, indicating that IL-9 acts via CD4 T cells. Therefore, IL-9 is a previously unknown but key modulator of antiviral immunity, regulating T and B cell responses and having potent and specific effects on viral lung disease.

  7. Human respiratory syncytial virus Memphis 37 grown in HEp-2 cells causes more severe disease in lambs than virus grown in vero cells

    USDA-ARS?s Scientific Manuscript database

    Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants and young children. A small percentage of these individuals develop severe and even fatal disease. To better understand the pathogenesis of severe disease and develop therapies unique to the less-developed infan...

  8. Differences in viral load among human respiratory syncytial virus genotypes in hospitalized children with severe acute respiratory infections in the Philippines.

    PubMed

    Kadji, Francois Marie Ngako; Okamoto, Michiko; Furuse, Yuki; Tamaki, Raita; Suzuki, Akira; Lirio, Irene; Dapat, Clyde; Malasao, Rungnapa; Saito, Mariko; Pedrera-Rico, Gay Anne Granada; Tallo, Veronica; Lupisan, Socorro; Saito, Mayuko; Oshitani, Hitoshi

    2016-06-27

    Human respiratory syncytial virus (HRSV) is a leading viral etiologic agent of pediatric lower respiratory infections, including bronchiolitis and pneumonia. Two antigenic subgroups, HRSV-A and B, each contain several genotypes. While viral load may vary among HRSV genotypes and affect the clinical course of disease, data are scarce regarding the actual differences among genotypes. Therefore, this study estimated and compared viral load among NA1 and ON1 genotypes of HRSV-A and BA9 of HRSV-B. ON1 is a newly emerged genotype with a 72-nucleotide duplication in the G gene as observed previously with BA genotypes in HRSV-B. Children <5 years of age with an initial diagnosis of severe or very severe pneumonia at a hospital in the Philippines from September 2012 to December 2013 were enrolled. HRSV genotypes were determined and the viral load measured from nasopharyngeal swabs (NPS). The viral load of HRSV genotype NA1 were significantly higher than those of ON1 and BA9. Regression analysis showed that both genotype NA1 and younger age were significantly associated with high HRSV viral load. The viral load of NA1 was higher than that of ON1 and BA9 in NPS samples. HRSV genotypes may be associated with HRSV viral load. The reasons and clinical impacts of these differences in viral load among HRSV genotypes require further evaluation.

  9. Molecular epidemiology of the SH (small hydrophobic) gene of human respiratory syncytial virus (HRSV), over 2 consecutive years.

    PubMed

    Lima, Hildenêr Nogueira; Botosso, Viviane Fongaro; Oliveira, Danielle Bruna Leal; Campos, Angélica Cristine de Almeida; Leal, Andrea Lima; Silva, Tereza Souza; Bosso, Patrícia Alves Ramos; Moraes, Claudia Trigo Pedroso; Filho, Claudionor Gomes da Silva; Vieira, Sandra Elisabete; Gilio, Alfredo Elias; Stewien, Klaus Eberhard; Durigon, Edison Luiz

    2012-01-01

    Human respiratory syncytial virus (HRSV) strains were isolated from nasopharyngeal aspirates collected from 965 children between 2004 and 2005, yielding 424 positive samples. We sequenced the small hydrophobic protein (SH) gene of 117 strains and compared them with other viruses identified worldwide. Phylogenetic analysis showed a low genetic variability among the isolates but allowed us to classify the viruses into different genotypes for both groups, HRSVA and HRSVB. It is also shown that the novel BA-like genotype was well segregated from the others, indicating that the mutations are not limited to the G gene.

  10. A dynamic cell entry pathway of respiratory syncytial virus revealed by tracking the quantum dot-labeled single virus.

    PubMed

    Zheng, Lin Ling; Li, Chun Mei; Zhen, Shu Jun; Li, Yuan Fang; Huang, Cheng Zhi

    2017-06-14

    Studying the cell entry pathway at the single-particle level can provide detailed and quantitative information for the dynamic events involved in virus entry. Indeed, the viral entry dynamics cannot be monitored by static staining methods used in cell biology, and thus virus dynamic tracking could be useful in the development of effective antiviral strategies. Therefore, the aim of this work was to use a quantum dot-based single-particle tracking approach to monitor the cell entry behavior of the respiratory syncytial virus (RSV) in living cells. The time-lapse fluorescence imaging and trajectory analysis of the quantum dot-labeled RSV showed that RSV entry into HEp-2 cells consisted of a typical endocytosis trafficking process. Three critical events during RSV entry were observed according to entry dynamic and fluorescence colocalization analysis. Firstly, RSV was attached to lipid rafts of the cell membrane, and then it was efficiently delivered into the perinuclear region within 2 h post-infection, mostly moving and residing into the lysosome compartment. Moreover, the relatively slow velocity of RSV transport across the cytoplasm and the formation of the actin tail indicated actin-based RSV motility, which was also confirmed by the effects of cytoskeletal inhibitors. Taken together, these findings provided new insights into the RSV entry mechanism and virus-cell interactions in RSV infection that could be beneficial in the development of antiviral drugs and vaccines.

  11. Evidence that the respiratory syncytial virus polymerase complex associates with lipid rafts in virus-infected cells: a proteomic analysis

    SciTech Connect

    McDonald, Terence P.; Pitt, Andrew R.; Brown, Gaie; Rixon, Helen W. McL.; Sugrue, Richard J. . E-mail: r.sugrue@vir.gla.ac.uk

    2004-12-05

    The interaction between the respiratory syncytial virus (RSV) polymerase complex and lipid rafts was examined in HEp2 cells. Lipid-raft membranes were prepared from virus-infected cells and their protein content was analysed by Western blotting and mass spectrometry. This analysis revealed the presence of the N, P, L, M2-1 and M proteins. However, these proteins appeared to differ from one another in their association with these structures, with the M2-1 protein showing a greater partitioning into raft membranes compared to that of the N, P or M proteins. Determination of the polymerase activity profile of the gradient fractions revealed that 95% of the detectable viral enzyme activity was associated with lipid-raft membranes. Furthermore, analysis of virus-infected cells by confocal microscopy suggested an association between these proteins and the raft-lipid, GM1. Together, these results provide evidence that the RSV polymerase complex is able to associate with lipid rafts in virus-infected cells.

  12. Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.

    PubMed

    Tonelli, Michele; Naesens, Lieve; Gazzarrini, Sabrina; Santucci, Matteo; Cichero, Elena; Tasso, Bruno; Moroni, Anna; Costi, Maria Paola; Loddo, Roberta

    2017-07-28

    We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC50 = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC50 = 5.8 μM, SI > 43). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Actin-Related Protein 2 (ARP2) and Virus-Induced Filopodia Facilitate Human Respiratory Syncytial Virus Spread

    PubMed Central

    McCarty, Thomas; Martin, Scott E.; Le Nouën, Cyril; Buehler, Eugen; Chen, Yu-Chi; Smelkinson, Margery; Ganesan, Sundar; Fischer, Elizabeth R.; Brock, Linda G.; Liang, Bo; Munir, Shirin; Collins, Peter L.; Buchholz, Ursula J.

    2016-01-01

    Human respiratory syncytial virus (RSV) is an enveloped RNA virus that is the most important viral cause of acute pediatric lower respiratory tract illness worldwide, and lacks a vaccine or effective antiviral drug. The involvement of host factors in the RSV replicative cycle remains poorly characterized. A genome-wide siRNA screen in human lung epithelial A549 cells identified actin-related protein 2 (ARP2) as a host factor involved in RSV infection. ARP2 knockdown did not reduce RSV entry, and did not markedly reduce gene expression during the first 24 hr of infection, but decreased viral gene expression thereafter, an effect that appeared to be due to inhibition of viral spread to neighboring cells. Consistent with reduced spread, there was a 10-fold reduction in the release of infectious progeny virions in ARP2-depleted cells at 72 hr post-infection. In addition, we found that RSV infection induced filopodia formation and increased cell motility in A549 cells and that this phenotype was ARP2 dependent. Filopodia appeared to shuttle RSV to nearby uninfected cells, facilitating virus spread. Expression of the RSV F protein alone from a plasmid or heterologous viral vector in A549 cells induced filopodia, indicating a new role for the RSV F protein, driving filopodia induction and virus spread. Thus, this study identified roles for ARP2 and filopodia in RSV-induced cell motility, RSV production, and RSV cell-to-cell spread. PMID:27926942

  14. Estimating the hospitalization burden associated with influenza and respiratory syncytial virus in New York City, 2003-2011.

    PubMed

    Goldstein, Edward; Greene, Sharon K; Olson, Donald R; Hanage, William P; Lipsitch, Marc

    2015-09-01

    Hospitalization burden associated with influenza and respiratory syncytial virus (RSV) is uncertain due to ambiguity in the inference methodologies employed for its estimation. Utilization of a new method to quantitate the above burden. Weekly hospitalization rates for several principal diagnoses from 2003 to 2011 in New York City by age group were regressed linearly against incidence proxies for the major influenza subtypes and RSV adjusting for temporal trends and seasonal baselines. Average annual rates of influenza-associated respiratory hospitalizations per 100 000 were estimated to be 129 [95% CI (79, 179)] for age <1, 36·3 (21·6, 51·4) for ages 1-4, 10·6 (7·5, 13·7) for ages 5-17, 25·6 (21·3, 29·8) for ages 18-49, 65·5 (54·0, 76·9) for ages 50-64, 125 (105, 147) for ages 65-74, and 288 (244, 331) for ages ≥75. Additionally, influenza had a significant contribution to hospitalization rates with a principal diagnosis of septicemia for ages 5-17 [0·76 (0·1, 1·4)], 18-49 [1·02 (0·3, 1·7)], 50-64 [4·0 (1·7, 6·3)], 65-74 [8·8 (2·2, 15·6)], and ≥75 [38·7 (25·7, 52·9)]. RSV had a significant contribution to the rates of respiratory hospitalizations for age <1 [1900 (1740, 2060)], ages 1-4 [117 (70, 167)], and ≥75 [175 (44, 312)] [including chronic lower respiratory disease, 90 (43, 140)] as well as pneumonia & influenza hospitalizations for ages 18-49 [6·2 (1·1, 11·3)] and circulatory hospitalizations for ages ≥75 [199 (13, 375)]. The high burden of RSV hospitalizations among young children and seniors age ≥75 suggests the need for additional control measures such as vaccination to mitigate the impact of annual RSV epidemics. Our estimates for influenza-associated hospitalizations provide further evidence of the burden of morbidity associated with influenza, supporting current guidelines regarding influenza vaccination and antiviral treatment. © 2015 The Authors. Influenza and Other Respiratory Viruses Published by John

  15. Relating plaque morphology to respiratory syncytial virus subgroup, viral load, and disease severity in children.

    PubMed

    Kim, Young-In; Murphy, Ryan; Majumdar, Sirshendu; Harrison, Lisa G; Aitken, Jody; DeVincenzo, John P

    2015-10-01

    Viral culture plaque morphology in human cell lines are markers for growth capability and cytopathic effect, and have been used to assess viral fitness and select preattenuation candidates for live viral vaccines. We classified respiratory syncytial virus (RSV) plaque morphology and analyzed the relationship between plaque morphology as compared to subgroup, viral load and clinical severity of infection in infants and children. We obtained respiratory secretions from 149 RSV-infected children. Plaque morphology and viral load was assessed within the first culture passage in HEp-2 cells. Viral load was measured by polymerase chain reaction (PCR), as was RSV subgroup. Disease severity was determined by hospitalization, length of stay, intensive care requirement, and respiratory failure. Plaque morphology varied between individual subjects; however, similar results were observed among viruses collected from upper and lower respiratory tracts of the same subject. Significant differences in plaque morphology were observed between RSV subgroups. No correlations were found among plaque morphology and viral load. Plaque morphology did not correlate with disease severity. Plaque morphology measures parameters that are viral-specific and independent of the human host. Morphologies vary between patients and are related to RSV subgroup. In HEp-2 cells, RSV plaque morphology appears unrelated to disease severity in RSV-infected children.

  16. Respiratory Syncytial Virus and Cellular Stress Responses: Impact on Replication and Physiopathology

    PubMed Central

    Cervantes-Ortiz, Sandra L.; Zamorano Cuervo, Natalia; Grandvaux, Nathalie

    2016-01-01

    Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is a major cause of severe acute lower respiratory tract infection in infants, elderly and immunocompromised adults. Despite decades of research, a complete integrated picture of RSV-host interaction is still missing. Several cellular responses to stress are involved in the host-response to many virus infections. The endoplasmic reticulum stress induced by altered endoplasmic reticulum (ER) function leads to activation of the unfolded-protein response (UPR) to restore homeostasis. Formation of cytoplasmic stress granules containing translationally stalled mRNAs is a means to control protein translation. Production of reactive oxygen species is balanced by an antioxidant response to prevent oxidative stress and the resulting damages. In recent years, ongoing research has started to unveil specific regulatory interactions of RSV with these host cellular stress responses. Here, we discuss the latest findings regarding the mechanisms evolved by RSV to induce, subvert or manipulate the ER stress, the stress granule and oxidative stress responses. We summarize the evidence linking these stress responses with the regulation of RSV replication and the associated pathogenesis. PMID:27187445

  17. Clinical outcomes in outpatient respiratory syncytial virus infection in immunocompromised children.

    PubMed

    Chu, Helen Y; Chin, Jennifer; Pollard, Jessica; Zerr, Danielle M; Englund, Janet A

    2016-05-01

    Immunocompromised patients are at high risk for morbidity and mortality due to respiratory syncytial virus (RSV) infection. Increasingly, pediatric patients with malignancy or undergoing transplantation are managed primarily as outpatients. Data regarding the clinical presentation and outcomes of RSV in the outpatient pediatric immunocompromised population are limited. We performed a retrospective cohort study of children with hematologic malignancy or hematopoietic or solid organ transplant with laboratory-confirmed RSV infection diagnosed as outpatients at an academic medical center between 2008 and 2013. Of 54 patients with RSV detected while outpatients, 15 (28%) were hospitalized, 7 (13%) received ribavirin, and one (2%) received intravenous immunoglobulin. One (2%) patient was critically ill, but there were no deaths due to RSV infection. Fever (P < 0·01) was associated with increased risk of hospitalization. Most immunocompromised children with RSV detected while outpatients did not require hospitalization or receive antiviral treatment. Potential studies of RSV therapies should consider inclusion of patients in an ambulatory setting. © 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

  18. Viral Load Drives Disease in Humans Experimentally Infected with Respiratory Syncytial Virus

    PubMed Central

    DeVincenzo, John P.; Wilkinson, Tom; Vaishnaw, Akshay; Cehelsky, Jeff; Meyers, Rachel; Nochur, Saraswathy; Harrison, Lisa; Meeking, Patricia; Mann, Alex; Moane, Elizabeth; Oxford, John; Pareek, Rajat; Moore, Ryves; Walsh, Ed; Studholme, Robert; Dorsett, Preston; Alvarez, Rene; Lambkin-Williams, Robert

    2010-01-01

    Rationale: Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties in performing pediatric proof-of-concept studies and the prevailing concept that the disease is immune-mediated rather than being driven by viral load. Objectives: The development of a human experimental wild-type RSV infection model to address these challenges. Methods: Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3.0–5.4 log plaque-forming units/person) of wild-type RSV-A intranasally. Measurements and Main Results: Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity, and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by real-time polymerase chain reaction) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6 and IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical examination, and amount of nasal mucus). Conclusions: Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates the development of future RSV therapeutics. PMID:20622030

  19. Bronchiolitis outbreak caused by respiratory syncytial virus in southwest Bangladesh, 2010☆

    PubMed Central

    Haque, Farhana; Husain, M. Mushtuq; Ameen, Kazi Mohammad Hassan; Rahima, Refat; Hossain, M. Jahangir; Alamgir, A.S.M.; Rahman, Mustafizur; Rahman, Mahmudur; Luby, Stephen P.

    2015-01-01

    SUMMARY Background During July 2010, newspapers reported a respiratory disease outbreak in southwestern Bangladesh resulting in the admission of children to a secondary care hospital. We investigated this outbreak to determine the etiology and explore possible risk factors. Methods The hospital’s physician diagnosed children aged <2 years with cough, tachypnea or dyspnea, and expiratory wheeze as having acute bronchiolitis. We reviewed the hospital records and listed case patients admitted between 26 June and 26 July 2010. We surveyed the case patients and collected nasal and throat swabs to test for respiratory viruses. Results We identified 101 admitted acute bronchiolitis case patients. Fifty-nine (58%) of these were admitted between 16 and 20 July. Among the 29 case patients surveyed, the median age was 4 months and 65% were males. We identified respiratory syncytial virus (RSV) in 91% (21/23) of the samples, 43% of which had a dual viral infection. Most case patients (90%) were treated with broad-spectrum antibiotics. There were no reported deaths. Conclusions The sudden increase in admitted acute bronchiolitis case patients, their median age, and identification of RSV in the majority of samples suggest an outbreak of RSV bronchiolitis. Research to identify strategies to prevent respiratory infections including RSV in low-income settings should be prioritized. Factors that perpetuate antibiotic use in managing this viral syndrome should also be explored. PMID:22938872

  20. Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus

    PubMed Central

    Killikelly, April M.; Kanekiyo, Masaru; Graham, Barney S.

    2016-01-01

    The lack of a licensed vaccine for respiratory syncytial virus (RSV) can be partly attributed to regulatory hurdles resulting from vaccine enhanced respiratory disease (ERD) subsequent to natural RSV infection that was observed in clinical trials of formalin-inactivated RSV (FI-RSV) in antigen-naïve infants. To develop an effective vaccine that does not enhance RSV illness, it is important to understand how formalin and heat inactivation affected the antigenicity and immunogenicity of FI-RSV compared to native virus. Informed by atomic structures of RSV fusion (F) glycoprotein in prefusion (pre-F) and postfusion (post-F) conformations, we demonstrate that FI-RSV predominately presents post-F on the virion surface, whereas infectious RSV presents both pre-F and post-F conformations. This significant antigenic distinction has not been previously appreciated. Thus, a stabilized pre-F antigen is more representative of live RSV than F in its post-F conformation, as displayed on the surface of FI-RSV. This finding has major implications for discriminating current pre-F-based immunogens from FI-RSV used in historical vaccine trials. PMID:27682426

  1. A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection.

    PubMed

    Ciencewicki, Jonathan M; Wang, Xuting; Marzec, Jacqui; Serra, M Elina; Bell, Douglas A; Polack, Fernando P; Kleeberger, Steven R

    2014-04-01

    Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract infection during childhood and causes severe symptoms in some patients, which may cause hospitalization and death. Mechanisms for differential responses to RSV are unknown. Our objective was to develop an in vitro model of RSV infection to evaluate interindividual variation in response to RSV and identify susceptibility genes. Populations of human-derived HapMap lymphoblastoid cell lines (LCLs) were infected with RSV. Compared with controls, RSV-G mRNA expression varied from ~1- to 400-fold between LCLs. Basal expression of a number of gene transcripts, including myxovirus (influenza virus) resistance 1 (MX1), significantly correlated with RSV-G expression in HapMap LCLs. Individuals in a case-control population of RSV-infected children who were homozygous (n=94) or heterozygous (n=172) for the predicted deleterious A allele in a missense G/A SNP in MX1 had significantly greater risk for developing severe RSV disease relative to those with the major allele (n=108) (χ(2)=5.305, P=0.021; OR: 1.750, 95% CI: 1.110, 2.758, P=0.021). We conclude that genetically diverse human LCLs enable identification of susceptibility genes (e.g., MX1) for RSV disease severity in children, providing insight for disease risk.

  2. Evidence for an intranasal immune response to human respiratory syncytial virus infection in cynomolgus macaques.

    PubMed

    Grandin, Clément; Lucas-Hourani, Marianne; Clavel, Marine; Taborik, Fabrice; Vabret, Astrid; Tangy, Frédéric; Contamin, Hugues; Vidalain, Pierre-Olivier

    2015-04-01

    There is no large-scale therapy available against human respiratory syncytial virus (hRSV), a major pathogen responsible for acute respiratory diseases. Macaques represent an interesting animal model to evaluate potential treatments because of their genetic, anatomical and immunological proximity with humans. However, the parameters that influence hRSV growth and control in this model are still poorly understood. We have documented in the following study the influence of age as well as repeated infections on the virological, clinical and immunological parameters of this animal model. Following intranasal inoculation, hRSV replicated in the upper respiratory tract for less than 15 days with no clinical signs regardless of age. Interestingly, we observed the induction of a local immune response at the nasal mucosa as assessed by expression profiles of inflammatory and IFN-stimulated genes. Animals also developed specific antibodies and were immune to reinfection. Thus, we showed that even in infant macaques, intranasal hRSV infection induced both local and systemic immune responses to efficiently control the virus.

  3. Biophysical characterization of G protein ectodomain of group B human respiratory syncytial virus from E. coli.

    PubMed

    Khan, Wajihul Hasan; Srungaram, V L N Raghuram; Islam, Asimul; Beg, Ilyas; Haider, Md Shakir H; Ahmad, Faizan; Broor, Shobha; Parveen, Shama

    2016-07-03

    Human respiratory syncytial virus (hRSV) is an important pathogen of acute respiratory tract infection. The G protein of hRSV is a transmembrane glycoprotein that is a neutralizing antigen and is thus a vaccine candidate. In this study, synthetic codon optimized ectodomain G protein [G(ΔTM)] of BA genotype of group B hRSV was cloned, expressed, and characterized using biophysical techniques. The molar absorption coefficient and mean residue ellipticity at 222 nm ([θ]222) of G (ΔTM) was found to be 7950 M(-1) cm(-1) and -19701.7 deg cm(2) dmol(-1) respectively. It was concluded that G(ΔTM) mainly consist of α-helix (74.9%) with some amount of β-sheet (4%). The protein was stable up to 85°C without any transition curve. However, heat-induced denaturation of G(ΔTM) resulted in total loss of β-sheet whereas not much change was observed in the α-helix part of the secondary structure. It was concluded that G(ΔTM) is an α-helical protein and it is highly stable at high temperature, but could be easily denatured using high concentrations of GdmCl/urea or acidic condition. This is the first investigation of cloning, expression, and characterization of G(ΔTM) of BA viruses from India. Structural characterization of G protein will assist in drug designing and vaccine development for hRSV.

  4. Heme Oxygenase-1 Modulates Human Respiratory Syncytial Virus Replication and Lung Pathogenesis during Infection.

    PubMed

    Espinoza, Janyra A; León, Miguel A; Céspedes, Pablo F; Gómez, Roberto S; Canedo-Marroquín, Gisela; Riquelme, Sebastían A; Salazar-Echegarai, Francisco J; Blancou, Phillipe; Simon, Thomas; Anegon, Ignacio; Lay, Margarita K; González, Pablo A; Riedel, Claudia A; Bueno, Susan M; Kalergis, Alexis M

    2017-07-01

    Human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in children. The development of novel prophylactic and therapeutic antiviral drugs against hRSV is imperative to control the burden of disease in the susceptible population. In this study, we examined the effects of inducing the activity of the host enzyme heme oxygenase-1 (HO-1) on hRSV replication and pathogenesis on lung inflammation induced by this virus. Our results show that after hRSV infection, HO-1 induction with metalloporphyrin cobalt protoporphyrin IX significantly reduces the loss of body weight due to hRSV-induced disease. Further, HO-1 induction also decreased viral replication and lung inflammation, as evidenced by a reduced neutrophil infiltration into the airways, with diminished cytokine and chemokine production and reduced T cell function. Concomitantly, upon cobalt protoporphyrin IX treatment, there is a significant upregulation in the production of IFN-α/β mRNAs in the lungs. Furthermore, similar antiviral and protective effects occur by inducing the expression of human HO-1 in MHC class II(+) cells in transgenic mice. Finally, in vitro data suggest that HO-1 induction can modulate the susceptibility of cells, especially the airway epithelial cells, to hRSV infection. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. Mapping the anatomy of respiratory syncytial virus infection of the upper airways in chinchillas (Chinchilla lanigera).

    PubMed

    Grieves, Jessica L; Jurcisek, Joseph A; Quist, Brian; Durbin, Russell K; Peeples, Mark E; Durbin, Joan E; Bakaletz, Lauren O

    2010-06-01

    Although most viral infections of the upper respiratory tract can predispose to bacterial otitis media, human respiratory syncytial virus (HRSV) is the predominant viral copathogen of this highly prevalent pediatric polymicrobial disease. Rigorous study of the specific mechanisms by which HRSV predisposes to otitis media has been hindered by lack of a relevant animal model. We recently reported that the chinchilla, the preferred rodent host for studying otitis media, is semipermissive for upper-airway HRSV infection. In the current study, we defined the anatomy and kinetics of HRSV infection and spread in the upper airway of chinchilla hosts. Chinchillas were challenged intranasally with a fluorescent-protein-expressing HRSV. Upper-airway tissues were recovered at multiple time points after viral challenge and examined by confocal microscopy and immunohistochemistry. HRSV replication was observed from the rostral- to caudalmost regions of the nasal cavity as well as throughout the Eustachian tube in a time-dependent manner. Although fluorescence was not observed and virus was not detected in nasopharyngeal lavage fluids 14 d after infection, the latest time point examined in this study, occasional clusters of immunopositive cells were present, suggesting that the nasal cavity may serve as a reservoir for HRSV. These data provide important new information concerning the time course of HRSV infection of the uppermost airway and suggest that chinchillas may be useful for modeling the HRSV-induced changes that predispose to secondary bacterial infection.

  6. Identification of a Linear Heparin Binding Domain for Human Respiratory Syncytial Virus Attachment Glycoprotein G

    PubMed Central

    Feldman, Steven A.; Hendry, R. Michael; Beeler, Judy A.

    1999-01-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children worldwide. Infection is mediated, in part, by an initial interaction between attachment protein (G) and a highly sulfated heparin-like glycosaminoglycan (Gag) located on the cell surface. Synthetic overlapping peptides derived from consensus sequences of the G protein ectodomain from both RSV subgroups A and B were tested by heparin-agarose affinity chromatography for their abilities to bind heparin. This evaluation identified a single linear heparin binding domain (HBD) for RSV subgroup A (184A→T198) and B (183K→K197). The binding of these peptides to Vero cells was inhibited by heparin. Peptide binding to two CHO cell mutants (pgsD-677 and pgsA-745) deficient in heparan sulfate or total Gag synthesis was decreased 50% versus the parental cell line, CHO-K1, and decreased an average of 87% in the presence of heparin. The RSV-G HBD peptides were also able to inhibit homologous and heterologous virus infectivity of Vero cells. These results indicate that the sequence 184A/183K→198T/K197 for RSV subgroups A and B, respectively, defines an important determinant of RSV-G interactions with heparin. PMID:10400758

  7. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years.

    PubMed

    Collins, Peter L; Melero, José A

    2011-12-01

    Human respiratory syncytial virus (RSV) is a ubiquitous pathogen that infects everyone worldwide early in life and is a leading cause of severe lower respiratory tract disease in the pediatric population as well as in the elderly and in profoundly immunosuppressed individuals. RSV is an enveloped, nonsegmented negative-sense RNA virus that is classified in Family Paramyxoviridae and is one of its more complex members. Although the replicative cycle of RSV follows the general pattern of the Paramyxoviridae, it encodes additional proteins. Two of these (NS1 and NS2) inhibit the host type I and type III interferon (IFN) responses, among other functions, and another gene encodes two novel RNA synthesis factors (M2-1 and M2-2). The attachment (G) glycoprotein also exhibits unusual features, such as high sequence variability, extensive glycosylation, cytokine mimicry, and a shed form that helps the virus evade neutralizing antibodies. RSV is notable for being able to efficiently infect early in life, with the peak of hospitalization at 2-3 months of age. It also is notable for the ability to reinfect symptomatically throughout life without need for significant antigenic change, although immunity from prior infection reduces disease. It is widely thought that re-infection is due to an ability of RSV to inhibit or subvert the host immune response. Mechanisms of viral pathogenesis remain controversial. RSV is notable for a historic, tragic pediatric vaccine failure involving a formalin-inactivated virus preparation that was evaluated in the 1960s and that was poorly protective and paradoxically primed for enhanced RSV disease. RSV also is notable for the development of a successful strategy for passive immunoprophylaxis of high-risk infants using RSV-neutralizing antibodies. Vaccines and new antiviral drugs are in pre-clinical and clinical development, but controlling RSV remains a formidable challenge. Published by Elsevier B.V.

  8. Gene Sequence Variability of the Three Surface Proteins of Human Respiratory Syncytial Virus (HRSV) in Texas

    PubMed Central

    Tapia, Lorena I.; Shaw, Chad A.; Aideyan, Letisha O.; Jewell, Alan M.; Dawson, Brian C.; Haq, Taha R.; Piedra, Pedro A.

    2014-01-01

    Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004–2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site Ø in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community. PMID:24625544

  9. Gene sequence variability of the three surface proteins of human respiratory syncytial virus (HRSV) in Texas.

    PubMed

    Tapia, Lorena I; Shaw, Chad A; Aideyan, Letisha O; Jewell, Alan M; Dawson, Brian C; Haq, Taha R; Piedra, Pedro A

    2014-01-01

    Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004-2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site Ø in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community.

  10. Human respiratory syncytial virus in children with acute respiratory tract infections in China.

    PubMed

    Zhang, Rong-Fang; Jin, Yu; Xie, Zhi-Ping; Liu, Na; Yan, Kun-Long; Gao, Han-Chun; Song, Jing-Rong; Yuan, Xin-Hui; Xiao, Ni-Guang; Guo, Ming-Wei; Zhou, Qiong-Hua; Hou, Yun-De; Duan, Zhaojun

    2010-11-01

    There are limited data on the prevalence and clinical and molecular characterization of human respiratory syncytial virus (HRSV) in children with acute respiratory tract infections (ARTIs) in China. From December 2006 to March 2009, 894 nasopharyngeal aspirates (NPAs) were collected from children under 14 years of age with ARTIs. Samples were screened for HRSV and genotyped by reverse transcription-PCR (RT-PCR) and sequencing. Demographic and clinical information was recorded. A total of 38.14% (341/894) of samples were positive for HRSV. Phylogenetic analysis revealed that 60.4% of the selected 227 RSV strains were GA2, 34.4% were BA, 4.8% were GB2, and 0.4% were GB3. A total of 40.47% of all of the RSV-positive samples were coinfected with other respiratory viruses, and adenovirus was the most common additional respiratory virus. No statistical differences were found in the frequency of diagnosis and symptoms between the coinfection group and monoinfection group. Additionally, no statistical differences were found in epidemiological characterizations or disease severity between genotype BA- and GA2-positive patients, except for a greater frequency of lower respiratory tract infections (LRTIs) (mostly bronchitis)with BA. HRSV is the most important viral pathogen in Chinese children with ARTIs. Four genotypes (i.e., GA2, BA, GB2, and GB3) circulate locally, and the predominant genotype may shift between seasons. Coinfection with other viruses does not affect disease severity. HRSV genotypes were not associated with different epidemiological characterizations or disease severity.

  11. Modification of the Respiratory Syncytial Virus F Protein in Virus-Like Particles Impacts Generation of B Cell Memory

    PubMed Central

    Schmidt, Madelyn R.; McGinnes-Cullen, Lori W.; Kenward, Sarah A.; Willems, Kristin N.; Woodland, Robert T.

    2014-01-01

    ABSTRACT Immunization with virus-like particles (VLPs) containing the Newcastle disease virus (NDV) core proteins, NP and M, and two chimera proteins (F/F and H/G) containing the respiratory syncytial virus (RSV) F- and G-protein ectodomains fused to the transmembrane and cytoplasmic domains of NDV F and HN proteins, respectively, stimulated durable RSV-neutralizing antibodies, F-protein-specific long-lived, bone marrow-associated plasma cells (LLPCs), and B cell memory, in striking contrast to RSV infection, which did not (M. R. Schmidt, L. W. McGinnes, S. A. Kenward, K. N. Willems, R. T. Woodland, and T. G. Morrison, J. Virol. 86:11654–11662, 2012). Here we report the characterization of a VLP with an RSV F-protein ectodomain fused to the NDV F-protein heptad repeat 2 (HR2), transmembrane, and cytoplasmic domain sequences, creating a chimera with two tandem HR2 domains, one from the RSV F protein and the other from the NDV F-protein ectodomain (F/HR2F). The F/HR2F chimera protein was efficiently assembled into VLPs along with the H/G chimera protein. This VLP (VLP-H/G+F/HR2F) stimulated anti-F-protein and anti-G-protein IgG, durable RSV-neutralizing antibodies, and anti-RSV F-protein-secreting LLPCs. However, the subtypes of anti-F-protein IgG induced were different from those elicited by VLPs containing the F/F chimera (VLP-H/G+F/F). Most importantly, VLP-H/G+F/HR2F did not induce RSV F-protein-specific B cell memory, as shown by the adoptive transfer of B cells from immunized animals to immunodeficient animals. The VLP did, however, induce B cell memory specific to the RSV G protein. Thus, the form of the F protein has a direct role in inducing anti-F-protein B cell memory. IMPORTANCE The development of vaccines for respiratory syncytial virus (RSV) is hampered by a lack of a clear understanding of the requirements for eliciting protective as well as durable human immune responses to virus antigens. The results of this study indicate that the form of the RSV

  12. A Druggable Pocket at the Nucleocapsid/Phosphoprotein Interaction Site of Human Respiratory Syncytial Virus

    PubMed Central

    Ouizougun-Oubari, Mohamed; Pereira, Nelson; Tarus, Bogdan; Galloux, Marie; Lassoued, Safa; Fix, Jenna; Tortorici, M. Alejandra; Hoos, Sylviane; Baron, Bruno; England, Patrick; Desmaële, Didier; Couvreur, Patrick; Bontems, François; Rey, Félix A.; Eléouët, Jean-François; Slama-Schwok, Anny

    2015-01-01

    ABSTRACT Presently, respiratory syncytial virus (RSV), the main cause of severe respiratory infections in infants, cannot be treated efficiently with antivirals. However, its RNA-dependent polymerase complex offers potential targets for RSV-specific drugs. This includes the recognition of its template, the ribonucleoprotein complex (RNP), consisting of genomic RNA encapsidated by the RSV nucleoprotein, N. This recognition proceeds via interaction between the phosphoprotein P, which is the main polymerase cofactor, and N. The determinant role of the C terminus of P, and more particularly of the last residue, F241, in RNP binding and viral RNA synthesis has been assessed previously. Here, we provide detailed structural insight into this crucial interaction for RSV polymerase activity. We solved the crystallographic structures of complexes between the N-terminal domain of N (N-NTD) and C-terminal peptides of P and characterized binding by biophysical approaches. Our results provide a rationale for the pivotal role of F241, which inserts into a well-defined N-NTD pocket. This primary binding site is completed by transient contacts with upstream P residues outside the pocket. Based on the structural information of the N-NTD:P complex, we identified inhibitors of this interaction, selected by in silico screening of small compounds, that efficiently bind to N and compete with P in vitro. One of the compounds displayed inhibitory activity on RSV replication, thereby strengthening the relevance of N-NTD for structure-based design of RSV-specific antivirals. IMPORTANCE Respiratory syncytial virus (RSV) is a widespread pathogen that is a leading cause of acute lower respiratory infections in infants worldwide. RSV cannot be treated efficiently with antivirals, and no vaccine is presently available, with the development of pediatric vaccines being particularly challenging. Therefore, there is a need for new therapeutic strategies that specifically target RSV. The interaction

  13. Virus-like nanoparticle and DNA vaccination confers protection against respiratory syncytial virus by modulating innate and adaptive immune cells

    PubMed Central

    Ko, Eun-Ju; Kwon, Young-Man; Lee, Jong Seok; Hwang, Hye Suk; Yoo, Si-Eun; Lee, Yu-Na; Lee, Young-Tae; Kim, Min-Chul; Cho, Min Kyoung; Lee, You Ri; Quan, Fu-Shi; Song, Jae-Min; Lee, Sujin; Moore, Martin L.; Kang, Sang-Moo

    2014-01-01

    Respiratory syncytial virus (RSV) is an important human pathogen. Expression of virus structural proteins produces self-assembled virus-like nanoparticles (VLP). We investigated immune phenotypes after RSV challenge of immunized mice with VLP containing RSV F and G glycoproteins mixed with F-DNA (FdFG VLP). In contrast to formalin-inactivated RSV (FIRSV) causing vaccination-associated eosinophilia, FdFG VLP immunization induced low bronchoalveolar cellularity, higher ratios of CD11c+ versus CD11b+ phenotypic cells and CD8+ T versus CD4+ T cells secreting interferon (IFN)-γ, T helper type-1 immune responses, and no sign of eosinophilia upon RSV challenge. Furthermore, RSV neutralizing activity, lung viral clearance, and histology results suggest that FdFG VLP can be comparable to live RSV in conferring protection against RSV and in preventing RSV disease. This study provides evidence that a combination of recombinant RSV VLP and plasmid DNA may have a potential anti-RSV prophylactic vaccine inducing balanced innate and adaptive immune responses. PMID:25109662

  14. Respiratory Syncytial Virus Persistence in Murine Macrophages Impairs IFN-β Response but Not Synthesis

    PubMed Central

    Rivera-Toledo, Evelyn; Torres-González, Laura; Gómez, Beatriz

    2015-01-01

    Type-I interferon (IFN-I) production is an early response to viral infection and pathogenic viruses have evolved multiple strategies to evade this cellular defense. Some viruses can establish and maintain persistent infections by altering the IFN-I signaling pathway. Here, we studied IFN-I synthesis and response in an in vitro model of persistent infection by respiratory syncytial virus (RSV) in a murine macrophage-like cell line. In this model, interferon regulatory factor 3 was constitutively active and located at nuclei of persistently infected cells, inducing expression of IFN-beta mRNA and protein. However, persistently infected macrophages did not respond in an autocrine manner to the secreted-IFN-beta or to recombinant-IFN-beta, since phosphorylated-STAT1 was not detected by western blot and transcription of the interferon-stimulated genes (ISGs) Mx1 and ISG56 was not induced. Treatment of non-infected macrophages with supernatants from persistently infected cells induced STAT1 phosphorylation and ISGs expression, mediated by the IFN-I present in the supernatants, because blocking the IFN-I receptor inhibited STAT1 phosphorylation. Results suggest that the lack of autocrine response to IFN-I by the host cell may be one mechanism for maintenance of RSV persistence. Furthermore, STAT1 phosphorylation and ISGs expression induced in non-infected cells by supernatants from persistently infected macrophages suggest that RSV persistence may trigger a proinflammatory phenotype in non-infected cells as part of the pathogenesis of RSV infection. PMID:26501312

  15. Efficacy of a saponin-adjuvanted inactivated respiratory syncytial virus vaccine in calves

    PubMed Central

    2005-01-01

    Abstract The objective of this study was to determine whether a commercially available, saponin-adjuvanted, inactivated bovine respiratory syncytial virus (BRSV) vaccine would protect calves from experimental infection with virulent BRSV. This was a randomized controlled trial comprising 14, 8- to 9-week-old calves seronegative for BRSV. Group 1 calves (n = 8) were not vaccinated and group 2 calves (n = 6) were vaccinated on days 0 and 19 with an inactivated BRSV vaccine. All calves were challenged with virulent BRSV on day 46. Clinical signs, arterial PO2, and immune responses were monitored after challenge. Calves were euthanatized on day 54 (8 d after challenge) and lungs were examined for lesions. Vaccination elicited increases in BRSV-specific immunoglobulin (Ig) G and virus neutralizing antibody titers. Challenge with BRSV resulted in severe respiratory tract disease and extensive pulmonary lesions in control calves, but no signs of clinical disease and minimal or no pulmonary lesions in vaccinated calves. Arterial blood oxygen values on day 53 (7 d after challenge) in control calves were significantly lower than those in vaccinated calves, which remained within normal limits. Control calves shed BRSV for several days after challenge, whereas BRSV was not detected on deep nasal swabs from vaccinated calves. In summary, the results indicated that this inactivated BRSV vaccine provided clinical protection from experimental infection with virulent virus 27 d after vaccination and significantly decreased the prevalence and severity of pulmonary lesions. Efficacy was similar to that reported for other commercial inactivated and modified-live BRSV vaccines. PMID:15825518

  16. Molecular epidemiology of human respiratory syncytial virus over three consecutive seasons in Latvia.

    PubMed

    Balmaks, Reinis; Ribakova, Irina; Gardovska, Dace; Kazaks, Andris

    2014-11-01

    Lower respiratory tract infections caused by the human respiratory syncytial virus (HRSV) represent an immense burden of the disease, especially in young children. This study aimed to investigate the evolutionary history of HRSV strains isolated in the Children's Clinical University Hospital (Riga, Latvia) over three consecutive HRSV seasons. Of 207 samples from children hospitalized with lower respiratory tract infections, 88 (42.5%) tested positive for HRSV by RT-PCR. The seasonal activity started and peaked later than the average for the Northern hemisphere. Patients with HRSV lower respiratory tract infection were significantly younger than patients not infected with HRSV. HRSV-A viruses predominated for two consecutive seasons and were followed by an HRSV-B dominant season. Phylogenetic analysis based on glycoprotein G gene partial sequences revealed that viruses of both groups belonged to the worldwide dominant genotypes NA1 (HRSV-A) and BA-IV (HRSV-B). High diversity of this gene was driven only partially by selection pressure, as only two positively selected sites were identified in each group. Two of the HRSV-A isolates in this study contained a 72-nt duplication in the C-terminal end of the G gene (genotype ON1) that was first described in Canada in the 2010-2011 season. Initial spatial and temporal dynamics of this novel genotype were reconstructed by discrete phylogeographic analysis. Fifteen years after acquiring comparable 60-nt duplication in the G gene, genotype BA lineages have replaced all other HRSV-B strains. However, the population size of genotype ON1 plateaued soon and even decreased slightly before the beginning of the 2012-2013 season.

  17. A molecular epidemiological study of human respiratory syncytial virus in Croatia, 2011-2014.

    PubMed

    Slovic, Anamarija; Ivancic-Jelecki, Jelena; Ljubin-Sternak, Sunčanica; Galinović, Gordana Mlinarić; Forcic, Dubravko

    2016-10-01

    Human respiratory syncytial virus (HRSV) causes common respiratory tract infections in infants, young children and the elderly. The diversity of HRSV strains circulating in Croatia was investigated throughout a period of four consecutive years from March 2011-March 2014. The analysis was based on sequences from the second hypervariable region of the G gene. A predominance of HRSV group A was observed in the first three years of the study, while group B became slightly predominant during the first few months of 2014. Overall, 76% of viruses belonged to group A including the genotypes NA1, ON1 and GA5. NA1 was by far the most common genotype within group A in 2011-2013; however, only ON1 and a few GA5 viruses were detected in the first three months of 2014. The majority of group B strains were of genotype BA9 (97%), and a few BA10 genotypes were detected. BA9 had the highest substitution rate of all the detected genotypes, followed by ON1. Multiple analyses showed that HRSV group A strains were more diverse than group B strains. Gly at residue 232 (previously described to be specific for ON1) was also detected in three NA1 strains, which were phylogenetically placed on separate branches within the NA1 genotype. For all genotypes, the diversity was higher at the amino acid level than at the nucleotide level, although positive selection of mutations was shown for only a few sites using four different methods of codon-based analysis of selective pressure. More codons were predicted to be negatively selected. The complexity of the HRSV pools present during each epidemic peak was determined and compared to previous epidemiological data. In addition to presenting genetic versatility of HRSV in this geographic region, the collected sequences provide data for further geographical and temporal comparative analyses of HRSV and its evolutionary pathways.

  18. Sequencing and analysis of globally obtained human respiratory syncytial virus A and B genomes.

    PubMed

    Bose, Michael E; He, Jie; Shrivastava, Susmita; Nelson, Martha I; Bera, Jayati; Halpin, Rebecca A; Town, Christopher D; Lorenzi, Hernan A; Noyola, Daniel E; Falcone, Valeria; Gerna, Giuseppe; De Beenhouwer, Hans; Videla, Cristina; Kok, Tuckweng; Venter, Marietjie; Williams, John V; Henrickson, Kelly J

    2015-01-01

    Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in children globally, with nearly all children experiencing at least one infection by the age of two. Partial sequencing of the attachment glycoprotein gene is conducted routinely for genotyping, but relatively few whole genome sequences are available for RSV. The goal of our study was to sequence the genomes of RSV strains collected from multiple countries to further understand the global diversity of RSV at a whole-genome level. We collected RSV samples and isolates from Mexico, Argentina, Belgium, Italy, Germany, Australia, South Africa, and the USA from the years 1998-2010. Both Sanger and next-generation sequencing with the Illumina and 454 platforms were used to sequence the whole genomes of RSV A and B. Phylogenetic analyses were performed using the Bayesian and maximum likelihood methods of phylogenetic inference. We sequenced the genomes of 34 RSVA and 23 RSVB viruses. Phylogenetic analysis showed that the RSVA genome evolves at an estimated rate of 6.72 × 10(-4) substitutions/site/year (95% HPD 5.61 × 10(-4) to 7.6 × 10(-4)) and for RSVB the evolutionary rate was 7.69 × 10(-4) substitutions/site/year (95% HPD 6.81 × 10(-4) to 8.62 × 10(-4)). We found multiple clades co-circulating globally for both RSV A and B. The predominant clades were GA2 and GA5 for RSVA and BA for RSVB. Our analyses showed that RSV circulates on a global scale with the same predominant clades of viruses being found in countries around the world. However, the distribution of clades can change rapidly as new strains emerge. We did not observe a strong spatial structure in our trees, with the same three main clades of RSV co-circulating globally, suggesting that the evolution of RSV is not strongly regionalized.

  19. Analysis of the interaction between respiratory syncytial virus and lipid-rafts in Hep2 cells during infection

    SciTech Connect

    Brown, Gaie; Jeffree, Chris E.; McDonald, Terence; McL Rixon, Helen W.; Aitken, James D.; Sugrue, Richard J. . E-mail: r.sugrue@vir.gla.ac.uk

    2004-10-01

    The assembly of respiratory syncytial virus (RSV) in lipid-rafts was examined in Hep2 cells. Confocal and electron microscopy showed that during RSV assembly, the cellular distribution of the complement regulatory proteins, decay accelerating factor (CD55) and CD59, changes and high levels of these cellular proteins are incorporated into mature virus filaments. The detergent-solubility properties of CD55, CD59, and the RSV fusion (F) protein were found to be consistent with each protein being located predominantly within lipid-raft structures. The levels of these proteins in cell-released virus were examined by immunoelectronmicroscopy and found to account for between 5% and 15% of the virus attachment (G) glycoprotein levels. Collectively, our findings suggest that an intimate association exists between RSV and lipid-raft membranes and that significant levels of these host-derived raft proteins, such as those regulating complement activation, are subsequently incorporated into the envelope of mature virus particles.

  20. Selection and characterization of human respiratory syncytial virus escape mutants resistant to a polyclonal antiserum raised against the F protein.

    PubMed

    Tomé, Lorena; Frabasile, Sandra; Candia, Claudia; Pittini, Alvaro; Farina, Natalia; Melero, José Antonio; Arbiza, Juan

    2012-06-01

    A human respiratory syncytial virus (HRSV) neutralization escape mutant was obtained after 56 serial passages in the presence of a polyclonal antiserum raised against the F protein. Nucleotide sequence analysis of this escape mutant virus revealed two amino acid substitutions: Asn268Ile and Val533Met. When this virus was allowed to grow in the absence of the anti-F polyclonal serum, only the mutation Asn268Ile was stably maintained. Both the double and single escape mutant viruses lost reactivity with mAbs belonging to antigenic site II of the fusion protein of RSV. Mutation Asn268Ile has already been reported in RS viruses that are resistant to mAbs 47F and 11 and palivizumab (PZ). We have thus identified a novel mutation (Val533Met) in the transmembrane domain of the F protein that was selected under immune pressure.

  1. A Comprehensive Proteomic View of Responses of A549 Type II Alveolar Epithelial Cells to Human Respiratory Syncytial Virus Infection*

    PubMed Central

    Dave, Keyur A.; Norris, Emma L.; Bukreyev, Alexander A.; Headlam, Madeleine J.; Buchholz, Ursula J.; Singh, Toshna; Collins, Peter L.; Gorman, Jeffrey J.

    2014-01-01

    Human respiratory syncytial virus is a major respiratory pathogen for which there are no suitable antivirals or vaccines. A better understanding of the host cell response to this virus may redress this problem. The present report concerns analysis of multiple independent biological replicates of control and 24 h infected lysates of A549 cells by two different proteomic workflows. One workflow involved fractionation of lysates by in-solution protein IEF and individual fractions were digested using trypsin prior to capillary HPLC-LTQ-OrbitrapXL-MS/MS. A second workflow involved digestion of whole cell lysates and analysis by nanoUltraHPLC-LTQ-OrbitrapElite-MS/MS. Both workflows resulted in the quantification of viral proteins exclusively in lysates of infected cells in the relative abundances anticipated from previous studies. Unprecedented numbers (3247 - 5010) of host cell protein groups were also quantified and the infection-specific regulation of a large number (191) of these protein groups was evident based on a stringent false discovery rate cut-off (<1%). Bioinformatic analyses revealed that most of the regulated proteins were potentially regulated by type I, II, and III interferon, TNF-α and noncanonical NF-κB2 mediated antiviral response pathways. Regulation of specific protein groups by infection was validated by quantitative Western blotting and the cytokine-/key regulator-specific nature of their regulation was confirmed by comparable analyses of cytokine treated A549 cells. Overall, it is evident that the workflows described herein have produced the most comprehensive proteomic characterization of host cell responses to human respiratory syncytial virus published to date. These workflows will form the basis for analysis of the impacts of specific genes of human respiratory syncytial virus responses of A549 and other cell lines using a gene-deleted version of the virus. They should also prove valuable for the analysis of the impact of other infectious

  2. A comprehensive proteomic view of responses of A549 type II alveolar epithelial cells to human respiratory syncytial virus infection.

    PubMed

    Dave, Keyur A; Norris, Emma L; Bukreyev, Alexander A; Headlam, Madeleine J; Buchholz, Ursula J; Singh, Toshna; Collins, Peter L; Gorman, Jeffrey J

    2014-12-01

    Human respiratory syncytial virus is a major respiratory pathogen for which there are no suitable antivirals or vaccines. A better understanding of the host cell response to this virus may redress this problem. The present report concerns analysis of multiple independent biological replicates of control and 24 h infected lysates of A549 cells by two different proteomic workflows. One workflow involved fractionation of lysates by in-solution protein IEF and individual fractions were digested using trypsin prior to capillary HPLC-LTQ-OrbitrapXL-MS/MS. A second workflow involved digestion of whole cell lysates and analysis by nanoUltraHPLC-LTQ-OrbitrapElite-MS/MS. Both workflows resulted in the quantification of viral proteins exclusively in lysates of infected cells in the relative abundances anticipated from previous studies. Unprecedented numbers (3247 - 5010) of host cell protein groups were also quantified and the infection-specific regulation of a large number (191) of these protein groups was evident based on a stringent false discovery rate cut-off (<1%). Bioinformatic analyses revealed that most of the regulated proteins were potentially regulated by type I, II, and III interferon, TNF-α and noncanonical NF-κB2 mediated antiviral response pathways. Regulation of specific protein groups by infection was validated by quantitative Western blotting and the cytokine-/key regulator-specific nature of their regulation was confirmed by comparable analyses of cytokine treated A549 cells. Overall, it is evident that the workflows described herein have produced the most comprehensive proteomic characterization of host cell responses to human respiratory syncytial virus published to date. These workflows will form the basis for analysis of the impacts of specific genes of human respiratory syncytial virus responses of A549 and other cell lines using a gene-deleted version of the virus. They should also prove valuable for the analysis of the impact of other infectious

  3. Immune enhancement of pulmonary bactericidal activity in murine virus pneumonia.

    PubMed

    Jakab, G J; Green, G M

    1973-11-01

    Bacterial multiplication in the lung associated with murine Sendai virus pneumonia is caused by virus-induced defects in pulmonary bactericidal mechanisms. The nature of this effect has been studied in animals immunized against the challenge bacteria. Mice were immunized against Proteus mirabilis by intraperitoneal inoculation and by aerosol inhalation. After the development of immunity, mice were infected aerogenically with 10(4) TCID(50) of Sendai virus. 7 days later, during the height of the bronchial inflammation and pulmonary consolidation, the mice were challenged with an aerosol of viable (35)S-labeled Proteus mirabilis or (32)P-labeled Staphylococcus aureus.Nonimmunized virus-infected animals showed marked impairment of pulmonary bactericidal activity with subsequent multiplication of the bacterial strain in the case of Proteus mirabilis. Immunized nonvirus-infected animals showed enhancement of pulmonary bactericidal activity for the homologous and heterologous strains in comparison with nonimmunized animals. Virus-infected animals immunized by aerosol showed enhanced bactericidal activity against the homologous but not the heterologous bacterial strain. Neither virus infection nor immunization had a significant effect on the transport of particles in the lung. The data demonstrated that the bacterial multiplication associated with the virus pneumonia was prevented by preceding immunization against the homologous challenge organism. The data suggest a mechanism for controlling bacterial multiplication associated with virus pneumonias.

  4. The Natural History of Respiratory Syncytial Virus in a Birth Cohort: The Influence of Age and Previous Infection on Reinfection and Disease

    PubMed Central

    Ohuma, E. O.; Okiro, E. A.; Ochola, R.; Sande, C. J.; Cane, P. A.; Medley, G. F.; Bottomley, C.; Nokes, D. J.

    2012-01-01

    This study aimed to quantify the effect of age, time since last infection, and infection history on the rate of respiratory syncytial virus infection and the effect of age and infection history on the risk of respiratory syncytial virus disease. A birth cohort of 635 children in Kilifi, Kenya, was monitored for respiratory syncytial virus infections from January 31, 2002, to April 22, 2005. Predictors of infection were examined by Cox regression and disease risk by binomial regression. A total of 598 respiratory syncytial virus infections were identified (411 primary, 187 repeat), with 409 determined by antigen assay and 189 by antibody alone (using a “most pragmatic” serologic definition). The incidence decreased by 70% following a primary infection (adjusted hazard ratio = 0.30, 95% confidence interval: 0.21, 0.42; P < 0.001) and by 59% following a secondary infection (hazard ratio = 0.41, 95% confidence interval: 0.22, 0.73; P = 0.003), for a period lasting 6 months. Relative to the age group <6 months, all ages exhibited a higher incidence of infection. A lower risk of severe disease following infection was independently associated with increasing age (P < 0.001) but not reinfection. In conclusion, observed respiratory syncytial virus incidence was lowest in the first 6 months of life, immunity to reinfection was partial and short lived, and disease risk was age related. PMID:23059788

  5. The Logistics and Coordination of Respiratory Syncytial Virus Immunoprophylaxis Use Among US Pediatric Specialists.

    PubMed

    Wong, Pierre C; Parimi, Prabhu S; Domachowske, Joseph B; Friedman, Deborah M; Marcus, Michael G; Garcia, Daniel F; La Via, William V; Syed, Iqra A; Szabo, Shelagh M; McLaurin, Kimmie K; Kumar, Veena R

    2016-11-01

    This study was conducted to survey US pediatric specialists about administration of respiratory syncytial virus (RSV) immunoprophylaxis, communication patterns among physicians and parents, and barriers to access. Separate surveys were sent to neonatologists, pediatricians, pediatric pulmonologists, and pediatric cardiologists. Most physicians (≥93.5%) routinely recommended immunoprophylaxis to high-risk children. Most respondents (≥71.8%) reported that >50.0% of eligible infants and young children received each monthly dose throughout the RSV season, with the first dose most commonly administered before discharge from the birth hospitalization. To ensure receipt of subsequent doses, specialists frequently scheduled a follow-up visit at the end of the current appointment. All specialists reported insurance denials as the biggest obstacle to the administration of immunoprophylaxis to high-risk children. These findings may be used to improve adherence to immunoprophylaxis by enhancing education and physician-parent communications about severe RSV disease prevention, and by reducing known barriers to use of this preventive therapy.

  6. A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading

    PubMed Central

    Gaillard, Vanessa; Galloux, Marie; Eléouët, Jean-François; Larcher, Thibaut; Rameix-Welti, Marie-Anne; Boukadiri, Abdelhak; Héritier, Julien; Segura, Jean-Manuel; Baechler, Elodie; Arrell, Miriam; Mottet-Osman, Geneviève

    2017-01-01

    ABSTRACT Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals. PMID:28137809

  7. Molecular evolution of the fusion protein gene in human respiratory syncytial virus subgroup A.

    PubMed

    Kimura, Hirokazu; Nagasawa, Koo; Tsukagoshi, Hiroyuki; Matsushima, Yuki; Fujita, Kiyotaka; Yoshida, Lay Myint; Tanaka, Ryota; Ishii, Haruyuki; Shimojo, Naoki; Kuroda, Makoto; Ryo, Akihide

    2016-09-01

    We studied the molecular evolution of the fusion protein (F) gene in the human respiratory syncytial virus subgroup A (HRSV-A). We performed time-scaled phylogenetic analyses using the Bayesian Markov chain Monte Carlo (MCMC) method. We also conducted genetic distance (p-distance), positive/negative selection, and Bayesian skyline plot analyses. Furthermore, we mapped the amino acid substitutions of the protein. The MCMC-constructed tree indicated that the HRSV F gene diverged from the bovine RSV (BRSV) gene approximately 550years ago and had a relatively low substitution rate (7.59×10(-4) substitutions/site/year). Moreover, a common ancestor of HRSV-A and -B diverged approximately 280years ago, which has since formed four distinct clusters. The present HRSV-A strains were assigned six genotypes based on F gene sequences and attachment glycoprotein gene sequences. The present strains exhibited high F gene sequence similarity values and low genetic divergence. No positive selection sites were identified; however, 50 negative selection sites were identified. F protein amino acid substitutions at 17 sites were distributed in the F protein. The effective population size of the gene has remained relatively constant, but the population size of the prevalent genotype (GA2) has increased in the last 10years. These results suggest that the HRSV-AF gene has evolved independently and formed some genotypes. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Immunobiotic Lactobacillus rhamnosus improves resistance of infant mice against respiratory syncytial virus infection.

    PubMed

    Chiba, Eriko; Tomosada, Yohsuke; Vizoso-Pinto, Maria Guadalupe; Salva, Susana; Takahashi, Takuya; Tsukida, Kohichiro; Kitazawa, Haruki; Alvarez, Susana; Villena, Julio

    2013-10-01

    Previously we showed that orally administered Lactobacillus rhamnosus CRL1505 beneficially regulated the balance between pro- and anti-inflammatory mediators in the lungs of poly(I:C)-challenged mice, allowing an effective inflammatory response against the TLR3/RIG-I agonist but at the same time reducing tissue damage. The aim of the present study was to investigate whether oral administration of the CRL1505 strain was able to improve resistance against respiratory syncytial virus (RSV) infection in infant mice and to evaluate the immunological mechanisms involved in the immunobiotic effect. We demonstrated that treatment of 3-week old BALB/c mice with L. rhamnosus CRL1505 significantly reduce lung viral loads and tissue injuries after the challenge with RSV. Moreover, we showed that the protective effect achieved by the CRL1505 strain is related to its capacity to differentially modulate respiratory antiviral immune response. Our results shows that IFN-γ and IL-10 secreted in response to L. rhamnosus CRL1505 oral stimulation would modulate the pulmonary innate immune microenvironment conducting to the activation of CD103(+) and CD11b(high) dendritic cells and the generation of CD3(+)CD4(+)IFN-γ(+) Th1 cells with the consequent attenuation of the strong and damaging Th2 reactions associated with RSV challenge. Our results indicate that modulation of the common mucosal immune system by immunobiotics could favor protective immunity against respiratory viral pathogens with a high attack rate in early infancy, such as RSV. © 2013.

  9. Understanding the transmission dynamics of respiratory syncytial virus using multiple time series and nested models

    PubMed Central

    White, L.J.; Mandl, J.N.; Gomes, M.G.M.; Bodley-Tickell, A.T.; Cane, P.A.; Perez-Brena, P.; Aguilar, J.C.; Siqueira, M.M.; Portes, S.A.; Straliotto, S.M.; Waris, M.; Nokes, D.J.; Medley, G.F.

    2007-01-01

    The nature and role of re-infection and partial immunity are likely to be important determinants of the transmission dynamics of human respiratory syncytial virus (hRSV). We propose a single model structure that captures four possible host responses to infection and subsequent reinfection: partial susceptibility, altered infection duration, reduced infectiousness and temporary immunity (which might be partial). The magnitude of these responses is determined by four homotopy parameters, and by setting some of these parameters to extreme values we generate a set of eight nested, deterministic transmission models. In order to investigate hRSV transmission dynamics, we applied these models to incidence data from eight international locations. Seasonality is included as cyclic variation in transmission. Parameters associated with the natural history of the infection were assumed to be independent of geographic location, while others, such as those associated with seasonality, were assumed location specific. Models incorporating either of the two extreme assumptions for immunity (none or solid and lifelong) were unable to reproduce the observed dynamics. Model fits with either waning or partial immunity to disease or both were visually comparable. The best fitting structure was a lifelong partial immunity to both disease and infection. Observed patterns were reproduced by stochastic simulations using the parameter values estimated from the deterministic models. PMID:17335858

  10. A Short Double-Stapled Peptide Inhibits Respiratory Syncytial Virus Entry and Spreading.

    PubMed

    Gaillard, Vanessa; Galloux, Marie; Garcin, Dominique; Eléouët, Jean-François; Le Goffic, Ronan; Larcher, Thibaut; Rameix-Welti, Marie-Anne; Boukadiri, Abdelhak; Héritier, Julien; Segura, Jean-Manuel; Baechler, Elodie; Arrell, Miriam; Mottet-Osman, Geneviève; Nyanguile, Origène

    2017-04-01

    Synthetic peptides derived from the heptad repeat (HR) of fusion (F) proteins can be used as dominant negative inhibitors to inhibit the fusion mechanism of class I viral F proteins. Here, we have performed a stapled-peptide scan across the HR2 domain of the respiratory syncytial virus (RSV) F protein with the aim to identify a minimal domain capable of disrupting the formation of the postfusion six-helix bundle required for viral cell entry. Constraining the peptides with a single staple was not sufficient to inhibit RSV infection. However, the insertion of double staples led to the identification of novel short stapled peptides that display nanomolar potency in HEp-2 cells and are exceptionally robust to proteolytic degradation. By replacing each amino acid of the peptides by an alanine, we found that the substitution of residues 506 to 509, located in a patch of polar contacts between HR2 and HR1, severely affected inhibition. Finally, we show that intranasal delivery of the most potent peptide to BALB/c mice significantly decreased RSV infection in upper and lower respiratory tracts. The discovery of this minimal HR2 sequence as a means for inhibition of RSV infection provides the basis for further medicinal chemistry efforts toward developing RSV fusion antivirals. Copyright © 2017 Gaillard et al.

  11. Iterative structure-based improvement of a respiratory syncytial virus fusion glycoprotein vaccine

    PubMed Central

    Ou, Li; Chen, Man; Chuang, Gwo-Yu; Druz, Aliaksandr; Kong, Wing-Pui; Lai, Yen-Ting; Rundlet, Emily J.; Tsybovsky, Yaroslav; Yang, Yongping; Georgiev, Ivelin S.; Guttman, Miklos; Lees, Christopher R.; Pancera, Marie; Sastry, Mallika; Soto, Cinque; Stewart-Jones, Guillaume B.E.; Thomas, Paul V.; Van Galen, Joseph G.; Baxa, Ulrich; Lee, Kelly K.; Mascola, John R.; Graham, Barney S.; Kwong, Peter D.

    2016-01-01

    Structure-based design of vaccines has been a long-sought goal, especially the iterative optimization used so successfully with structure-based design of drugs. We previously developed a 1st-generation vaccine antigen called DS-Cav1, comprising a pre-fusion-stabilized form of the fusion (F) glycoprotein, which elicited high titers of protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant 2nd-generation “DS2”-stabilized immunogens have F subunits genetically linked, fusion peptide deleted, and interprotomer movements stabilized by an additional disulfide bond. These DS2-immunogens are promising vaccine candidates with superior attributes, such as the absence of a requirement for furin cleavage and increased antigenic stability to heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens. PMID:27478931

  12. Respiratory syncytial virus increases lung cellular bioenergetics in neonatal C57BL/6 mice

    SciTech Connect

    Alsuwaidi, Ahmed R.; Albawardi, Alia; Almarzooqi, Saeeda; Benedict, Sheela; Othman, Aws R.; Hartwig, Stacey M.; Varga, Steven M.; Souid, Abdul-Kader

    2014-04-15

    We have previously reported that lung cellular bioenergetics (cellular respiration and ATP) increased in 4–10 week-old BALB/c mice infected with respiratory syncytial virus (RSV). This study examined the kinetics and changes in cellular bioenergetics in ≤2-week-old C57BL/6 mice following RSV infection. Mice (5–14 days old) were inoculated intranasally with RSV and the lungs were examined on days 1–10 post-infection. Histopathology and electron microscopy revealed preserved pneumocyte architectures and organelles. Increased lung cellular bioenergetics was noted from days 1–10 post-infection. Cellular GSH remained unchanged. These results indicate that the increased lung cellular respiration (measured by mitochondrial O{sub 2} consumption) and ATP following RSV infection is independent of either age or genetic background of the host. - Highlights: • RSV infection increases lung cellular respiration and ATP in neonatal C57BL/6 mice. • Increased lung cellular bioenergetics is a biomarker of RSV infection. • Lung cellular glutathione remains unchanged in RSV infection.

  13. Screening for respiratory syncytial virus and assignment to a cohort at admission to reduce nosocomial transmission.

    PubMed

    Krasinski, K; LaCouture, R; Holzman, R S; Waithe, E; Bonk, S; Hanna, B

    1990-06-01

    To limit nosocomial spread of respiratory syncytial virus (RSV) infection, a longitudinal intervention trial was instituted. Nasal secretions or washes were screened for RSV antigen by enzyme-linked immunosorbent assay, and patients were assigned to an RSV-infected or an RSV-uninfected cohort. The baseline (preintervention) rate of 7.17 nosocomial cases of RSV per 1000 patient-days of care was used for comparison. Despite continued infections in the community after screening was initiated, there were no cases of RSV infection in 1880 patient-days of care for 3 months (p = 0.039). During the fourth month, an RSV-infected child was erroneously assigned to the RSV-uninfected cohort, and three nosocomial cases occurred--5.33/1000 patient-days of care (p = 0.286). Overall, there were three nosocomial RSV infections in 2443 patient-days of care in the 1987 season after screening was introduced--1.23/1000 patient-days of care (p = 0.026). In the subsequent RSV season, there was one nosocomial case--0.461/1000 patient-days of care for 3 months (p = 0.0074). During the same period, nosocomial cases of RSV were observed in the pediatric and neonatal intensive care units, where assignment to a cohort was not possible. We conclude that entry into a cohort at the time of admission, on the basis of prospective RSV screening by enzyme-linked immunosorbent assay, effectively reduces nosocomial transmission of RSV.

  14. The compound DATEM inhibits respiratory syncytial virus fusion activity with epithelial cells.

    PubMed

    Ohki, Shinpei; Liu, Jin-Zhou; Schaller, Joseph; Welliver, Robert C

    2003-04-01

    The effect of diacetyltartaric acid esters of mono and diglycerides (DATEM) on fusion of respiratory syncytial virus (RSV) with HEp-2 cells was studied using the R18 fluorescence dequenching fusion assay. At DATEM concentrations less than 2.0 microg/ml, the inhibition of fusion increased with the concentration of DATEM. At 2 microg/ml of DATEM, the fusion was suppressed by 80-90%. Studies examining possible mechanism of fusion-inhibition indicated that DATEM was likely adsorbed onto lipid membranes of both viral envelope and target cell membranes. Quantitative measurements of DATEM adsorption onto membranes were also performed using lipid monolayers and vesicles. The surface pressure of lipid monolayer formed at the air/aqueous interface increased as the concentration of DATEM in the monolayer subphase increased, suggesting that DATEM was inserted into the monolayer. As the concentration of DATEM in vesicle suspensions increased, electrophoretic mobility of initially uncharged lipid vesicles also increased, reflective of increased negative charge at vesicle surfaces. These results strongly suggest that the insertion of DATEM onto membranes inhibited viral fusion. DATEM may prove to be effective in limiting the infectivity of RSV by interference with the fusion of the viral envelope with target cell membranes.

  15. Transcriptome assists prognosis of disease severity in respiratory syncytial virus infected infants

    PubMed Central

    Jong, Victor L.; Ahout, Inge M. L.; van den Ham, Henk-Jan; Jans, Jop; Zaaraoui-Boutahar, Fatiha; Zomer, Aldert; Simonetti, Elles; Bijl, Maarten A.; Brand, H. Kim; van IJcken, Wilfred F. J.; de Jonge, Marien I.; Fraaij, Pieter L.; de Groot, Ronald; Osterhaus, Albert D. M. E.; Eijkemans, Marinus J.; Ferwerda, Gerben; Andeweg, Arno C.

    2016-01-01

    Respiratory syncytial virus (RSV) causes infections that range from common cold to severe lower respiratory tract infection requiring high-level medical care. Prediction of the course of disease in individual patients remains challenging at the first visit to the pediatric wards and RSV infections may rapidly progress to severe disease. In this study we investigate whether there exists a genomic signature that can accurately predict the course of RSV. We used early blood microarray transcriptome profiles from 39 hospitalized infants that were followed until recovery and of which the level of disease severity was determined retrospectively. Applying support vector machine learning on age by sex standardized transcriptomic data, an 84 gene signature was identified that discriminated hospitalized infants with eventually less severe RSV infection from infants that suffered from most severe RSV disease. This signature yielded an area under the receiver operating characteristic curve (AUC) of 0.966 using leave-one-out cross-validation on the experimental data and an AUC of 0.858 on an independent validation cohort consisting of 53 infants. A combination of the gene signature with age and sex yielded an AUC of 0.971. Thus, the presented signature may serve as the basis to develop a prognostic test to support clinical management of RSV patients. PMID:27833115

  16. Stability Characterization of a Vaccine Antigen Based on the Respiratory Syncytial Virus Fusion Glycoprotein.

    PubMed

    Flynn, Jessica A; Durr, Eberhard; Swoyer, Ryan; Cejas, Pedro J; Horton, Melanie S; Galli, Jennifer D; Cosmi, Scott A; Espeseth, Amy S; Bett, Andrew J; Zhang, Lan

    2016-01-01

    Infection with Respiratory Syncytial Virus (RSV) causes both upper and lower respiratory tract disease in humans, leading to significant morbidity and mortality in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. During the infection process, the type I viral fusion (F) glycoprotein on the surface of the RSV particle rearranges from a metastable prefusion conformation to a highly stable postfusion form. In people naturally infected with RSV, most potent neutralizing antibodies are directed to the prefusion form of the F protein. Therefore, an engineered RSV F protein stabilized in the prefusion conformation (DS-Cav1) is an attractive vaccine candidate. Long-term stability at 4°C or higher is a desirable attribute for a commercial subunit vaccine antigen. To assess the stability of DS-Cav1, we developed assays using D25, an antibody which recognizes the prefusion F-specific antigenic site Ø, and a novel antibody 4D7, which was found to bind antigenic site I on the postfusion form of RSV F. Biophysical analysis indicated that, upon long-term storage at 4°C, DS-Cav1 undergoes a conformational change, adopting alternate structures that concomitantly lose the site Ø epitope and gain the ability to bind 4D7.

  17. Respiratory syncytial virus in adults with severe acute respiratory illness in a high HIV prevalence setting.

    PubMed

    Moyes, Jocelyn; Walaza, Sibongile; Pretorius, Marthi; Groome, Michelle; von Gottberg, Anne; Wolter, Nicole; Haffejee, Sumayya; Variava, Ebrahim; Cohen, Adam L; Tempia, Stefano; Kahn, Kathleen; Dawood, Halima; Venter, Marietjie; Cohen, Cheryl; Madhi, Shabir A

    2017-10-01

    There are limited data on the epidemiology of respiratory syncytial virus (RSV) illness in HIV-infected adults or the elderly in Africa. We studied the epidemiology of RSV-associated severe acute respiratory illness (SARI) hospitalizations in adults in South Africa from 2009 through 2013. Individuals admitted to sentinel surveillance hospitals were investigated by respiratory tract swabs for RSV, using a multiplex real-time polymerase chain reaction assay. The incidence of RSV-associated SARI was calculated for the one site with population denominators. Of 7796 participants investigated, 329 (4%) tested positive for RSV. On multivariable analysis, HIV-infected individuals with RSV-associated SARI had greater odds of being in the age groups 18-44 and 45-64 years (odd ratios (OR) 26.3; 95% confidence interval (CI) 6.2-112.1 and OR 11.4; 95% CI 2.6-50.0) compared with those ≥65 years and being female (OR 2.7; 95% CI 1.4-5.4). The relative risk of hospitalization with RSV-associated SARI was 12-18 times higher in HIV infected individual compared to that of HIV-uninfected. The incidence of RSV-associated SARI was higher in HIV-infected individuals and those aged 65 years and older. Further studies are warranted to describe the disease association of RSV detected in adults with SARI. Copyright © 2017 The British Infection Association. All rights reserved.

  18. Relationship between meteorological conditions and respiratory syncytial virus in a tropical country.

    PubMed

    Rodriguez-Martinez, C E; Sossa-Briceño, M P; Acuña-Cordero, R

    2015-09-01

    This study aimed to determine which meteorological conditions are associated with respiratory syncytial virus (RSV) isolates in a population of children hospitalized with acute lower respiratory infection (ALRI) in Bogota, Colombia. In an analytical cross-sectional study, links were examined between the number of monthly RSV infections and monthly average climatic variation (temperature, relative humidity, rainfall, wind speed, solar radiation) between 1 January 2010 and 30 April 2011 in a population of hospitalized children aged <3 years with ALRI caused by RSV. Out of a total of 1548 children included in the study (mean age 9·2 ± 8·5 months), 1194 (77·1%) presented RSV infection during the 3-month period from March to May. In the multivariate analysis, after controlling for wind speed, relative humidity, and solar radiation, monthly average temperature [incident rate ratio (IRR) 3·14, 95% confidence interval (CI) 1·56-6·30, P = 0·001] and rainfall (IRR 1·008, 95% CI 1·00-1·01, P = 0·048) were independently associated with the monthly number of RSV infections. In conclusion, in Bogota, a tropical Latin American city, average temperature and rainfall are the meteorological variables most strongly associated with RSV isolation in children hospitalized with ALRI in the city.

  19. Epidemic activity of respiratory syncytial virus is related to temperature and rainfall in equatorial tropical countries.

    PubMed

    Gamba-Sanchez, N; Rodriguez-Martinez, C E; Sossa-Briceño, M P

    2016-07-01

    Although viral acute lower respiratory infections (ALRIs) are a major public health problem in tropical low- and middle-income countries (LMICs), and there is growing evidence showing their relationship with meteorological parameters, studies performed in these countries are scarce. In an analytical cross-sectional study, we determined which of the main meteorological parameters (temperature, absolute humidity, rainfall, wind speed, and solar radiation) predicted respiratory syncytial virus (RSV) activity in a population of hospitalized children with ALRI during a 5-year period, from January 2009 to December 2013. Out of a total of 4559 children included in the study (mean age 9·2 ± 8·5 months), 2953 (64·8%) presented RSV infection during the 3-month period from March to May. In the multivariate analysis, after controlling for absolute humidity, wind speed, and solar radiation, temperature [incidence rate ratio (IRR) 2·25, 95% confidence interval (CI) 1·11-4·53, P = 0·024], and rainfall (IRR 1·01, 95% CI 1·00-1·02, P = 0·044) were independently associated with the monthly number of RSV infections. In conclusion, in Bogota, the capital of a tropical LMIC lying slightly above the equator, RSV activity peaks in the 3-month period from March to May, the main rainy period of the year in the city. In addition, rainfall and temperature are the two most important meteorological parameters that are independently associated with RSV activity in hospitalized children with ALRI in the city.

  20. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG

    PubMed Central

    Bueno, Susan M.; González, Pablo A.; Cautivo, Kelly M.; Mora, Jorge E.; Leiva, Eduardo D.; Tobar, Hugo E.; Fennelly, Glenn J.; Eugenin, Eliseo A.; Jacobs, William R.; Riedel, Claudia A.; Kalergis, Alexis M.

    2008-01-01

    Respiratory syncytial virus (RSV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, because of an inefficient immunological memory, RSV infection provides limited immune protection against reinfection. Furthermore, RSV can induce an inadequate Th2-type immune response that causes severe respiratory tract inflammation and obstruction. It is thought that effective RSV clearance requires the induction of balanced Th1-type immunity, involving the activation of IFN-γ-secreting cytotoxic T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette–Guérin (BCG), which has been used in newborns for decades in several countries as a tuberculosis vaccine. Here, we show that immunization with recombinant BCG strains expressing RSV antigens promotes protective Th1-type immunity against RSV in mice. Activation of RSV-specific T cells producing IFN-γ and IL-2 was efficiently obtained after immunization with recombinant BCG. This type of T cell immunity was protective against RSV challenge and caused a significant reduction of inflammatory cell infiltration in the airways. Furthermore, mice immunized with recombinant BCG showed no weight loss and reduced lung viral loads. These data strongly support recombinant BCG as an efficient vaccine against RSV because of its capacity to promote protective Th1 immunity. PMID:19075247

  1. Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

    SciTech Connect

    Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet; Quistgaard, Esben M.; Nordlund, Par; Thanabalu, Thirumaran; Torres, Jaume

    2015-08-15

    The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.

  2. Profilin Is Required for Optimal Actin-Dependent Transcription of Respiratory Syncytial Virus Genome RNA

    PubMed Central

    Burke, Emily; Mahoney, Nicole M.; Almo, Steven C.; Barik, Sailen

    2000-01-01

    Transcription of human respiratory syncytial virus (RSV) genome RNA exhibited an obligatory need for the host cytoskeletal protein actin. Optimal transcription, however, required the participation of another cellular protein that was characterized as profilin by a number of criteria. The amino acid sequence of the protein, purified on the basis of its transcription-optimizing activity in vitro, exactly matched that of profilin. RSV transcription was inhibited 60 to 80% by antiprofilin antibody or poly-l-proline, molecules that specifically bind profilin. Native profilin, purified from extracts of lung epithelial cells by affinity binding to a poly-l-proline matrix, stimulated the actin-saturated RSV transcription by 2.5- to 3-fold. Recombinant profilin, expressed in bacteria, stimulated viral transcription as effectively as the native protein and was also inhibited by poly-l-proline. Profilin alone, in the absence of actin, did not activate viral transcription. It is estimated that at optimal levels of transcription, every molecule of viral genomic RNA associates with approximately the following number of protein molecules: 30 molecules of L, 120 molecules of phosphoprotein P, and 60 molecules each of actin and profilin. Together, these results demonstrated for the first time a cardinal role for profilin, an actin-modulatory protein, in the transcription of a paramyxovirus RNA genome. PMID:10623728

  3. Respiratory Syncytial Virus-Associated Hospitalizations in Pre-Mature Infants in Lima, Peru

    PubMed Central

    Ochoa, Theresa J.; Bautista, Rossana; Dávila, Carmen; Salazar, José Antonio; Bazán, Carlos; Guerra, Oscar; Llanos, Jean Pierre; López, Luis; Zea-Vera, Alonso; Ecker, Lucie

    2014-01-01

    We conducted a prospective cohort study in four hospitals in Lima, Peru in infants with a birth weight ≤ 1,500 g followed from birth hospital discharge up to 1 year of age to determine the incidence of respiratory syncytial virus (RSV) hospitalizations. We enrolled 222 infants from March of 2009 to March of 2010: 48 infants with a birth weight < 1,000 g and 174 infants with a birth weight of 1,000–1,500 g (birth weight = 1,197 ± 224 g; gestational age = 30.1 ± 2.6 weeks). There were 936 episodes of respiratory infections; the incidence of respiratory infections during the first 1 year of life was 5.7 episodes/child-years. The incidence of RSV respiratory infections that required emergency room management was 103.9 per 1,000 child-years, and the incidence of RSV hospitalizations was 116.2 per 1,000 child-years (244.9 in infants with a birth weight < 1,000 g and 88.9 in infants 1,000–1,500 g; P < 0.05). The incidence of RSV respiratory infections that required emergency management or hospitalization is high among pre-mature infants in Lima. PMID:25294617

  4. Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

    PubMed

    Lukacs, N W; Tekkanat, K K; Berlin, A; Hogaboam, C M; Miller, A; Evanoff, H; Lincoln, P; Maassab, H

    2001-07-15

    The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.

  5. Respiratory syncytial virus-induced CCL5/RANTES contributes to exacerbation of allergic airway inflammation.

    PubMed

    John, Alison E; Berlin, Aaron A; Lukacs, Nicholas W

    2003-06-01

    Severe respiratory syncytial virus (RSV) infection has a significant impact on airway function and may induce or exacerbate the response to a subsequent allergic challenge. In a murine model combining early RSV infection with later cockroach allergen (CRA) challenge, we examined the role of RSV-induced CCL5/RANTES production on allergic airway responses. RSV infection increased CCL5 mRNA and protein levels, peaking at days 8 and 12, respectively. Administration of CCL5 antiserum during days 0-14 of the RSV infection did not significantly alter viral protein expression when compared to mice treated with control serum. In mice receiving the combined RSV-allergen challenge, lungs collected on day 22 exhibited significantly increased numbers of CD4- and CD8-positive T cells. This increase in T cell numbers was not observed in mice receiving alpha-CCL5. On day 43, peribronchial eosinophilia and leukotriene levels were increased in RSV-allergen mice. Pretreatment with CCL5 antiserum resulted in decreased recruitment of inflammatory cells to bronchoalveolar and peribronchial regions of the lungs and these reductions were associated with a reduction in both T cell recruitment into the bronchoalveolar space, leukotriene release and chemokine generation. Thus, CCL5 released during RSV infection has a significant effect on the inflammatory response to subsequent allergic airway challenges.

  6. Activation of the granzyme pathway in children with severe respiratory syncytial virus infection.

    PubMed

    Bem, Reinout A; Bos, Albert P; Bots, Michael; Wolbink, Angela M; van Ham, S Marieke; Medema, Jan Paul; Lutter, Rene; van Woensel, Job B M

    2008-06-01

    Granzymes (Grs), serine proteases present in granules of effector lymphocytes, are involved in several host immune responses, including the activation of cell death and inflammatory pathways. The main goal of this study was to determine whether the local cell-mediated Gr pathway is activated during severe respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) in children. Tracheal aspirates (TA) from 23 children with RSV-LRTI and 12 controls without pulmonary disease were analyzed for Gr A and B. Bronchoalveolar lavage fluid samples from seven children with RSV-LRTI were analyzed for cellular expression of GrB. Levels of GrA and GrB in TA were significantly increased in RSV patients compared with controls and both Grs showed preserved activity. Gr levels correlated with the total leukocyte counts and IL-8 levels in the airways at several time points. However, no correlation between Gr levels and release of caspase-cleaved cytokeratin-18 was found. There was evidence for marked expression of GrB by both CD8(+) and CD4(+) T cells and natural killer cells in the respiratory tract. These findings suggest activation of the cell-mediated Gr pathway during severe RSV-LRTI in children.

  7. Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus

    PubMed Central

    Martínez, Isidoro; García-Carpizo, Verónica; Guijarro, Trinidad; García-Gomez, Ana; Navarro, Diego; Aranda, Ana; Zambrano, Alberto

    2016-01-01

    ABSTRACT Human respiratory syncytial virus (HRSV) accounts for the majority of lower respiratory tract infections during infancy and childhood and is associated with significant morbidity and mortality. HRSV provokes a proliferation arrest and characteristic syncytia in cellular systems such as immortalized epithelial cells. We show here that HRSV induces the expression of DNA damage markers and proliferation arrest such as P-TP53, P-ATM, CDKN1A and γH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained γH2AFX and TP53BP1, indicative of double-strand breaks (DSBs) and could be reversed by antioxidant treatments such as N-Acetylcysteine (NAC) or reduced glutathione ethyl ester (GSHee). The damage observed is associated with the accumulation of senescent cells, displaying a canonical senescent phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging such as γH2AFX and CDKN2A expression in the respiratory epithelia of infected mice long after viral clearance. Altogether, these results show that HRSV triggers a DNA damage-mediated cellular senescence program probably mediated by oxidative stress. The results also suggest that this program might contribute to the physiopathology of the infection, tissue remodeling and aging, and might be associated to long-term consequences of HRSV infections. PMID:26809688

  8. Elective cesarean delivery as a predisposing factor of respiratory syncytial virus bronchiolitis in children.

    PubMed

    Shang, Xiaoli; Liabsuetrakul, Tippawan; Sangsupawanich, Pasuree; Xia, Xiaoling; He, Ping; Cao, Hong

    2014-08-01

    To investigate the effect of cesarean delivery and other predisposing factors of respiratory syncytial virus (RSV)-positive acute bronchiolitis in children. The case-control study was conducted in three main tertiary hospitals in Kunming, China between September 2012 and July 2013. Children with first episode of wheezing diagnosed as bronchiolitis and testedfor RSV were included RSV was detected by real-time reverse transcription polymerase chain reaction. Mode ofdelivery and characteristics of children, parents, and household were interviewed and analyzed with RSV-positive status by multiple logistic regression. Of 265 children, RSV-positive was found in 75.5%, and the majority of children (83.3%) were younger than 12 months. Compared to vaginal delivery, the odds of RSV-positive detection were double in children born by elective cesarean delivery (adjusted odds ratio 2.32; 95% confidence interval 1.19-4.52). Children aged less than 6 months, born in the rainy season, having maternal history of asthma and living in family that smoked more than 20 cigarettes per day were more likely to be RSV-positive. Children born by elective cesarean delivery increased the risk of RSV-positive acute bronchiolitis after adjusting for age, birth season, maternal asthma, and family smoking status.

  9. Respiratory syncytial virus infection as a cause of hospitalization in population under 1 year in Colombia.

    PubMed

    Piñeros, Juan Gabriel; Baquero, Hernando; Bastidas, Jaime; García, Jorge; Ovalle, Oscar; Patiño, Carlos M; Restrepo, Juan C

    2013-01-01

    to determine the frequency, complications and seasonality at which respiratory syncytial virus (RSV) infection of the lower respiratory tract causes hospitalization in infants of age 1 year or less in 6 cities of Colombia. one-year prospective multicentric observational study that included 717 patients presenting to the emergency department with respiratory symptoms in 6 cities of Colombia. Hospitalized children were tested for RSV with an immunofluorescence rapid test in nasopharyngeal secretions. Descriptive and statistical analyses of the population were conducted. the study population included 717 patients with a mean age of 3.6 months (SD 3.25), 4:3 male: female ratio and a positive RSV LRTI prevalence of 30.0% (216 infants/City, range 26.0 - 49.0%). Risk factors for RSV LRTI were found in 8.2% of the population, of which 28.8% were RSV positive. RSV positive and negative groups were compared using a two-tailed t test with 95.0%CI, p < 0.05. No statistically significant differences were found. All cities presented specific year trimesters in the occurrence of RSV LRTI. the RSV caused 1 in 3 LRTI hospitalizations in the population, with an incidence of 30.0%. This confirms a continuous circulation of RSV in Colombia varying by geographic location. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  10. [Incidence and severity of pertussis in infants with a respiratory syncytial virus infection].

    PubMed

    Moreno Samos, María; Amores Torres, María; Pradillo Martín, María Cristina; Moreno-Pérez, David; Cordón Martínez, Ana; Urda Cardona, Antonio; Ramos Fernández, José Miguel

    2015-01-01

    Pertussis is a re-emerging disease that mostly affects infants. At this age, the severity can be affected by intercurrent infections such as respiratory syncytial virus (RSV). To estimate the incidence of RSV infection during an epidemic period in patients hospitalized due to pertussis. The impact on the severity was also observed during hospitalization. A descriptive study of cases diagnosed with pertussis admitted to a tertiary hospital over a 3year period, where the presence of co-infection with RSV was analyzed. The estimate of severity was estimated using the incidence of complications and the level of care required. From a total of 73 infants with pertussis, 34 occurred in a bronchiolitis season epidemic. A co-infection due to RSV was detected in 17 patients. The mean age was not significantly different compared to the non co-infected. The mean stay and the need for intensive care was similar in both groups. The need for oxygen therapy care and nutritional support was higher in the coinfected patients. Coinfection with RSV in infants hospitalized with pertussis occurred in ono in 2 patients during a RSV epidemic season, in infants of similar age. Severity in terms of stay, presence of apnea and admission to intensive care was similar, but more need for respiratory care and nutritional support was found. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  11. Structure of Respiratory Syncytial Virus Fusion Glycoprotein in the Postfusion Conformation Reveals Preservation of Neutralizing Epitopes

    SciTech Connect

    McLellan, Jason S.; Yang, Yongping; Graham, Barney S.; Kwong, Peter D.

    2011-09-16

    Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies, such as 101F, palivizumab, and motavizumab, target two major antigenic sites on the RSV F glycoprotein. The structures of these sites as peptide complexes with motavizumab and 101F have been previously determined, but a structure for the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here, we present the 2.8-{angstrom} crystal structure of the trimeric RSV F ectodomain in its postfusion conformation. The structure revealed that the 101F and motavizumab epitopes are present in the postfusion state and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the postfusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and motavizumab can bind to multiple conformations of the fusion glycoprotein and can neutralize late in the entry process. The structural preservation of neutralizing epitopes in the postfusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen.

  12. High Viral Load and Respiratory Failure in Adults Hospitalized for Respiratory Syncytial Virus Infections.

    PubMed

    Lee, Nelson; Chan, Martin C W; Lui, Grace C Y; Li, Ran; Wong, Rity Y K; Yung, Irene M H; Cheung, Catherine S K; Chan, Eugenia C Y; Hui, David S C; Chan, Paul K S

    2015-10-15

    A prospective study among adults hospitalized for polymerase chain reaction-confirmed respiratory syncytial virus infections (n = 123) showed frequent occurrence of lower respiratory-tract complications causing respiratory insufficiency (52.8%), requirement for assisted ventilation (16.3%), and intensive care unit admission/death (12.2%). High viral RNA concentration was detected at time of hospitalization, including in patients who presented later than 2 days of illness (day 1-2, 7.29 ± 1.47; day 3-4, 7.28 ± 1.41; day 5-8, 6.66 ± 1.87 log10 copies/mL). RNA concentration was independently associated with risk of complications and respiratory insufficiency (adjusted odds ratio 1.40 per log10 copies/mL increase, 95% confidence interval, 1.03-1.90; P = .034). Our data indicate the need and provide a basis for clinical research on antiviral therapy in this population.

  13. Expression of chemokine receptor CX3CR1 in infants with respiratory syncytial virus bronchiolitis.

    PubMed

    Cepika, Alma-Martina; Gagro, Alenka; Bace, Ana; Tjesic-Drinkovic, Dorian; Kelecic, Jadranka; Baricic-Voskresensky, Tamara; Matic, Mladen; Drazenovic, Vladimir; Marinic, Igor; Mlinaric-Galinovic, Gordana; Tjesic-Drinkovic, Duska; Vrtar, Zvonimir; Rabatic, Sabina

    2008-03-01

    Respiratory syncytial virus (RSV) glycoprotein G mimics fractalkine, a CX(3)C chemokine, which mediates chemotaxis of leukocytes expressing its receptor, CX(3)CR1. The aim of this study was to examine the relationship between RSV infection and expression of perforin and IFN-gamma in CX(3)CR1-expressing peripheral blood CD8(+) T cells. Samples were collected from infants with RSV bronchiolitis, both in the acute and convalescence phase (n = 12), and from their age- and sex-matched healthy controls (n = 15). Perforin expression and IFN-gamma secretion in CX(3)CR1(+) CD8(+) T cells were assessed by four-color flow cytometry. The NF-kappaB p50 and p65 subunit levels were also determined as markers of RSV-induced inflammation. Study results showed perforin and CX(3)CR1 expression to be significantly lower in the convalescent phase of infected infants than in healthy controls. There was no significant difference in IFN-gamma secretion and NF-kappaB binding activity between two time-points in RSV-infected infants, or when compared with healthy controls. Infants with prolonged wheezing had lower acute-phase CX(3)CR1 levels in peripheral blood. These data indicate existence of an event persisting after acute RSV infection that is able to modulate effector functions of cytotoxic T cells, and also link disease severity with CX(3)CR1 expression.

  14. Multicenter clinical performance evaluation of BD Veritor™ system for rapid detection of respiratory syncytial virus.

    PubMed

    Bell, J Jeremiah; Anderson, Evan J; Greene, Wallace H; Romero, José R; Merchant, Moheet; Selvarangan, Rangaraj

    2014-09-01

    BD Veritor™ System for Rapid Detection of Respiratory Syncytial Virus (RSV) is a new-generation lateral flow immunochromatographic assay for objective detection of RSV in respiratory specimens from children. To evaluate the performance of BD Veritor™ System for Rapid Detection of RSV in respiratory specimens collected from pediatric patients. A prospective, multicenter clinical trial was undertaken at five study sites representing geographically diverse regions of the U.S. to assess the performance of the BD Veritor™ System for Rapid Detection of RSV in comparison to R-mix shell vial culture and ProFlu+ reverse transcription-PCR assay (Gen-Probe/Prodesse). 440 nasopharyngeal washes/aspirates (NPW/A) and 706 nasopharyngeal swab (NPS) specimens from U.S. subjects<20 years of age were collected and tested using the BD Veritor™ System and compared with shell vial culture and real-time RT-PCR results. Analysis of the data indicates the overall sensitivity and specificity for BD Veritor™ System for all sample types combined was 90% and 97.0% versus shell vial culture and 75.5% and 98.7% versus RT-PCR respectively. Overall, the BD Veritor™ System for the Rapid Detection of RSV performed well when compared to both viral cell culture and RT-PCR in children. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Induction of long-term immunity against respiratory syncytial virus glycoprotein by an osmotic polymeric nanocarrier.

    PubMed

    Firdous, Jannatul; Islam, Mohammad Ariful; Park, Sung-Moo; Cheon, In-Su; Shim, Byoung-Shik; Yoon, Hyo-Shin; Song, Manki; Chang, Jun; Choi, Yun-Jaie; Park, Yeong-Min; Boraschi, Diana; Han, Seung-Hyun; Cho, Chong-Su; Yun, Cheol-Heui

    2014-11-01

    Respiratory syncytial virus (RSV) is one of the most common causes of viral deaths in infants worldwide, yet no effective vaccines are available. Here, we report an osmotically active polysaccharide-based polysorbitol transporter (PST) prepared from sorbitol diacrylate and low-molecular-weight polyethylenimine (PEI) showing a potent, yet safe, adjuvant activity and acting as an effective delivery tool for RSV glycoprotein (RGp) antigen. PST showed no toxicity in vitro or in vivo, unlike PEI and the well-known experimental mucosal adjuvant cholera toxin (CT). PST formed nano-sized complexes with RGp by simple mixing, without affecting antigenic stability. The complexes exhibited negative surface charges that made them highly efficient in the selective activation of phagocytic cells and enhancement of phagocytic uptake. This resulted in an improved cytokine production and in the significant augmentation of RGp-specific antibody production, which persisted for over 200 days. Interestingly, PST/RGp enhanced phagocytic uptake owing to the osmotic property of PST and its negative zeta potential, suggesting that PST could selectively stimulate phagocytic cells, thereby facilitating a long-lived antigen-specific immune response, which was presumably further enhanced by the polysaccharide properties of PST.

  16. Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation.

    PubMed

    Kaltenborn, Eva; Kern, Suncana; Frixel, Sabrina; Fragnet, Laetitia; Conzelmann, Karl-Klaus; Zarbock, Ralf; Griese, Matthias

    2012-06-15

    ATP-binding cassette transporter A3 (ABCA3) is a lipid transporter active in lung alveolar epithelial type II cells (ATII) and is essential for their function as surfactant-producing cells. ABCA3 mutational defects cause respiratory distress in newborns and interstitial lung disease (ILD) in children. The molecular pathomechanisms are largely unknown; however, viral infections may initiate or aggravate ILDs. Here, we investigated the impact of the clinically relevant ABCA3 mutations, p.Q215K and p.E292V, by stable transfection of A549 lung epithelial cells. ABCA3 mutations strongly impaired expression of the ATII differentiation marker SP-C and the key epithelial cell adhesion proteins E-cadherin and zonula occludens-1. Concurrently, cells expressing ABCA3 mutation acquired mesenchymal features as observed by increased expression of SNAI1, MMP-2 and TGF-β1, and elevated phosphorylation of Src. Infection with respiratory syncytial virus (RSV), the most common viral respiratory pathogen in small children, potentiated the observed mutational effects on loss of epithelial and acquisition of mesenchymal characteristics. In addition, RSV infection of cells harboring ABCA3 mutations resulted in a morphologic shift to a mesenchymal phenotype. We conclude that ABCA3 mutations, potentiated by RSV infection, induce loss of epithelial cell differentiation in ATII. Loss of key epithelial features may disturb the integrity of the alveolar epithelium, thereby comprising its functionality. We suggest the impairment of epithelial function as a mechanism by which ABCA3 mutations cause ILD.

  17. Exploring the dynamics of respiratory syncytial virus (RSV) transmission in children.

    PubMed

    Hogan, Alexandra B; Glass, Kathryn; Moore, Hannah C; Anderssen, Robert S

    2016-08-01

    Respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in children. Whilst highly seasonal, RSV dynamics can have either one-year (annual) or two-year (biennial) cycles. Furthermore, some countries show a 'delayed biennial' pattern, where the epidemic peak in low incidence years is delayed. We develop a compartmental model for RSV infection, driven by a seasonal forcing function, and conduct parameter space and bifurcation analyses to document parameter ranges that give rise to these different seasonal patterns. The model is sensitive to the birth rate, transmission rate, and seasonality parameters, and can replicate RSV dynamics observed in different countries. The seasonality parameter must exceed a threshold for the model to produce biennial cycles. Intermediate values of the birth rate produce the greatest delay in these biennial cycles, while the model reverts to annual cycles if the duration of immunity is too short. Finally, the existence of period doubling and period halving bifurcations suggests robust model dynamics, in agreement with the known regularity of RSV outbreaks. These findings help explain observed RSV data, such as regular biennial dynamics in Western Australia, and delayed biennial dynamics in Finland. From a public health perspective, our findings provide insight into the drivers of RSV transmission, and a foundation for exploring RSV interventions.

  18. NK cell immunophenotypic and genotypic analysis of infants with severe respiratory syncytial virus infection.

    PubMed

    Noyola, Daniel E; Juárez-Vega, Guillermo; Monjarás-Ávila, César; Escalante-Padrón, Francisco; Rangel-Ramírez, Verónica; Cadena-Mota, Sandra; Monsiváis-Urenda, Adriana; García-Sepúlveda, Christian A; González-Amaro, Roberto

    2015-07-01

    Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants. Reduced numbers of NK cells have been reported in infants with severe RSV infection; however, the precise role of NK cells during acute RSV infection is unclear. In this study the NK and T cell phenotypes, LILRB1 gene polymorphisms and KIR genotypes of infants hospitalized with RSV infection were analyzed. Compared to controls, infants with acute RSV infection showed a higher proportion of LILRB1+ T cells; in addition, a subgroup of infants with RSV infection showed an increase in LILRB1+ NK cells. No differences in NKG2C, NKG2A, or CD161 expression between RSV infected infants and controls were observed. LILRB1 genotype distribution of the rs3760860 A>G, and rs3760861 A>G single nucleotide polymorphisms differed between infants with RSV infection and healthy donors, whereas no differences in any of the KIR genes were observed. Our results suggest that LILRB1 participates in the pathogenesis of RSV infection. Further studies are needed to define the role of LILRB1+ NK in response to RSV and to confirm an association between LILRB1 polymorphisms and the risk of severe RSV infection.

  19. Ginseng Protects Against Respiratory Syncytial Virus by Modulating Multiple Immune Cells and Inhibiting Viral Replication

    PubMed Central

    Lee, Jong Seok; Lee, Yu-Na; Lee, Young-Tae; Hwang, Hye Suk; Kim, Ki-Hye; Ko, Eun-Ju; Kim, Min-Chul; Kang, Sang-Moo

    2015-01-01

    Ginseng has been used in humans for thousands of years but its effects on viral infection have not been well understood. We investigated the effects of red ginseng extract (RGE) on respiratory syncytial virus (RSV) infection using in vitro cell culture and in vivo mouse models. RGE partially protected human epithelial (HEp2) cells from RSV-induced cell death and viral replication. In addition, RGE significantly inhibited the production of RSV-induced pro-inflammatory cytokine (TNF-α) in murine dendritic and macrophage-like cells. More importantly, RGE intranasal pre-treatment prevented loss of mouse body weight after RSV infection. RGE treatment improved lung viral clearance and enhanced the production of interferon (IFN-γ) in bronchoalveolar lavage cells upon RSV infection of mice. Analysis of cellular phenotypes in bronchoalveolar lavage fluids showed that RGE treatment increased the populations of CD8+ T cells and CD11c+ dendritic cells upon RSV infection of mice. Taken together, these results provide evidence that ginseng has protective effects against RSV infection through multiple mechanisms, which include improving cell survival, partial inhibition of viral replication and modulation of cytokine production and types of immune cells migrating into the lung. PMID:25658239

  20. Respiratory syncytial virus M2-1 protein induces the activation of nuclear factor kappa B

    SciTech Connect

    Reimers, Kerstin . E-mail: reimers.kerstin@mh-hannover.de; Buchholz, Katja; Werchau, Hermann

    2005-01-20

    Respiratory syncytial virus (RSV) induces the production of a number of cytokines and chemokines by activation of nuclear factor kappa B (NF-{kappa}B). The activation of NF-{kappa}B has been shown to depend on viral replication in the infected cells. In this study, we demonstrate that expression of RSV M2-1 protein, a transcriptional processivity and anti-termination factor, is sufficient to activate NF-{kappa}B in A549 cells. Electromobility shift assays show increased NF-{kappa}B complexes in the nuclei of M2-1-expressing cells. M2-1 protein is found in nuclei of M2-1-expressing cells and in RSV-infected cells. Co-immunoprecipitations of nuclear extracts of M2-1-expressing cells and of RSV-infected cells revealed an association of M2-1 with Rel A protein. Furthermore, the activation of NF-{kappa}B depends on the C-terminus of the RSV M2-1 protein, as shown by NF-{kappa}B-induced gene expression of a reporter gene construct.

  1. Extrapulmonary manifestations of severe respiratory syncytial virus infection – a systematic review

    PubMed Central

    Eisenhut, Michael

    2006-01-01

    Introduction Respiratory syncytial virus (RSV) bronchiolitis is the most important cause for admission to the paediatric intensive care unit in infants with lower respiratory tract infection. In recent years the importance of extrapulmonary manifestations of RSV infection has become evident. This systematic review aimed at summarizing the available evidence on manifestations of RSV infection outside the respiratory tract, their causes and the changes in clinical management required. Methods Databases searched were Medline (1950 to present), EMBASE (1974 to present), PubMed and reference lists of relevant articles. Summarized were the findings of articles reporting on manifestations of RSV infection outside the respiratory tract in patients of all age groups. Results Extrapulmonary manifestations reported in previous observational studies included cardiovascular failure with hypotension and inotrope requirements associated with myocardial damage as evident from elevated cardiac troponin levels (35–54% of ventilated infants), cardiac arrhythmias like supraventricular tachycardias and ventricular tachycardias, central apnoeas (16–21% of admissions), focal and generalized seizures, focal neurological abnormalities, hyponatraemia (33%) associated with increased antidiuretic hormone secretion, and hepatitis (46–49% of ventilated infants). RSV or its genetic material have been isolated from cerebrospinal fluid, myocardium, liver and peripheral blood. Conclusion The data summarized indicate a systemic dissemination of RSV during severe disease. Cerebral and myocardial involvement may explain the association of RSV with some cases of sudden infant death. In infants with severe RSV infection cardiac rhythm, blood pressure and serum sodium need to be monitored and supportive treatment including fluid management adjusted accordingly. PMID:16859512

  2. Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus.

    PubMed

    Martínez, Isidoro; García-Carpizo, Verónica; Guijarro, Trinidad; García-Gomez, Ana; Navarro, Diego; Aranda, Ana; Zambrano, Alberto

    2016-05-18

    Human respiratory syncytial virus (HRSV) accounts for the majority of lower respiratory tract infections during infancy and childhood and is associated with significant morbidity and mortality. HRSV provokes a proliferation arrest and characteristic syncytia in cellular systems such as immortalized epithelial cells. We show here that HRSV induces the expression of DNA damage markers and proliferation arrest such as P-TP53, P-ATM, CDKN1A and γH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained γH2AFX and TP53BP1, indicative of double-strand breaks (DSBs) and could be reversed by antioxidant treatments such as N-Acetylcysteine (NAC) or reduced glutathione ethyl ester (GSHee). The damage observed is associated with the accumulation of senescent cells, displaying a canonical senescent phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging such as γH2AFX and CDKN2A expression in the respiratory epithelia of infected mice long after viral clearance. Altogether, these results show that HRSV triggers a DNA damage-mediated cellular senescence program probably mediated by oxidative stress. The results also suggest that this program might contribute to the physiopathology of the infection, tissue remodeling and aging, and might be associated to long-term consequences of HRSV infections.

  3. Development of two salmonella-based oral vaccines against human respiratory syncytial virus.

    PubMed

    Azizi Jalilian, F; Yusoff, K; Suhaimi, S; Amini, R; Sekawi, Z; Jahanshiri, F

    2015-01-01

    Human respiratory syncytial virus is the most common cause of bronchiolitis and other respiratory infections in infants and the elderly worldwide. We have developed two new oral vaccines using Salmonella typhi TY21a to carry and express the immunogenic epitopes of RSV fusion (F) and attachment (G) glycoproteins on its surface, separately. To evaluate the efficacy of the designed vaccines, BALB/c mice were orally immunized and then infected with RSV. Immune response analyses showed that cellmediated, mucosal and humoral immunity in the vaccinated mice were significantly enhanced compared to the control group. Both vaccines generated a balanced Th1/Th2 immune response which is crucial for efficiency of vaccines against RSV. Furthermore, histopathological examination proved that these vaccines were safe as they did not cause any Th2-associated adverse effects in the lungs of RSV-infected mice. The findings of this research suggest that Salmonella-F and Salmonella-G vaccine candidates may have strong potential to prevent RSV infection.

  4. Retrospective Parameter Estimation and Forecast of Respiratory Syncytial Virus in the United States

    PubMed Central

    Shaman, Jeffrey

    2016-01-01

    Recent studies have shown that systems combining mathematical modeling and Bayesian inference methods can be used to generate real-time forecasts of future infectious disease incidence. Here we develop such a system to study and forecast respiratory syncytial virus (RSV). RSV is the most common cause of acute lower respiratory infection and bronchiolitis. Advanced warning of the epidemic timing and volume of RSV patient surges has the potential to reduce well-documented delays of treatment in emergency departments. We use a susceptible-infectious-recovered (SIR) model in conjunction with an ensemble adjustment Kalman filter (EAKF) and ten years of regional U.S. specimen data provided by the Centers for Disease Control and Prevention. The data and EAKF are used to optimize the SIR model and i) estimate critical epidemiological parameters over the course of each outbreak and ii) generate retrospective forecasts. The basic reproductive number, R0, is estimated at 3.0 (standard deviation 0.6) across all seasons and locations. The peak magnitude of RSV outbreaks is forecast with nearly 70% accuracy (i.e. nearly 70% of forecasts within 25% of the actual peak), four weeks before the predicted peak. This work represents a first step in the development of a real-time RSV prediction system. PMID:27716828

  5. Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses.

    PubMed

    Owczarczyk, Anna B; Schaller, Matthew A; Reed, Michelle; Rasky, Andrew J; Lombard, David B; Lukacs, Nicholas W

    2015-08-15

    Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, has been associated with the induction of autophagy and the regulation of inflammatory mediators. We found that Sirt1 was upregulated in mouse lung after RSV infection. Infected animals that received EX-527, a selective SIRT1 inhibitor, displayed exacerbated lung pathology, with increased mucus production, elevated viral load, and enhanced Th2 cytokine production. Gene expression analysis of isolated cell populations revealed that Sirt1 was most highly upregulated in RSV-treated dendritic cells (DCs). Upon RSV infection, EX-527-treated DCs, Sirt1 small interfering RNA-treated DCs, or DCs from conditional knockout (Sirt1(f/f)-CD11c-Cre(+)) mice showed downregulated inflammatory cytokine gene expression and attenuated autophagy. Finally, RSV infection of Sirt1(f/f)-CD11c-Cre(+) mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. These data indicate that SIRT1 promotes DC activation associated with autophagy-mediated processes during RSV infection, thereby directing efficient antiviral immune responses.

  6. Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection

    PubMed Central

    Yamaguchi, Yuko; Harker, James A.; Wang, Belinda; Openshaw, Peter J.

    2012-01-01

    Severe respiratory viral infection in early life is associated with recurrent wheeze and asthma in later childhood. Neonatal immune responses tend to be skewed toward T helper 2 (Th2) responses, which may contribute to the development of a pathogenic recall response to respiratory infection. Since neonatal Th2 skewing can be modified by stimulation with Toll-like receptor (TLR) ligands, we investigated the effect of exposure to CpG oligodeoxynucleotides (TLR9 ligands) prior to neonatal respiratory syncytial virus (RSV) infection in mice. CpG preexposure was protective against enhanced disease during secondary adult RSV challenge, with a reduction in viral load and an increase in Th1 responses. A similar Th1 switch and reduction in disease were observed if CpG was administered in the interval between neonatal infection and challenge. In neonates, CpG pretreatment led to a transient increase in expression of major histocompatibility complex class II (MHCII) and CD80 on CD11c-positive cells and gamma interferon (IFN-γ) production by NK cells after RSV infection, suggesting that the protective effects may be mediated by antigen-presenting cells (APC) and NK cells. We conclude that the adverse effects of early-life respiratory viral infection on later lung health might be mitigated by conditions that promote TLR activation in the infant lung. PMID:22811525

  7. IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice.

    PubMed

    Loebbermann, Jens; Schnoeller, Corinna; Thornton, Hannah; Durant, Lydia; Sweeney, Nathan P; Schuijs, Martijn; O'Garra, Anne; Johansson, Cecilia; Openshaw, Peter J

    2012-01-01

    Interleukin (IL-) 10 is a pleiotropic cytokine with broad immunosuppressive functions, particularly at mucosal sites such as the intestine and lung. Here we demonstrate that infection of BALB/c mice with respiratory syncytial virus (RSV) induced IL-10 production by CD4(+) and CD8(+) T cells in the airways at later time points (e.g. day 8); a proportion of these cells also co-produced IFN-γ. Furthermore, RSV infection of IL-10(-/-) mice resulted in more severe disease with enhanced weight loss, delayed recovery and greater cell infiltration of the respiratory tract without affecting viral load. In addition, IL-10(-/-) mice had a pronounced airway neutrophilia and heightened levels of pro-inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid. Notably, the proportion of lung T cells producing IFN-γ was enhanced, suggesting that IL-10 may act in an autocrine manner to dampen effector T cell responses. Similar findings were made in mice treated with anti-IL-10R antibody and infected with RSV. Therefore, IL-10 inhibits disease and inflammation in mice infected with RSV, especially during recovery from infection.

  8. Potential therapeutic implications of new insights into respiratory syncytial virus disease.

    PubMed

    Openshaw, Peter J M

    2002-01-01

    Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-alpha, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease.

  9. Genetic susceptibility to the delayed sequelae of neonatal respiratory syncytial virus infection is MHC dependent.

    PubMed

    Tregoning, John S; Yamaguchi, Yuko; Wang, Belinda; Mihm, Dagmar; Harker, James A; Bushell, Ellen S C; Zheng, Ming; Liao, Guochun; Peltz, Gary; Openshaw, Peter J M

    2010-11-01

    Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection.

  10. Understanding the transmission dynamics of respiratory syncytial virus using multiple time series and nested models.

    PubMed

    White, L J; Mandl, J N; Gomes, M G M; Bodley-Tickell, A T; Cane, P A; Perez-Brena, P; Aguilar, J C; Siqueira, M M; Portes, S A; Straliotto, S M; Waris, M; Nokes, D J; Medley, G F

    2007-09-01

    The nature and role of re-infection and partial immunity are likely to be important determinants of the transmission dynamics of human respiratory syncytial virus (hRSV). We propose a single model structure that captures four possible host responses to infection and subsequent reinfection: partial susceptibility, altered infection duration, reduced infectiousness and temporary immunity (which might be partial). The magnitude of these responses is determined by four homotopy parameters, and by setting some of these parameters to extreme values we generate a set of eight nested, deterministic transmission models. In order to investigate hRSV transmission dynamics, we applied these models to incidence data from eight international locations. Seasonality is included as cyclic variation in transmission. Parameters associated with the natural history of the infection were assumed to be independent of geographic location, while others, such as those associated with seasonality, were assumed location specific. Models incorporating either of the two extreme assumptions for immunity (none or solid and lifelong) were unable to reproduce the observed dynamics. Model fits with either waning or partial immunity to disease or both were visually comparable. The best fitting structure was a lifelong partial immunity to both disease and infection. Observed patterns were reproduced by stochastic simulations using the parameter values estimated from the deterministic models.

  11. Pharmacokinetics-Pharmacodynamics of a Respiratory Syncytial Virus Fusion Inhibitor in the Cotton Rat Model▿

    PubMed Central

    Rouan, Marie-Claude; Gevers, Tom; Roymans, Dirk; de Zwart, Loeckie; Nauwelaers, David; De Meulder, Marc; van Remoortere, Pieter; Vanstockem, Marc; Koul, Anil; Simmen, Kenny; Andries, Koen

    2010-01-01

    Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple Emax model with a maximal viral titer reduction (Emax) of 1.5 log10. The plasma drug level required to achieve 50% of the Emax (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors. PMID:20823290

  12. Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections.

    PubMed Central

    Hemming, V G; Prince, G A; Groothuis, J R; Siber, G R

    1995-01-01

    Respiratory syncytial virus (RSV) is an important community and nosocomial respiratory pathogen for infants and young children. RSV causes especially severe disease in the prematurely born or those with chronic cardiopulmonary diseases. Elderly persons and those with T-cell deficiencies, such as bone marrow transplant recipients, are also at high risk for serious lower respiratory tract infections. To date, prevention of RSV infections by vaccination has proven elusive and no preventive drugs exist. Studies in animals and humans have shown that the lower respiratory tract can be protected from RSV infection by sufficient circulating RSV neutralizing antibody levels. Recently, an RSV hyperimmune immune globulin (RSVIG) was developed and tested for the prevention of RSV infections or reduction of disease severity. Passive immunization of high-risk children with RSVIG during the respiratory disease season effected significant reductions in RSV infections, hospitalizations, days of hospitalization, intensive care unit admissions, days in the intensive care unit, and ribavirin use. Studies in cotton rats and owl monkeys show that RSV infections can also be treated with inhalation of immune globulin at doses substantially smaller than required for parenteral treatment. Therapeutic trials of parenteral RSVIG have been completed and are pending analysis. The use of polyclonal, hyperimmune globulins and perhaps human monoclonal antibodies provides an additional approach to the prevention and perhaps the treatment of certain viral lower respiratory tract infections such as those caused by RSV. PMID:7704893

  13. Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections.

    PubMed

    Hemming, V G; Prince, G A; Groothuis, J R; Siber, G R

    1995-01-01

    Respiratory syncytial virus (RSV) is an important community and nosocomial respiratory pathogen for infants and young children. RSV causes especially severe disease in the prematurely born or those with chronic cardiopulmonary diseases. Elderly persons and those with T-cell deficiencies, such as bone marrow transplant recipients, are also at high risk for serious lower respiratory tract infections. To date, prevention of RSV infections by vaccination has proven elusive and no preventive drugs exist. Studies in animals and humans have shown that the lower respiratory tract can be protected from RSV infection by sufficient circulating RSV neutralizing antibody levels. Recently, an RSV hyperimmune immune globulin (RSVIG) was developed and tested for the prevention of RSV infections or reduction of disease severity. Passive immunization of high-risk children with RSVIG during the respiratory disease season effected significant reductions in RSV infections, hospitalizations, days of hospitalization, intensive care unit admissions, days in the intensive care unit, and ribavirin use. Studies in cotton rats and owl monkeys show that RSV infections can also be treated with inhalation of immune globulin at doses substantially smaller than required for parenteral treatment. Therapeutic trials of parenteral RSVIG have been completed and are pending analysis. The use of polyclonal, hyperimmune globulins and perhaps human monoclonal antibodies provides an additional approach to the prevention and perhaps the treatment of certain viral lower respiratory tract infections such as those caused by RSV.

  14. Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein.

    PubMed

    Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet; Quistgaard, Esben M; Nordlund, Par; Thanabalu, Thirumaran; Torres, Jaume

    2015-08-01

    The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target.

  15. Respiratory syncytial virus infection: denominator-based studies in Indonesia, Mozambique, Nigeria and South Africa.

    PubMed Central

    Robertson, Susan E.; Roca, Anna; Alonso, Pedro; Simoes, Eric A. F.; Kartasasmita, Cissy B.; Olaleye, David O.; Odaibo, Georgina N.; Collinson, Mark; Venter, Marietjie; Zhu, Yuwei; Wright, Peter F.

    2004-01-01

    OBJECTIVE: To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries. METHODS: A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions. FINDINGS: Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants. CONCLUSION: These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life. PMID:15654405

  16. Antiviral effect of cimicifugin from Cimicifuga foetida against human respiratory syncytial virus.

    PubMed

    Wang, Kuo-Chih; Chang, Jung-San; Lin, Liang-Tzung; Chiang, Lien-Chai; Lin, Chun-Ching

    2012-01-01

    Human respiratory syncytial virus (RSV) causes serious infection of the lower respiratory tract in children and an effective antiviral therapy against the viral pathogen remains unavailable. We previously demonstrated that the oriental medicinal plant, Cimicifuga foetida L. (C. foetida), possessed inhibitory activity against RSV. Since cimicifugin is a major constituent of C. foetida, we sought to examine in this study its anti-RSV effect on both the human upper (HEp-2) and lower (A549) respiratory tract cell lines. Results revealed that cimicifugin dose-dependently inhibited RSV-induced plaque formation in both HEp-2 and A549 cells (p < 0.0001), with a superior effect in the latter cell type (p < 0.0001). The antiviral activity of cimicifugin was time-dependent (p < 0.0001) and was most effective when cells were treated with the compound before viral inoculation. Additional experiments demonstrated that cimicifugin could inhibit viral attachment (p < 0.0001) and viral internalization (p < 0.0001). Furthermore, the drug could potentiate heparin's effect against attachment of RSV, particularly in A549 cells. Enzyme-linked immunosorbent assay (ELISA) analysis of antiviral cytokines induction revealed that cimicifugin could also stimulate epithelial cells to secrete IFN-β to counteract viral infection. Taken together, these results indicate that cimicifugin is an efficient antiviral agent against RSV infection. We suggest that cimicifugin might be useful for the management of RSV pathogenesis.

  17. Cimicifuga foetida L. inhibited human respiratory syncytial virus in HEp-2 and A549 cell lines.

    PubMed

    Wang, Kuo Chih; Chang, Jung San; Chiang, Lien Chai; Lin, Chun Ching

    2012-01-01

    Human respiratory syncytial virus (HRSV) causes serious pediatric infection of the lower respiratory tract without effective therapeutic modality. Sheng-Ma-Ge-Gen-Tang (SMGGT; Shoma-kakkon-to) has been proven to be effective at inhibiting HRSV-induced plaque formation, and Cimicifuga foetida is the major constituent of SMGGT. We tested the hypothesis that C. foetida effectively inhibited the cytopathic effects of HRSV by a plaque reduction assay in both human upper (HEp2) and lower (A549) respiratory tract cell lines. Its ability to stimulate anti-viral cytokines was evaluated by an enzyme-linked immunosorbent assay (ELISA). C. foetida dose-dependently inhibited HRSV-induced plaque formation (p < 0.0001) before and after viral inoculation, especially in A549 cells (p < 0.0001). C. foetida dose-dependently inhibited viral attachment (p < 0.0001) and could increase heparins effect on viral attachment. In addition, C. foetida time-dependently and dose-dependently (p < 0.0001) inhibited HRSV internalization. C. foetida could stimulate epithelial cells to secrete IFN-β to counteract viral infection. However, C. foetida did not stimulate TNF-α secretion. Therefore, C. foetida could be useful in managing HRSV infection. This is the first evidence to support that C. foetida possesses antiviral activity.

  18. The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis▿

    PubMed Central

    Eckardt-Michel, Julia; Lorek, Markus; Baxmann, Diane; Grunwald, Thomas; Keil, Günther M.; Zimmer, Gert

    2008-01-01

    Infection with respiratory syncytial virus (RSV) frequently causes inflammation and obstruction of the small airways, leading to severe pulmonary disease in infants. We show here that the RSV fusion (F) protein, an integral membrane protein of the viral envelope, is a strong elicitor of apoptosis. Inducible expression of F protein in polarized epithelial cells triggered caspase-dependent cell death, resulting in rigorous extrusion of apoptotic cells from the cell monolayer and transient loss of epithelial integrity. A monoclonal antibody directed against F protein inhibited apoptosis and was also effective if administered to A549 lung epithelial cells postinfection. F protein expression in epithelial cells caused phosphorylation of tumor suppressor p53 at serine 15, activation of p53 transcriptional activity, and conformational activation of proapoptotic Bax. Stable expression of dominant-negative p53 or p53 knockdown by RNA interference inhibited the apoptosis of RSV-infected A549 cells. HEp-2 tumor cells with low levels of p53 were not sensitive to RSV-triggered apoptosis. We propose a new model of RSV disease with the F protein as an initiator of epithelial cell shedding, airway obstruction, secondary necrosis, and consequent inflammation. This makes the RSV F protein a key target for the development of effective postinfection therapies. PMID:18216092

  19. Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus.

    PubMed

    Lukacs, Nicholas W; Moore, Martin L; Rudd, Brian D; Berlin, Aaron A; Collins, Robert D; Olson, Sandra J; Ho, Samuel B; Peebles, R Stokes

    2006-09-01

    In this study we performed comparisons of pulmonary responses between two different respiratory syncytial virus (RSV) antigenic subgroup A strains, A2 and Line 19. Line 19 strain induced significant dose-responsive airway hyperreactivity (AHR) in BALB/c mice at days 6 and 9 after infection, whereas the A2 strain induced no AHR at any dose. Histological examination indicated that A2 induced no goblet cell hyper/metaplasia, whereas the Line 19 induced goblet cell expansion and significant increases in gob5 and MUC5AC mRNA and protein levels in vivo. When examining cytokine responses, A2 strain induced significant interleukin (IL)-10 expression, whereas Line 19 strain induced significant IL-13 expression. When IL-13-/- mice were infected with Line 19 RSV, the AHR responses were abrogated along with gob5 gene expression. There was little difference in viral titer throughout the infection between the line 19- and A2-infected mice. However, the A2 strain grew to significantly higher titers than the Line 19 strain in HEp-2 cells in vitro. Thus, RSV Line 19-induced airway dysfunction does not correlate with viral load in vivo. These data demonstrate that different RSV strains of the same antigenic subgroup can elicit differential immune responses that impact the phenotypic expression of RSV-induced illness.

  20. Estimating the hospitalization burden associated with influenza and respiratory syncytial virus in New York City, 2003–2011

    PubMed Central

    Goldstein, Edward; Greene, Sharon K; Olson, Donald R; Hanage, William P; Lipsitch, Marc

    2015-01-01

    Background Hospitalization burden associated with influenza and respiratory syncytial virus (RSV) is uncertain due to ambiguity in the inference methodologies employed for its estimation. Objectives Utilization of a new method to quantitate the above burden. Methods Weekly hospitalization rates for several principal diagnoses from 2003 to 2011 in New York City by age group were regressed linearly against incidence proxies for the major influenza subtypes and RSV adjusting for temporal trends and seasonal baselines. Results Average annual rates of influenza-associated respiratory hospitalizations per 100 000 were estimated to be 129 [95% CI (79, 179)] for age <1, 36·3 (21·6, 51·4) for ages 1–4, 10·6 (7·5, 13·7) for ages 5–17, 25·6 (21·3, 29·8) for ages 18–49, 65·5 (54·0, 76·9) for ages 50–64, 125 (105, 147) for ages 65–74, and 288 (244, 331) for ages ≥75. Additionally, influenza had a significant contribution to hospitalization rates with a principal diagnosis of septicemia for ages 5–17 [0·76 (0·1, 1·4)], 18–49 [1·02 (0·3, 1·7)], 50–64 [4·0 (1·7, 6·3)], 65–74 [8·8 (2·2, 15·6)], and ≥75 [38·7 (25·7, 52·9)]. RSV had a significant contribution to the rates of respiratory hospitalizations for age <1 [1900 (1740, 2060)], ages 1–4 [117 (70, 167)], and ≥75 [175 (44, 312)] [including chronic lower respiratory disease, 90 (43, 140)] as well as pneumonia & influenza hospitalizations for ages 18–49 [6·2 (1·1, 11·3)] and circulatory hospitalizations for ages ≥75 [199 (13, 375)]. Conclusions The high burden of RSV hospitalizations among young children and seniors age ≥75 suggests the need for additional control measures such as vaccination to mitigate the impact of annual RSV epidemics. Our estimates for influenza-associated hospitalizations provide further evidence of the burden of morbidity associated with influenza, supporting current guidelines regarding influenza vaccination and antiviral treatment. PMID

  1. Impaired immune response to vaccination against infection with human respiratory syncytial virus at advanced age.

    PubMed

    Guichelaar, Teun; Hoeboer, Jeroen; Widjojoatmodjo, Myra N; Reemers, Sylvia S N; van Els, Cécile A C M; Otten, Rob; van Remmerden, Yvonne; Boes, Jolande; Luytjes, Willem

    2014-09-01

    Elderly humans are prone to severe infection with human respiratory syncytial virus (HRSV). The aging of today's human population warrants the development of protective vaccination strategies aimed specifically at the elderly. This may require special approaches due to deteriorating immune function. To design and test vaccination strategies tailored to the elderly population, we need to understand the host response to HRSV vaccination and infection at old age. Moreover, the preclinical need for testing of candidate vaccines requires translational models resembling susceptibility to the (unadapted) human pathogen. Here, we explored the effects of aging on immunity and protection induced by a model HRSV vaccine candidate in a translational aging model in cotton rats (Sigmodon hispidus) and examined possibilities to optimize vaccination concepts for the elderly. We immunized young and aged cotton rats with a live-attenuated recombinant HRSV vaccine candidate and analyzed the induced immune response to and protection against challenge with HRSV. In old cotton rats, HRSV infection persisted longer, and vaccination induced less protection against infection. Aged animals developed lower levels of vaccine-induced IgG, virus-neutralizing serum antibodies, and IgA in lungs. Moreover, booster responses to HRSV challenge were impaired in animals vaccinated at an older age. However, increased dose and reduced attenuation of vaccine improved protection even in old animals. This study shows that cotton rats provide a model for studying the effects of aging on the immune response to the human respiratory pathogen HRSV and possibilities to optimize vaccine concepts for the elderly. HRSV infection poses a risk for severe disease in the elderly. The aging of the population warrants increased efforts to prevent disease at old age, whereas HRSV vaccines are only in the developmental phase. The preclinical need for testing of candidate human vaccines requires translational models

  2. Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses

    PubMed Central

    Palomo, Concepción; Mas, Vicente; Thom, Michelle; Vázquez, Mónica; Cano, Olga; Terrón, María C.; Luque, Daniel

    2016-01-01

    ABSTRACT Human respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates. IMPORTANCE Protection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion

  3. Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein.

    PubMed

    Leemans, A; De Schryver, M; Van der Gucht, W; Heykers, A; Pintelon, I; Hotard, A L; Moore, M L; Melero, J A; McLellan, J S; Graham, B S; Broadbent, L; Power, U F; Caljon, G; Cos, P; Maes, L; Delputte, P

    2017-07-15

    Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs in vivo and how this might impact RSV replication.IMPORTANCE Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are

  4. Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses.

    PubMed

    Palomo, Concepción; Mas, Vicente; Thom, Michelle; Vázquez, Mónica; Cano, Olga; Terrón, María C; Luque, Daniel; Taylor, Geraldine; Melero, José A

    2016-06-01

    Human respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates. Protection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion F (found after

  5. Genetic analysis and antigenic characterization of human respiratory syncytial virus group A viruses isolated in Germany 1996-2008.

    PubMed

    Adams, Ortwin; Werzmirzowsky, Judith; Hengel, Hartmut

    2013-10-01

    The genetic and antigenic variability of 18 human respiratory syncytial virus group A viruses isolated in Germany from 1996 to 2008 was evaluated by nucleotide sequencing of the complete G and F genes and enzyme-linked immunosorbent assay analysis with anti-G and anti-F monoclonal antibodies. Phylogenetic analyses showed that the G-proteins clustered into the two genotypes GA2 and GA5. The antigenic analysis of G-gene was carried out with a panel of anti-G and anti-F monoclonal antibodies that recognized strain-specific or variable epitopes which were originally derived against long strain (subtype GA1) and MON-3-88 strain (GA2). An amino acid substitution was found in a potential O-glycosylation site leading to a loss of reactivity with a strain-specific MAb. A score was calculated for quantifying the overall reactivity of the antibodies. If reactivity of all MAbs was totalized, a net sum loss of reactivity was seen over the time suggesting that antigenic drift due to immune selection may be occurring.

  6. Pulmonary cyclooxygenase-1 (COX-1) and COX-2 cellular expression and distribution after respiratory syncytial virus and parainfluenza virus infection.

    PubMed

    Radi, Zaher A; Meyerholz, David K; Ackermann, Mark R

    2010-02-01

    Prostaglandins (PGs) play an important role in pulmonary physiology and various pathophysiological processes following infection. The initial step in the biosynthesis of PGs is regulated by two distinct cyclooxygenase enzymes, cyclooxygenase-1 (COX-1) and COX-2. The goal of this study was to investigate the pulmonary cellular localization and distribution of COX-1 and COX-2 in a neonatal lamb model following respiratory syncytial virus (RSV) and parainfluenza virus 3 (PI3) infection, organisms that also cause significant respiratory disease in children. No significant differences were seen in pulmonary COX-1 expression at various microanatomical locations following RSV or PI3 infection compared to controls. In contrast, COX-2 was upregulated following RSV and PI3 infection. Strong expression was restricted to bronchial and bronchiolar epithelial cells and macrophages, while minimal expression was present in the same microanatomical locations in the uninfected lungs. Other microanatomical locations in both the controls and the infected lungs lacked expression. This work suggests that during RSV or PI3 infection: (1) COX-1 cellular expression is not altered, (2) COX-2 cellular expression is upregulated in airway bronchiolar and bronchial epithelial cells and macrophages, (3) respiratory epithelium along with macrophages are important microanatomical compartments regulating the host inflammatory response during viral infection, and (4) COX-2 may be a potential target for RSV and PI3 therapy.

  7. Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

    PubMed Central

    Mata, Manuel; Martinez, Isidoro; Melero, Jose A.; Tenor, Herman; Cortijo, Julio

    2013-01-01

    Respiratory syncytial virus (RSV) causes acute exacerbations in COPD and asthma. RSV infects bronchial epithelial cells (HBE) that trigger RSV associated lung pathology. This study explores whether the phosphodiesterase 4 (PDE4) inhibitor Roflumilast N-oxide (RNO), alters RSV infection of well-differentiated HBE (WD-HBE) in vitro. WD-HBE were RSV infected in the presence or absence of RNO (0.1-100 nM). Viral infection (staining of F and G proteins, nucleoprotein RNA level), mRNA of ICAM-1, ciliated cell markers (digital high speed videomicroscopy, β-tubulin immunofluorescence, Foxj1 and Dnai2 mRNA), Goblet cells (PAS), mRNA of MUC5AC and CLCA1, mRNA and protein level of IL-13, IL-6, IL-8, TNFα, formation of H2O2 and the anti-oxidative armamentarium (mRNA of Nrf2, HO-1, GPx; total antioxidant capacity (TAC) were measured at day 10 or 15 post infection. RNO inhibited RSV infection of WD-HBE, prevented the loss of ciliated cells and markers, reduced the increase of MUC5AC and CLCA1 and inhibited the increase of IL-13, IL-6, IL-8, TNFα and ICAM-1. Additionally RNO reversed the reduction of Nrf2, HO-1 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation. RNO inhibits RSV infection of WD-HBE cultures and mitigates the cytopathological changes associated to this virus. PMID:23936072

  8. Inhibition of Human Respiratory Syncytial Virus Infectivity by a Dendrimeric Heparan Sulfate-Binding Peptide

    PubMed Central

    Donalisio, Manuela; Rusnati, Marco; Cagno, Valeria; Civra, Andrea; Bugatti, Antonella; Giuliani, Andrea; Pirri, Giovanna; Volante, Marco; Papotti, Mauro; Landolfo, Santo

    2012-01-01

    Respiratory syncytial virus (RSV) interacts with cell surface heparan sulfate proteoglycans (HSPGs) to initiate infection. The interaction of RSV with HSPGs thus presents an attractive target for the development of novel inhibitors of RSV infection. In the present study, a minilibrary of linear, dimeric, and dendrimeric peptides containing clusters of basic amino acids was screened with the aim of identifying peptides able to bind HSPGs and thus block RSV attachment and infectivity. Of the compounds identified, the dendrimer SB105-A10 was the most potent inhibitor of RSV infectivity, with 50% inhibitory concentrations (IC50s) of 0.35 μM and 0.25 μM measured in Hep-2 and A549 cells, respectively. SB105-A10 was found to bind to both cell types via HSPGs, suggesting that its antiviral activity is indeed exerted by competing with RSV for binding to cell surface HSPGs. SB105-A10 prevented RSV infection when added before the viral inoculum, in line with its proposed HSPG-binding mechanism of action; moreover, antiviral activity was also exhibited when SB105-A10 was added postinfection, as it was able to reduce the cell-to-cell spread of the virus. The antiviral potential of SB105-A10 was further assessed using human-derived tracheal/bronchial epithelial cells cultured to form a pseudostratified, highly differentiated model of the epithelial tissue of the human respiratory tract. SB105-A10 strongly reduced RSV infectivity in this model and exhibited no signs of cytotoxicity or proinflammatory effects. Together, these features render SB105-A10 an attractive candidate for further development as a RSV inhibitor to be administered by aerosol delivery. PMID:22850525

  9. Anti-Respiratory Syncytial Virus Compounds from Two Endophytic Fungi Isolated from Nigerian Medicinal Plants.

    PubMed

    Uzor, P F; Odimegwu, D C; Ebrahim, W; Osadebe, P O; Nwodo, N J; Okoye, F B C; Liu, Z; Proksch, P

    2016-10-01

    Background: Respiratory syncytial virus (RSV) is known to cause severe respiratory infections particularly in infants younger than 2 years of age. The only approved drug, ribavirin, is expensive and is not likely to improve therapeutic outcome, thereby necessitating the search for safer and more potent alternatives from natural sources such as endophytic fungi. The present study aimed to investigate the anti-RSV activity of compounds from endophytic fungi. Methods: Two endophytic fungi Colletotrichum gloeosporioides and Pestalotiopsis thea were isolated from the fresh leaves of the host Nigerian plants Anthocleista djalonensis and Fagara zanthoxyloides, respectively. After fermentation in solid rice media, C. gloeosporioides afforded 4 known compounds 4-hydroxybenzoic acid (1), vanillic acid (2), ferulic acid (3) and Nb-acetyltryptamine (4) while P. thea afforded 3 known compounds chloroisosulochrin (5), ficipyrone A (6) and pestheic acid (7). The compounds were investigated for their anti-RSV activity using the HEP-2 cell lines and ribavirin as the standard drug. Results: Compound 5 was found to show the strongest inhibition of the RSV with IC50 of 4.22±1.03 µM (ribavirin 4.91±1.85 µM). Other compounds showed moderate inhibition of the virus (IC50 ranging from 45.00±0.98 to 259.23±2.36 µM). Conclusion: The results of the present study have shown that chloroisosulochrin (5), isolated from an endophytic fungus P. thea, possesses strong activity against RSV. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Respiratory Syncytial Virus Aggravates Renal Injury through Cytokines and Direct Renal Injury

    PubMed Central

    Zhai, Songhui; Hu, Lijuan; Zhong, Lin; Guo, Yannan; Dong, Liqun; Jia, Ruizhen; Wang, Zheng

    2016-01-01

    The purpose of this study was to investigate the relationship between renal injury and reinfection that is caused by respiratory syncytial virus (RSV) and to analyze the mechanism of renal injury. Rats were repeatedly infected with RSV on days 4, 8, 14, and 28, then sacrificed and examined on day 56 after the primary infection. Renal injury was examined by transmission electron microscopy and histopathology. The F protein of RSV was detected in the renal tissue by indirect immunofluorescence. Proteinuria and urinary glycosaminoglycans (GAGs), serum levels of albumin, urea nitrogen, and creatinine, secretion of cytokines, T lymphocyte population and subsets, and dendritic cell (DC) activation state were examined. The results showed that renal injury was more serious in the reinfection group than in the primary infection group. At a higher infection dose, 6 × 106 PFU, the renal injury was more severe, accompanied by higher levels of proteinuria and urinary GAGs excretion, and lower levels of serum albumin. Podocyte foot effacement was more extensive, and hyperplasia of mesangial cells and proliferation of mesangial matrix were observed. The maturation state of DCs was specific, compared with the primary infection. There was also a decrease in the ratio of CD4+ to CD8+ T lymphocytes, due to an increase in the percentage of CD8+ T lymphocytes and a decrease in the percentage of CD4+ T lymphocytes, and a dramatic increase in the levels of IL-6 and IL-17. In terms of the different reinfection times, the day 14 reinfection group yielded the most serious renal injury and the most significant change in immune function. RSV F protein was still expressed in the glomeruli 56 days after RSV infection. Altogether, these results reveal that RSV infection could aggravate renal injury, which might be due to direct renal injury caused by RSV and the inflammatory lesions caused by the anti-virus response induced by RSV. PMID:27747195

  11. A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model

    PubMed Central

    Walsh, Paul; Behrens, Nicole; Carvallo Chaigneau, Francisco R.; McEligot, Heather; Agrawal, Karan; Newman, John W.; Anderson, Mark; Gershwin, Laurel J.

    2016-01-01

    Background Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase. Hypotheses We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected. Methods We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-γ in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. Results One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (p<0.01) and weight gain (p = 0.08) seemed better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-γ gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen. Conclusions Ibuprofen decreased PGE2, modulated the immune

  12. A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model.

    PubMed

    Walsh, Paul; Behrens, Nicole; Carvallo Chaigneau, Francisco R; McEligot, Heather; Agrawal, Karan; Newman, John W; Anderson, Mark; Gershwin, Laurel J

    2016-01-01

    Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase. We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected. We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-γ in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (p<0.01) and weight gain (p = 0.08) seemed better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-γ gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen. Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung

  13. Molecular Epidemiology and Phylodynamics of the Human Respiratory Syncytial Virus Fusion Protein in Northern Taiwan

    PubMed Central

    Chi, Hsin; Liu, Hsin-Fu; Weng, Li-Chuan; Wang, Nai-Yu; Chiu, Nan-Chang; Lai, Mei-Ju; Lin, Yung-Cheng; Chiu, Yu-Ying; Hsieh, Wen-Shyang; Huang, Li-Min

    2013-01-01

    Background and Aims The glycoprotein (G protein) and fusion protein (F protein) of respiratory syncytial virus (RSV) both show genetic variability, but few studies have examined the F protein gene. This study aimed to characterize the molecular epidemiology and phylodynamics of the F protein gene in clinical RSV strains isolated in northern Taiwan from 2000–2011. Methods RSV isolates from children presenting with acute respiratory symptoms between July 2000 and June 2011 were typed based on F protein gene sequences. Phylogeny construction and evaluation were performed using the neighbor-joining (NJ) and maximum likelihood (ML) methods. Phylodynamic patterns in RSV F protein genes were analyzed using the Bayesian Markov Chain Monte Carlo framework. Selection pressure on the F protein gene was detected using the Datamonkey website interface. Results From a total of 325 clinical RSV strains studied, phylogenetic analysis showed that 83 subgroup A strains (RSV-A) could be further divided into three clusters, whereas 58 subgroup B strains (RSV-B) had no significant clustering. Three amino acids were observed to differ between RSV-A and -B (positions 111, 113, and 114) in CTL HLA-B*57- and HLA-A*01-restricted epitopes. One positive selection site was observed in RSV-B, while none was observed in RSV-A. The evolution rate of the virus had very little change before 2000, then slowed down between 2000 and 2005, and evolved significantly faster after 2005. The dominant subtypes of RSV-A in each epidemic were replaced by different subtypes in the subsequent epidemic. Conclusions Before 2004, RSV-A infections were involved in several small epidemics and only very limited numbers of strains evolved and re-emerged in subsequent years. After 2005, the circulating RSV-A strains were different from those of the previous years and continued evolving through 2010. Phylodynamic pattern showed the evolutionary divergence of RSV increased significantly in the recent 5 years in

  14. Molecular Epidemiology and Disease Severity of Human Respiratory Syncytial Virus in Vietnam

    PubMed Central

    Tran, Dinh Nguyen; Pham, Thi Minh Hong; Ha, Manh Tuan; Tran, Thi Thu Loan; Dang, Thi Kim Huyen; Yoshida, Lay-Myint; Okitsu, Shoko; Hayakawa, Satoshi; Mizuguchi, Masashi; Ushijima, Hiroshi

    2013-01-01

    Respiratory syncytial virus (RSV) is a major cause of acute respiratory infections (ARIs) in children worldwide and can cause high mortality, especially in developing countries. However, information on the clinical and molecular characteristics of RSV infection in developing countries is limited. From April 2010 to May 2011, 1,082 nasopharyngeal swabs were collected from children with ARI admitted to the Children's Hospital 2, Ho Chi Minh City, Vietnam. Samples were screened for RSV and genotyped by reverse transcription-PCR and sequencing. Demographic and clinical data was also recorded. RSV was found in 23.8% (257/1,082) of samples. RSV A was the dominant subgroup, accounting for 91.4% (235/257), followed by RSV B, 5.1% (13/257), and 9 cases (3.5%) were mixed infection of these subgroups. The phylogenetic analysis revealed that all group A strains belonged to the GA2 genotype. All group B strains belonged to the recently identified BA genotype, and further clustered into 2 recently described subgenotypes BA9 and BA10. One GA2 genotype strain had a premature stop codon which shortened the G protein length. RSV infection was significantly associated with younger age and higher severity score than those without. Co-infection with other viruses did not affect disease severity. RSV A caused more severe disease than RSV B. The results from this study will not only contribute to the growing database on the molecular diversity of RSV circulating worldwide but may be also useful in clinical management and vaccine development. PMID:23349659

  15. Biological challenges and technological opportunities for respiratory syncytial virus vaccine development.

    PubMed

    Graham, Barney S

    2011-01-01

    Respiratory syncytial virus (RSV) is an important cause of respiratory disease causing high rates of hospitalizations in infants, significant morbidity in children and adults, and excess mortality in the elderly. Major barriers to vaccine development include early age of RSV infection, capacity of RSV to evade innate immunity, failure of RSV-induced adaptive immunity to prevent reinfection, history of RSV vaccine-enhanced disease, and lack of an animal model fully permissive to human RSV infection. These biological challenges, safety concerns, and practical issues have significantly prolonged the RSV vaccine development process. One great advantage compared to other difficult viral vaccine targets is that passively administered neutralizing monoclonal antibody is known to protect infants from severe RSV disease. Therefore, the immunological goals for vaccine development are to induce effective neutralizing antibody to prevent infection and to avoid inducing T-cell response patterns associated with enhanced disease. Live-attenuated RSV and replication-competent chimeric viruses are in advanced clinical trials. Gene-based strategies, which can control the specificity and phenotypic properties of RSV-specific T-cell responses utilizing replication-defective vectors and which may improve on immunity from natural infection, are progressing through preclinical testing. Atomic level structural information on RSV envelope glycoproteins in complex with neutralizing antibodies is guiding design of new vaccine antigens that may be able to elicit RSV-specific antibody responses without induction of RSV-specific T-cell responses. These new technologies may allow development of vaccines that can protect against RSV-mediated disease in infants and establish a new immunological paradigm in the host to achieve more durable protection against reinfection.

  16. Respiratory Syncytial Virus Coinfections With Rhinovirus and Human Bocavirus in Hospitalized Children

    PubMed Central

    Calvo, Cristina; García-García, María Luz; Pozo, Francisco; Paula, Gallardo; Molinero, Mar; Calderón, Ana; González-Esguevillas, Mónica; Casas, Inmaculada

    2015-01-01

    Abstract It is not clearly established if coinfections are more severe than single viral respiratory infections. The aim of the study was to study and to compare simple infections and viral coinfections of respiratory syncytial virus (RSV) in hospitalized children. From September 2005 to August 2013, a prospective study was conducted on children younger than 14 years of age, admitted with respiratory infection to the Pediatric Department of the Severo Ochoa Hospital, in Spain. Specimens of nasopharyngeal aspirate were taken for virological study by using polymerase chain reaction, and clinical data were recorded. Simple RSV infections were selected and compared with double infections of RSV with rhinovirus (RV) or with human bocavirus (HBoV). In this study, 2993 episodes corresponding to 2525 children were analyzed. At least 1 virus was detected in 77% (2312) of the episodes. Single infections (599 RSV, 513 RV, and 81 HBoV) were compared with 120 RSV-RV and 60 RSV-HBoV double infections. The RSV-RV coinfections had fever (63% vs 43%; P < 0.001) and hypoxia (70% vs 43%; P < 0.001) more often than RV infections. Hypoxia was similar between single or dual infections (71%). Bronchiolitis was more frequent in the RSV simple group (P < 0.001). Pediatric intensive care unit admission was more common in RSV simple or RSV-RV groups than in the RV monoinfection (P = 0.042). Hospitalization was longer for both RSV simple group and RSV-HBoV coinfection, lasting about 1 day (4.7 vs 3.8 days; P < 0.001) longer than in simple HBoV infections. There were no differences in PICU admission. RSV single group was of a younger age than the other groups. Coinfections between RSV-RV and RSV-HBoV are frequent. Overall viral coinfections do not present greater severity, but have mixed clinical features. PMID:26496310

  17. Expression and antigenicity of recombinant human respiratory syncytial virus glycoproteins having different affinity tags.

    PubMed

    Lee, Han Saem; Kim, A-Reum; Kim, Kisoon; Lee, Wan-Ji; Kim, Sung Soon; Kim, You-Jin

    2017-04-01

    Human respiratory syncytial virus (HRSV) is a main cause of lower respiratory tract infections in infants and the elderly. Glycoprotein (G) is major antigen on the viral surface, and plays a key role for virus entry. Therefore, purification of the glycoprotein of HRSV is critical for the development of HRSV vaccine and serological diagnosis. In this study, we report the design and characterization of glycoprotein engineered rationally to enhance the protein solubility and to facilitate efficient purification. We permuted HRSV glycoproteins with two tags: (i) an immunoglobulin (Ig) M signal peptide and a protein A B domain tag to render HRSV glycoprotein secret into the culture media and (ii) a foldon and 6 × histidine tag with or without transmembrane domain. Three recombinant baculoviruses were constructed: (i) transmembrane-truncated HRSV glycoprotein (amino acid positions 66-298) inserted with the N-terminal IgM signal peptide and protein A B domain (MG-GΔTM), (ii) truncated HRSV glycoprotein (amino acid positions 66-298) fused with a C-terminal foldon and 6 × histidine tag (GΔTM-FH), and (iii) full-length HRSV glycoprotein (amino acid positions 1-298) fused with a C-terminal foldon and 6 × histidine tag (G-FH). Highly soluble recombinant MG-GΔTM protein was clearly purified using one-step affinity chromatography with IgG-sepharose resin, whereas the recombinant G-FH protein and truncated GΔTM-FH were purified partially using nickel-resin. Although, the antigenicity of GΔTM-FH was stronger than highly mannose-rich MG-GΔTM protein, MG-GΔTM induced neutralizing antibodies efficiently in the mice to protect from infectious HRSV. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Baculovirus expression of the respiratory syncytial virus fusion protein using Trichoplusia ni insect cells.

    PubMed

    Parrington, M; Cockle, S; Wyde, P; Du, R P; Snell, E; Yan, W Y; Wang, Q; Gisonni, L; Sanhueza, S; Ewasyshyn, M; Klein, M

    1997-01-01

    Respiratory syncytial virus (RSV) is a major viral pathogen responsible for severe respiratory tract infections in infants, young children, and the elderly. The RSV fusion (F) protein is highly conserved among RSV subgroups A and B and is the major protective immunogen. A genetically-engineered version of the RSV F protein was produced in insect cells using the baculovirus expression system. To express a secreted form of this protein, the transmembrane domain was eliminated by removing the region of the gene encoding 48 amino acids at the C-terminus. Production of the truncated RSV F protein (RSV-Fs) was compared in two different insect cell lines, Spodoptera frugiperda (Sf9) and Trichoplusia ni (High Five). The yield of RSV-Fs secreted from High Five insect cells was over 7-fold higher than that from Sf9 insect cells. Processing of the RSV-Fs protein was also different in the two insect cell lines. N-terminal sequencing demonstrated that while most of the RSV-Fs protein secreted by High Five cells was correctly processed at the F2-F1 proteolytic cleavage site, most of the RSV-Fs protein secreted by Sf9 cells was unprocessed or incorrectly processed. Antigenicity of the major RSV F neutralization epitopes was maintained in the RSV-Fs protein secreted from High Five cells. The RSV-specific neutralizing antibody titres in the sera of cotton rats immunized with the RSV-Fs protein were equivalent to those in the sera of animals intranasally inoculated with live RSV. Animals immunized with either live RSV or the immunoaffinity purified RSV-Fs protein from High Five cells were completely protected against live virus challenge.

  19. Macrophages are required for dendritic cell uptake of respiratory syncytial virus from an infected epithelium.

    PubMed

    Ugonna, Kelechi; Bingle, Colin D; Plant, Karen; Wilson, Kirsty; Everard, Mark L

    2014-01-01

    We have previously shown that the respiratory syncytial virus [RSV] can productively infect monocyte derived dendritic cells [MoDC] and remain dormant within the same cells for prolonged periods. It is therefore possible that infected dendritic cells act as a reservoir within the airways of individuals between annual epidemics. In the present study we explored the possibility that sub-epithelial DCs can be infected with RSV from differentiated bronchial epithelium and that in turn RSV from DCs can infect the epithelium. A dual co-culture model was established in which a differentiated primary airway epithelium on an Air Liquid Interface (ALI) was cultured on a transwell insert and MoDCs were subsequently added to the basolateral membrane of the insert. Further experiments were undertaken using a triple co-culture model in which in which macrophages were added to the apical surface of the differentiated epithelium. A modified RSV [rr-RSV] expressing a red fluorescent protein marker of replication was used to infect either the MoDCs or the differentiated epithelium and infection of the reciprocal cell type was assessed using confocal microscopy. Our data shows that primary epithelium became infected when rr-RSV infected MoDCs were introduced onto the basal surface of the transwell insert. MoDCs located beneath the epithelium did not become infected with virus from infected epithelial cells in the dual co-culture model. However when macrophages were present on the apical surface of the primary epithelium infection of the basal MoDCs occurred. Our data suggests that RSV infected dendritic cells readily transmit infection to epithelial cells even when they are located beneath the basal layer. However macrophages appear to be necessary for the transmission of infection from epithelial cells to basal dendritic cells.

  20. Macrophages Are Required for Dendritic Cell Uptake of Respiratory Syncytial Virus from an Infected Epithelium

    PubMed Central

    Ugonna, Kelechi; Bingle, Colin D.; Plant, Karen; Wilson, Kirsty; Everard, Mark L.

    2014-01-01

    We have previously shown that the respiratory syncytial virus [RSV] can productively infect monocyte derived dendritic cells [MoDC] and remain dormant within the same cells for prolonged periods. It is therefore possible that infected dendritic cells act as a reservoir within the airways of individuals between annual epidemics. In the present study we explored the possibility that sub-epithelial DCs can be infected with RSV from differentiated bronchial epithelium and that in turn RSV from DCs can infect the epithelium. A dual co-culture model was established in which a differentiated primary airway epithelium on an Air Liquid Interface (ALI) was cultured on a transwell insert and MoDCs were subsequently added to the basolateral membrane of the insert. Further experiments were undertaken using a triple co-culture model in which in which macrophages were added to the apical surface of the differentiated epithelium. A modified RSV [rr-RSV] expressing a red fluorescent protein marker of replication was used to infect either the MoDCs or the differentiated epithelium and infection of the reciprocal cell type was assessed using confocal microscopy. Our data shows that primary epithelium became infected when rr-RSV infected MoDCs were introduced onto the basal surface of the transwell insert. MoDCs located beneath the epithelium did not become infected with virus from infected epithelial cells in the dual co-culture model. However when macrophages were present on the apical surface of the primary epithelium infection of the basal MoDCs occurred. Our data suggests that RSV infected dendritic cells readily transmit infection to epithelial cells even when they are located beneath the basal layer. However macrophages appear to be necessary for the transmission of infection from epithelial cells to basal dendritic cells. PMID:24651119

  1. Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort.

    PubMed

    Sande, C J; Mutunga, M N; Okiro, E A; Medley, G F; Cane, P A; Nokes, D J

    2013-11-01

    The kinetics of respiratory syncytial virus (RSV) neutralizing antibodies following birth, primary and secondary infections are poorly defined. The aims of the study were to measure and compare neutralizing antibody responses at different time points in a birth cohort followed-up over three RSV epidemics. Rural Kenyan children, recruited at birth between 2002 and 2003, were monitored for RSV infection over three epidemic seasons. Cord and 3-monthly sera, and acute and convalescent sera following RSV infection, were assayed in 28 children by plaque reduction neutralization test (PRNT). Relative to the neutralizing antibody titers of pre-exposure control sera (1.8 log10 PRNT), antibody titers following primary infection were (i) no different in sera collected between 0 and 0.4 months post-infection (1.9 log10 PRNT, P=0.146), (ii) higher in sera collected between 0.5 and 0.9 (2.8 log10 PRNT, P<0.0001), 1.0-1.9 (2.5 log10 PRNT, P<0.0001), and 2.0-2.9 (2.3 log10 PRNT, P<0.001) months post-infection, and (iii) no different in sera collected at between 3.0 and 3.9 months post-infection (2.0 log10 PRNT, P=0.052). The early serum neutralizing response to secondary infection (3.02 log10 PRNT) was significantly greater than the early primary response (1.9 log10 PRNT, P<0.0001). Variation in population-level virus transmission corresponded with changes in the mean cohort-level neutralizing titers. It is concluded that following primary RSV infection the neutralizing antibody response declines to pre-infection levels rapidly (~3 months) which may facilitate repeat infection. The kinetics of the aggregate levels of acquired antibody reflect seasonal RSV occurrence, age, and infection history.

  2. Respiratory syncytial virus infection in older adults: an under-recognized problem.

    PubMed

    Branche, Angela R; Falsey, Ann R

    2015-04-01

    Human respiratory syncytial virus (RSV) is an enveloped, single-stranded, negative-sense RNA virus and member of the Paramyxoviridae family of the genus Pneumovirus that was first reported as a major pathogen in pediatric populations. However, since its discovery, RSV has not infrequently been detected in adults. Reinfection occurs throughout life, with more severe disease occurring in older adults, immunocompromised patients, and those with underlying cardiopulmonary disease. Initially described as the cause of nursing home outbreaks of respiratory disease, there is a now significant body of literature describing the clinical importance of RSV in older adults in a multitude of settings including long-term care, adult daycares, and in community-dwelling adults. Moreover, recent reports from China and other countries emphasize that RSV is a global pathogen that will become increasingly important in developed nations with aging populations. Annual attack rates in the USA range from 2 to 10% in community-dwelling older adults and 5-10% in older adults living in congregate settings. Population-based calculations of the proportion of acute respiratory illnesses attributable to RSV estimate that 11,000 elderly persons die annually in the USA of illnesses related to RSV infection. Clinical manifestations of RSV infections are similar to that of other viral respiratory pathogens and include cough, nasal congestion, rhinorrhea, sore throat, and dyspnea. Lower respiratory tract disease is common and may result in respiratory failure (8-13%) or death (2-5%). Recent advances in molecular diagnostics have made it possible to rapidly identify RSV infection using nucleic acid amplification tests, although clinicians will need to suspect the diagnosis when viral activity is high. At the present time, treatment is supportive. Effective antiviral agents for the treatment and vaccines for prevention of RSV remain a significant unmet medical need in the older adult population.

  3. The impact of viral dynamics on the clinical severity of infants with respiratory syncytial virus bronchiolitis.

    PubMed

    Zhou, Lili; Xiao, Qiuyan; Zhao, Yao; Huang, Ailong; Ren, Luo; Liu, Enmei

    2015-08-01

    The impact of dynamic respiratory syncytial virus (RSV) load on the clinical severity of hospitalized infants with bronchiolitis has not been clarified. Nasopharyngeal aspirates were obtained from 60 infants who were diagnosed with bronchiolitis within 96 hr of wheezing onset upon admission and on days 3, 5, and 7 in the hospital, and 17 respiratory viruses were detected. The RSV load was quantified by real-time qPCR for RSV subtypes A and B at different time points. Scoring criteria were used to evaluate the degree of severity. A total of 40 infants were determined to be RSV-positive, nine were identified as RSV subtype A (RSVA), and 31 were RSV subtype B (RSVB). The peak RSV load was observed upon admission, and the RSV load decreased significantly over time; in addition, this decrease began to have significant differences on day 5. There was a positive correlation between the RSV load and the clinical score (r(2)  = 0.121 and P < 0.001). According to the clinical scores, the infants in the severe group tended to have higher RSV loads than those in the moderate and mild groups. Multivariate logistic regression models revealed that the viral load on day 3 was independently associated with the degree of severity. This study elucidated that a higher mean RSV load was associated with a more severe disease and a longer duration of hospitalization and symptoms. This study also clarified RSV replication in infants and provides a theoretical basis for specifying an anti-RSV therapy strategy.

  4. Genetic variability of human respiratory syncytial virus in Pune, Western India.

    PubMed

    Choudhary, M L; Anand, S P; Wadhwa, B S; Chadha, M S

    2013-12-01

    Human respiratory syncytial virus (RSV) is one of the most important respiratory viruses causing acute respiratory tract infections amongst children. Based on genotyping of the attachment glycoprotein (G) gene, it is divided into two groups, RSV-A and RSV-B. Infection with one group does not confer immunity against the other and children infected with one antigenic group are more likely to be reinfected with the heterologous group. We tested 854 samples of patients with influenza like illness (ILI)/severe respiratory illness (SARI) during the period 2009-2012 for RSV using a conventional multiplex RT-PCR and found 159 (18.61%) samples to be positive for RSV of which 130 (15.22%) were positive for RSV-B and 29 (3.39%) for RSV-A suggesting that RSV-B was the predominant group circulating in Western India during the study period. Seasonal RSV outbreaks were observed in the monsoon and winter months. RSV was more prevalent amongst children in the 0-24 month age group (21.53%) in comparison to children in the 24-60 month age group (13.01%). Phylogenetic analysis using the G gene of 27 representative RSV-A positive samples revealed that all sequences belonged to the NA1 genotype. Of these, 5 sequences exhibited the novel 72 nucleotide duplication in the C-terminal of the G gene first reported from Ontario, Canada and clustered in the newly designated ON1 genotype. Also, 32 of the 33 RSV-B sequences exhibited the 60 nucleotide duplication associated with genotype BA and phylogenetic analysis showed that these sequences belonged to the genotype BA9 and BA12. We also found one RSV-B sequence belonging to genotype GB2, which has not been previously reported in India.

  5. Respiratory syncytial virus, adenoviruses, and mixed acute lower respiratory infections in children in a developing country.

    PubMed

    Rodríguez-Martínez, Carlos E; Rodríguez, Diego Andrés; Nino, Gustavo

    2015-05-01

    There is growing evidence suggesting greater severity and worse outcomes in children with mixed as compared to single respiratory virus infections. However, studies that assess the risk factors that may predispose a child to a mixture of respiratory syncytial virus (RSV) and adenoviral infections, are scarce. In a retrospective cohort study, the study investigated the epidemiology of RSV and adenovirus infections and predictors of mixed RSV-adenoviral infections in young children hospitalized with acute lower respiratory infection in Bogota, Colombia, South America, over a 2-year period 2009-2011. Of a total of 5,539 children admitted with a diagnosis of acute lower respiratory infection, 2,267 (40.9%) who were positive for RSV and/or adenovirus were selected. Out the total number of cases, 1,416 (62.5%) infections occurred during the 3-month period from March to May, the first rainy season of Bogota, Colombia. After controlling for gender, month when the nasopharyngeal sample was taken, and other pre-existing conditions, it was found that an age greater than 6 months (OR:1.74; CI 95%:1.05-2.89; P = 0.030) and malnutrition as a comorbidity (OR:9.92; CI 95%:1.01-100.9; P = 0.049) were independent predictors of mixed RSV-adenoviral infections in the sample of patients. In conclusion, RSV and adenovirus are significant causes of acute lower respiratory infection in infants and young children in Bogota, Colombia, especially during the first rainy season. The identified predictors of mixed RSV-adenoviral infections should be taken into account when planning intervention, in order to reduce the burden of acute lower respiratory infection in young children living in the country.

  6. Molecular investigations of an outbreak of parainfluenza virus type 3 and respiratory syncytial virus infections in a hematology unit.

    PubMed

    Jalal, Hamid; Bibby, David F; Bennett, Julie; Sampson, Rebecca E; Brink, Nicola S; MacKinnon, Stephen; Tedder, Richard S; Ward, Katherine N

    2007-06-01

    A large simultaneous outbreak of respiratory syncytial virus (RSV) and parainfluenza type 3 (PIV-3) infections occurred on an adult hematology unit. Implementation of enhanced infection control was complicated by cocirculation of the two different viruses, with prolonged viral shedding from infected patients, and placed great pressure on health care staff; of 27 infected hematopoietic stem cell transplant patients, 9 died, and the unit was closed for 2 months. Retrospective molecular investigation of the virus strains involved in the outbreak was performed by analyzing part of the fusion gene of PIV-3 and part of the glycoprotein gene of RSV. Reverse transcription-PCR on nasopharyngeal aspirates from patients infected before and during the simultaneous outbreak generated amplicons for sequence analysis. A single strain of RSV and a single strain of PIV-3 had spread from person to person within the unit; 7 patients were infected with RSV, 22 were infected with PIV-3, and 4 were infected with both viruses. The PIV-3 outbreak had started at the beginning of August 3 months before the RSV outbreak; it had arisen when PIV-3 was introduced from the community by a patient and passed to another patient, who became chronically infected with the identical strain and, in spite of being nursed in isolation, was most likely the source from which widespread infection occurred in November. Had these early cases been linked to a common PIV-3 strain at the time of diagnosis, enhanced infection control precautions might have prevented the eventual extensive spread of PIV-3, making it much easier to deal with the later RSV outbreak.

  7. Serological responses in calves to vaccines against bovine respiratory syncytial, infectious bovine rhinotracheitis, bovine viral diarrhoea and parainfluenza-3 viruses.

    PubMed

    Tollis, M; Di Trani, L; Cordioli, P; Vignolo, E; Di Pasquale, I

    1996-01-01

    The Istituto Superiore di Sanità (ISS), the National Veterinary Services Laboratory in Italy, is in charge of assessing the quality, safety and efficacy of veterinary vaccines before and after licensing. To evaluate the relative potency of several vaccines against bovine respiratory syncytial virus (BRSV), infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhoea virus (BVDV) and parainfluenza-3 virus (PI3V), the serological responses in vaccinated calves were studied. Vaccination with any of the vaccines under study induced specific antibody titres against the different viral antigens. The differences of the mean antibody titres within and among the test group vaccines were statistically significant. The results confirm and support those obtained by other authors in similar studies, suggesting that serological responses in vaccinated calves can be used as a helpful means of assessing the relative potency of vaccines against viral respiratory diseases of cattle. The criteria allowing such an evaluation are discussed.

  8. Real-Time Light Scattering Tracking of Gold Nanoparticles- bioconjugated Respiratory Syncytial Virus Infecting HEp-2 Cells

    NASA Astrophysics Data System (ADS)

    Wan, Xiao-Yan; Zheng, Lin-Ling; Gao, Peng-Fei; Yang, Xiao-Xi; Li, Chun-Mei; Li, Yuan Fang; Huang, Cheng Zhi

    2014-03-01

    Real-time tracking of virus invasion is crucial for understanding viral infection mechanism, which, however, needs simple and efficient labeling chemistry with improved signal-to-noise ratio. For that purpose, herein we investigated the invasion dynamics of respiratory syncytial virus (RSV) through dark-field microscopic imaging (iDFM) technique by using Au nanoparticles (AuNPs) as light scattering labels. RSV, a ubiquitous, non-segmented, pleiomorphic and negative-sense RNA virus, is an important human pathogen in infants, the elderly, and the immunocompromised. In order to label the enveloped virus of paramyxoviridae family, an efficient streptavidin (SA)-biotin binding chemistry was employed, wherein AuNPs and RSV particles modified with SA and biotin, respectively, allowing the AuNP-modified RSVs to maintain their virulence without affecting the native activities of RSV, making the long dynamic visualization successful for the RSV infections into human epidermis larynx carcinoma cells.

  9. Eliminating a Region of Respiratory Syncytial Virus Attachment Protein Allows Induction of Protective Immunity without Vaccine-enhanced Lung Eosinophilia

    PubMed Central

    Sparer, Tim E.; Matthews, Stephen; Hussell, Tracy; Rae, Aaron J.; Garcia-Barreno, Blanca; Melero, Jose A.; Openshaw, Peter J.M.

    1998-01-01

    In a murine model of respiratory syncytial virus disease, prior sensitization to the attachment glycoprotein (G) leads to pulmonary eosinophilia and enhanced illness. Three different approaches were taken to dissect the region of G responsible for enhanced disease and protection against challenge. First, mutant viruses, containing frameshifts that altered the COOH terminus of the G protein, were used to challenge mice sensitized by scarification with recombinant vaccinia virus (rVV) expressing wild-type G. Second, cDNA expressing these mutated G proteins were expressed by rVV and used to vaccinate mice before challenge with wild-type respiratory syncytial virus (RSV). These studies identified residues 193–205 to be responsible for G-induced weight loss and lung eosinophilia and showed that this region was not was not necessary for induction of protective immunity. Third, mice were sensitized using an rVV that expressed only amino acids 124–203 of the G protein. Upon RSV challenge, mice sensitized with this rVV developed enhanced weight loss and eosinophilia. This is the first time that a region within RSV (amino acids 193–203) has been shown to be responsible for induction of lung eosinophilia and disease enhancement. Moreover, we now show that it is possible to induce protective immunity with an altered G protein without inducing a pathological response. PMID:9607931

  10. Development and laboratory evaluation of a real-time PCR assay for detecting viruses and bacteria of relevance for community-acquired pneumonia.

    PubMed

    Edin, Alicia; Granholm, Susanne; Koskiniemi, Satu; Allard, Annika; Sjöstedt, Anders; Johansson, Anders

    2015-05-01

    Community-acquired pneumonia may present with similar clinical symptoms, regardless of viral or bacterial cause. Diagnostic assays are needed to rapidly discriminate between causes, because this will guide decisions on appropriate treatment. Therefore, a quantitative real-time PCR (qPCR) assay with duplex reactions targeting eight bacteria and six viruses was developed. Technical performance was examined with linear plasmids. Upper and lower respiratory tract specimens were used to compare the qPCR assay with standard microbiological methods. The limit of detection was 5 to 20 DNA template copies with approximately 1000-fold differences in concentrations of the two competing templates. SDs for positive controls were <5%. The use of the qPCR assay resulted in 113 positive identifications in 94 respiratory specimens compared with 38 by using standard diagnostics. Diagnostic accuracy of the qPCR assay varied between 60% positive agreement with standard tests for Streptococcus pneumoniae and 100% for Mycoplasma pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus. Negative percentage of agreement was >95% for M. pneumoniae, Streptococcus pyogenes, respiratory syncytial virus, and influenza A virus; whereas it was only 56% for Haemophilus influenzae. Multiple microbial agents were identified in 19 of 44 sputum and 19 of 50 nasopharynx specimens. We conclude that in parallel qPCR detection of the targeted respiratory bacteria and viruses is feasible. The results indicate good technical performance of the assay in clinical specimens. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  11. Respiratory syncytial virus infection in infants with acute leukemia: a retrospective survey of the Japanese Pediatric Leukemia/Lymphoma Study Group.

    PubMed

    Hatanaka, Michiki; Miyamura, Takako; Koh, Katsuyoshi; Taga, Takashi; Tawa, Akio; Hasegawa, Daisuke; Kajihara, Ryosuke; Adachi, Souichi; Ishii, Eiichi; Tomizawa, Daisuke

    2015-12-01

    Respiratory syncytial virus (RSV) can cause life-threatening complications of lower respiratory tract infection (LRTI) in young children with malignancies, but reports remain limited. We performed a retrospective nationwide survey to clarify the current status of RSV disease among infants with hematological malignancies. Clinical course, treatment, and outcome of patients with hematological malignancies who suffered from RSV infections at the age of <24 months during anti-tumor therapy from April 2006 to March 2009 were investigated by sending a questionnaire to all member institutions of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Twelve patients with acute leukemia were identified as having experienced RSV disease. The primary diseases were acute myeloid leukemia (n = 8) and acute lymphoblastic leukemia (n = 4). RSV infection occurred pre- or during induction therapy (n = 8) and during consolidation therapy (n = 4). Eight patients developed LRTI, four of whom had severe pneumonia or acute respiratory distress syndrome; these four patients died despite receiving intensive care. In our survey, the prognosis of RSV disease in pediatric hematological malignancies was poor, and progression of LRTI in particular was associated with high mortality. In the absence of RSV-specific therapy, effective prevention and treatment strategies for severe RSV disease must be investigated.

  12. A study of the genetic variability of human respiratory syncytial virus (HRSV) in Cambodia reveals the existence of a new HRSV group B genotype.

    PubMed

    Arnott, Alicia; Vong, Sirenda; Mardy, Sek; Chu, Simon; Naughtin, Monica; Sovann, Ly; Buecher, Carole; Beauté, Julien; Rith, Sareth; Borand, Laurence; Asgari, Nima; Frutos, Roger; Guillard, Bertrand; Touch, Sok; Deubel, Vincent; Buchy, Philippe

    2011-10-01

    Human respiratory syncytial virus (HRSV) is the leading cause of hospitalization of children aged <5 years due to respiratory illness in industrialized countries, and pneumonia is the leading cause of mortality among children aged <5 years worldwide. Although HRSV was first identified in 1956, a preventative vaccine has yet to be developed. Here we report the results of the first study to investigate the circulation and genetic diversity of HRSV in Cambodia among an all-ages population over 5 consecutive years. The incidences of HRSV infection among all-ages outpatient and hospitalized populations were equivalent, at 9.5% and 8.2%, respectively. Infection was most prevalent among children aged <5 years, with bronchiolitis being the most frequently observed clinical syndrome in the same age group. Circulation of HRSV was seasonal, typically coinciding with the rainy season between July and November annually. Strains belonging to HRSV groups A and B were detected with equivalent frequencies; however, we observed a potentially biennial shift in the predominant circulating HRSV genotype. The majority of HRSV group B strains belonged to the recently described BA genotype, with the exception of 10 strains classified as belonging to a novel HRSV group B genotype, SAB4, first reported here.

  13. Sequencing and Analysis of Globally Obtained Human Respiratory Syncytial Virus A and B Genomes

    PubMed Central

    Bose, Michael E.; He, Jie; Shrivastava, Susmita; Nelson, Martha I.; Bera, Jayati; Halpin, Rebecca A.; Town, Christopher D.; Lorenzi, Hernan A.; Noyola, Daniel E.; Falcone, Valeria; Gerna, Giuseppe; De Beenhouwer, Hans; Videla, Cristina; Kok, Tuckweng; Venter, Marietjie; Williams, John V.; Henrickson, Kelly J.

    2015-01-01

    Background Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in children globally, with nearly all children experiencing at least one infection by the age of two. Partial sequencing of the attachment glycoprotein gene is conducted routinely for genotyping, but relatively few whole genome sequences are available for RSV. The goal of our study was to sequence the genomes of RSV strains collected from multiple countries to further understand the global diversity of RSV at a whole-genome level. Methods We collected RSV samples and isolates from Mexico, Argentina, Belgium, Italy, Germany, Australia, South Africa, and the USA from the years 1998-2010. Both Sanger and next-generation sequencing with the Illumina and 454 platforms were used to sequence the whole genomes of RSV A and B. Phylogenetic analyses were performed using the Bayesian and maximum likelihood methods of phylogenetic inference. Results We sequenced the genomes of 34 RSVA and 23 RSVB viruses. Phylogenetic analysis showed that the RSVA genome evolves at an estimated rate of 6.72 × 10-4 substitutions/site/year (95% HPD 5.61 × 10-4 to 7.6 × 10-4) and for RSVB the evolutionary rate was 7.69 × 10-4 substitutions/site/year (95% HPD 6.81 × 10-4 to 8.62 × 10-4). We found multiple clades co-circulating globally for both RSV A and B. The predominant clades were GA2 and GA5 for RSVA and BA for RSVB. Conclusions Our analyses showed that RSV circulates on a global scale with the same predominant clades of viruses being found in countries around the world. However, the distribution of clades can change rapidly as new strains emerge. We did not observe a strong spatial structure in our trees, with the same three main clades of RSV co-circulating globally, suggesting that the evolution of RSV is not strongly regionalized. PMID:25793751

  14. Immunogenicity of a modified-live virus vaccine against bovine viral diarrhea virus types 1 and 2, infectious bovine rhinotracheitis virus, bovine parainfluenza-3 virus, and bovine respiratory syncytial virus when administered intranasally in young calves.

    PubMed

    Xue, Wenzhi; Ellis, John; Mattick, Debra; Smith, Linda; Brady, Ryan; Trigo, Emilio

    2010-05-14

    The immunogenicity of an intranasally-administered modified-live virus (MLV) vaccine in 3-8 day old calves was evaluated against bovine viral diarrhea virus (BVDV) types 1 and 2, infectious bovine rhinotracheitis (IBR) virus, parainfluenza-3 (PI-3) virus and bovine respiratory syncytial virus (BRSV). Calves were intranasally vaccinated with a single dose of a multivalent MLV vaccine and were challenged with one of the respective viruses three to four weeks post-vaccination in five separate studies. There was significant sparing of diseases in calves intranasally vaccinated with the MLV vaccine, as indicated by significantly fewer clinical signs, lower rectal temperatures, reduced viral shedding, greater white blood cell and platelet counts, and less severe pulmonary lesions than control animals. This was the first MLV combination vaccine to demonstrate efficacy against BVDV types 1 and 2, IBR, PI-3 and BRSV in calves 3-8 days of age.

  15. Short report: seasonal pattern of respiratory syncytial virus in a region with a tropical climate in southeastern Brazil.

    PubMed

    Checon, Rita Elizabeth; Siqueira, Marilda M; Lugon, Ana Kelly; Portes, Silvana; Dietze, Reynaldo

    2002-11-01

    Among acute respiratory infections (ARIs), respiratory syncytial virus (RSV) is an important pathogen, especially in infants and preschool children. This study focused on RSV epidemiology in a region of southeastern Brazil with a tropical climate. A total of 406 nasopharyngeal secretion samples were taken from children less than five years of age with ARIs. Of these, 114 (28%) were RSV-positive. These samples were found in all age groups, but showed a higher prevalence in newborns. Infection with RSV was identified in 10 of the 12 months of the study period, but the majority (88.5%) of cases occurred from late summer to mid-fall.

  16. Circulation of a novel human respiratory syncytial virus Group B genotype during the 2014-2015 season in Catalonia (Spain).

    PubMed

    Gimferrer, L; Andrés, C; Campins, M; Codina, M G; Rodrigo, J A; Melendo, S; Martin, M C; Fuentes, F; Saiz, M R; Esperalba, J; Bruguera, A; Vilca, L M; Armadans, L; Pumarola, T; Antón, A

    2016-01-01

    Human respiratory syncytial virus (HRSV) is one of the most common viral aetiological agents in the youngest population. In the present study a novel HRSV-B BA genotype is first described based on the phylogenetic analysis of the coding hypervariable region 2 sequences of G protein from strains detected during the 2014-2015 season. Among all strains detected in the last season, 44% belonged to this new genotype. Therefore, it highlights the importance of a continuous HRSV surveillance to monitor the emergence and spread of new genotypes or variants with genetic changes that may affect antigenic and tropism features.

  17. Molecular characterization and clinical epidemiology of human respiratory syncytial virus (HRSV) A and B in hospitalized children, Southern Brazil.

    PubMed

    Moreira, Francielli B; Rosario, Cristine S; Santos, Jucelia S; Avanzi, Valéria M; Nogueira, Meri Bordignon; Vidal, Luine R; Raboni, Sonia Mara

    2017-02-18

    Human respiratory syncytial virus (HRSV) is a major etiologic agent of pediatric respiratory infections. Genetic variability of its glycoprotein G enables HRSV to evade the immune response and determines its seasonal dissemination. This study reports genetic variability and clinical profiles of HRSV-infected patients from Southern Brazil. Seventy positive samples, 78% type A and 22% type B, were analyzed. Of the patients (median age, 6 months; interquartile range, 2-11 years), 16% had co-morbidities and 17% developed severe disease. The ON1 HRSV genotype first appeared in 2012, and patients infected with this genotype showed an increased tendency to develop severe disease.

  18. Respiratory syncytial virus infection in Navajo and White Mountain Apache children.

    PubMed

    Bockova, Jana; O'Brien, Katherine L; Oski, Jane; Croll, Janne'; Reid, Raymond; Weatherholtz, Robert C; Santosham, Mathuram; Karron, Ruth A

    2002-08-01

    The hospitalization rate for bronchiolitis of any cause among US children younger than 1 year is estimated at 31.2 per 1000. No data exist on respiratory syncytial virus (RSV)-specific hospitalization rates among high-risk Native Americans other than Alaska Natives, for whom the incidence of RSV hospitalization was estimated at 150 per 1000 among infants younger than 1 year. We aimed to estimate RSV hospitalization rates among Navajo and White Mountain Apache children younger than 2 years. We conducted prospective population-level hospital-based surveillance to determine RSV hospitalization rates among Navajo and White Mountain Apache children younger than 2 years. From 1997 to 2000, all children who were admitted for acute lower respiratory tract infection between October 1 and March 31 had a nasopharyngeal aspirate obtained and tested for RSV by commercial enzyme immunoassay kits. We reviewed charts of children who tested positive for RSV antigen to determine disease severity. During 3 RSV seasons (1997-2000), 51.3% of 1837 admissions for acute lower respiratory tract infection among children younger than 2 years were attributed to RSV infection. The overall seasonal RSV hospitalization rate among children younger than 2 years was 63.6 per 1000 and 91.3 per 1000 among children younger than 1 year. In a univariate analysis, predictors of severity included age <6 months (relative risk: 6.8; 95% confidence interval: 3.1-17.0). Navajo and White Mountain Apache children are at high risk for RSV disease requiring hospitalization. A lower threshold for hospitalization or underlying chronic conditions that predispose to severe RSV disease do not seem to explain high RSV hospitalization rates in this population.

  19. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.

    PubMed

    Stein, R T; Sherrill, D; Morgan, W J; Holberg, C J; Halonen, M; Taussig, L M; Wright, A L; Martinez, F D

    1999-08-14

    The relation between lower respiratory tract illnesses in early life caused by the respiratory syncytial virus (RSV) and the subsequent development of wheezing and atopy in childhood is not well understood. We studied this relation in children who had lower respiratory tract illnesses that occurred before 3 years of age. Children were enrolled at birth and cases of lower respiratory tract illness were ascertained by a physician. Viral tests were done for specimens collected at the time of the illness. Children were classified into five groups according to type and cause of lower respiratory tract illness. Children were then followed prospectively up to age 13, and we measured frequency of wheezing, pulmonary function, and atopic status (allergy skin-prick tests, serum IgE concentrations). RSV lower respiratory tract illnesses were associated with an increased risk of infrequent wheeze (odds ratio 3.2 [95% CI 2.0-5.0], p < 0.001), and an increased risk of frequent wheeze (4.3 [2.2-8.7], p < or = 0.001) by age 6. Risk decreased markedly with age and was not significant by age 13. There was no association between RSV lower respiratory tract illnesses and subsequent atopic status. RSV lower respiratory tract illnesses were associated with significantly lower measurements of forced expiratory volume (2.11 [2.05-2.15], p < or = 0.001) when compared with those of children with no lower respiratory tract illnesses, but there was no difference in forced expiratory volume after inhalation of salbutamol. RSV lower respiratory tract illnesses in early childhood are an independent risk factor for the subsequent development of wheezing up to age 11 years but not at age 13. This association is not caused by an increased risk of allergic sensitisation.

  20. DP2 (CRTh2) antagonism reduces ocular inflammation induced by allergen challenge and respiratory syncytial virus.

    PubMed

    Stebbins, Karin J; Broadhead, Alexander R; Musiyenko, Alla; Barik, Sailen; Scott, Jill M; Truong, Yen P; Stearns, Brian A; Hutchinson, John H; Prasit, Peppi; Evans, Jilly F; Lorrain, Daniel S

    2012-01-01

    Allergic conjunctivitis is characterized by itchy, watery and swollen eyes which occur in response to exposure to seasonal or environmental allergens. The early phase reaction of allergic conjunctivitis is primarily mediated by mast cell degranulation while the late phase reaction is driven by Th2 cells and eosinophils. Prostaglandin D(2) (PGD(2)), released from mast cells, is present in allergic conjunctival tears and may elicit classical allergic responses via interaction with the high-affinity DP2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Furthermore, antagonism of this receptor is well known to inhibit eosinophil chemotaxis, basophil activation and Th2 cytokine production. PGD(2), therefore, may be involved in both early and late phase reactions in response to allergen challenge. Thus, we explored whether our novel and selective DP2 antagonist AM156 would be efficacious in animal models of allergic conjunctivitis. Furthermore, as respiratory syncytial virus (RSV) has been implicated in the pathogenesis of allergic conjunctivitis, we examined the effects of DP2 antagonism in a murine model of RSV ocular infection. Utilizing a guinea pig ovalbumin model and a murine ragweed model we demonstrated that AM156 reduces redness, discharge and swelling in response to allergen challenge. These effects were equal to or greater than those of current clinical treatment options for allergic conjunctivitis including topical corticosteroids and a dual-mechanism antihistamine and decongestant. AM156 significantly reduced RSV-induced ocular inflammation and IL-4 production. These results suggest that a topical DP2 antagonist such as AM156 may represent a novel therapeutic for allergic conjunctivitis. Copyright © 2011 S. Karger AG, Basel.

  1. Facile and rapid detection of respiratory syncytial virus using metallic nanoparticles.

    PubMed

    Valdez, Jesus; Bawage, Swapnil; Gomez, Idalia; Singh, Shree Ram

    2016-02-27

    Respiratory syncytial virus (RSV) causes severe respiratory infection in infants, children and elderly. Currently, there is no effective vaccine or RSV specific drug for the treatment. However, an antiviral drug ribavirin and palivizumab is prescribed along with symptomatic treatment. RSV detection is important to ensure appropriate treatment of children. Most commonly used detection methods for RSV are DFA, ELISA and Real-time PCR which are expensive and time consuming. Newer approach of plasmonic detection techniques like localized surface plasmon resonance (LSPR) spectroscopy using metallic nanomaterials has gained interest recently. The LSPR spectroscopy is simple and easy than the current biophysical detection techniques like surface-enhanced Raman scattering (SERS) and mass-spectroscopy. In this study, we utilized LSPR shifting as an RSV detection method by using an anti-RSV polyclonal antibody conjugated to metallic nanoparticles (Cu, Ag and Au). Nanoparticles were synthesized using alginate as a reducing and stabilizing agent. RSV dose and time dependent LSPR shifting was measured for all three metallic nanoparticles (non-functionalized and functionalized). Specificity of the functionalized nanoparticles for RSV was evaluated in the presence Pseudomonas aeruginosa and adenovirus. We found that functionalized copper nanoparticles were efficient in RSV detection. Functionalized copper and silver nanoparticles were specific for RSV, when tested in the presence of adenovirus and P. aeruginosa, respectively. Limit of detection and limit of quantification values reveal that functionalized copper nanoparticles are superior in comparison with silver and gold nanoparticles. The study demonstrates successful application of LSPR for RSV detection, and it provides an easy and inexpensive alternative method for the potential development of LSPR-based detection devices.

  2. Predicting the start week of respiratory syncytial virus outbreaks using real time weather variables.

    PubMed

    Walton, Nephi A; Poynton, Mollie R; Gesteland, Per H; Maloney, Chris; Staes, Catherine; Facelli, Julio C

    2010-11-02

    Respiratory Syncytial Virus (RSV), a major cause of bronchiolitis, has a large impact on the census of pediatric hospitals during outbreak seasons. Reliable prediction of the week these outbreaks will start, based on readily available data, could help pediatric hospitals better prepare for large outbreaks. Naïve Bayes (NB) classifier models were constructed using weather data from 1985-2008 considering only variables that are available in real time and that could be used to forecast the week in which an RSV outbreak will occur in Salt Lake County, Utah. Outbreak start dates were determined by a panel of experts using 32,509 records with ICD-9 coded RSV and bronchiolitis diagnoses from Intermountain Healthcare hospitals and clinics for the RSV seasons from 1985 to 2008. NB models predicted RSV outbreaks up to 3 weeks in advance with an estimated sensitivity of up to 67% and estimated specificities as high as 94% to 100%. Temperature and wind speed were the best overall predictors, but other weather variables also showed relevance depending on how far in advance the predictions were made. The weather conditions predictive of an RSV outbreak in our study were similar to those that lead to temperature inversions in the Salt Lake Valley. We demonstrate that Naïve Bayes (NB) classifier models based on weather data available in real time have the potential to be used as effective predictive models. These models may be able to predict the week that an RSV outbreak will occur with clinical relevance. Their clinical usefulness will be field tested during the next five years.

  3. Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

    PubMed

    Carroll, Kecia N; Gebretsadik, Tebeb; Escobar, Gabriel J; Wu, Pingsheng; Li, Sherian Xu; Walsh, Eileen M; Mitchel, Ed; Sloan, Chantel D; Dupont, William D; Hartert, Tina V

    2017-01-01

    Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV-related hospitalizations and has been associated with decreased wheezing in the first years of life. We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma. We conducted a retrospective cohort investigation including children born from 1996-2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma-specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]-adjusted and PS-matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. By using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS-matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50-0.78). This investigation of RSV immunoprophylaxis in high-risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high-risk children. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc

  4. Human Respiratory Syncytial Virus Memphis 37 Causes Acute Respiratory Disease in Perinatal Lamb Lung

    PubMed Central

    van Geelen, Albert; Gallup, Jack M.; Kienzle, Thomas; Shelly, Daniel A.; Cihlar, Tomas; King, Robert R.; Ackermann, Mark R.

    2014-01-01

    Abstract Respiratory syncytial virus (RSV) is the leading cause of hospitalization due to respiratory illness among infants and young children of industrialized countries. There is a lack of understanding of the severe disease mechanisms as well as limited treatment options, none of which are fully satisfactory. This is partly due to lack of a relevant animal model of perinatal RSV infection that mimics moderate to severe disease in infants. We and others have shown mild disease in perinatal lambs with either a bovine or a human A2 strain of RSV. The Memphis 37 clinical strain of human RSV has been used to produce mild to moderate upper respiratory disease in healthy adult volunteers. We hypothesized that the Memphis 37 strain of RSV would infect perinatal lambs and produce clinical disease similar to that in human infants. Perinatal (3- to 5-day-old) lambs were inoculated intranasally with 2 mL/nostril of 1×105 focus-forming units (FFU)/mL (n=2) or 2.1×108 FFU/mL (n=3) of RSV Memphis 37. Clinical signs, gross and histological lesions, and immune and inflammatory responses were assessed. Memphis 37 caused moderate to severe gross and histologic lesions along with increased mRNA expression of macrophage inflammatory protein. Clinically, four of the five infected lambs had a mild to severe increase in expiratory effort. Intranasally administered RSV strain Memphis 37 infects neonatal lambs with gross, histologic, and immune responses similar to those observed in human infants. PMID:24804166

  5. Epidemiology of respiratory syncytial virus in various regions within North Carolina during multiple seasons.

    PubMed

    Wilfret, David A; Baker, Brent T; Palavecino, Elizabeth; Moran, Cassandra; Benjamin, Daniel K

    2008-01-01

    The Centers for Disease Control and Prevention (CDC) monitors the occurrence of respiratory syncytial virus (RSV) in the United States and has historically reported on activity at the regional level. Prior to the 2007-2008 RSVseason, the CDC did not report seasonal RSV data for cities within North Carolina or for the state. The purpose of the present study is to characterize RSV seasonal activity within North Carolina and to determine the appropriate months in which at-risk children should receive prophylaxis. We prospectively collected RSV test data monthly over three seasons (fall through spring), from September 2003 through July 2006, from a diverse group of hospitals and a community pediatric practice located within five regions throughout North Carolina. Approximately 14,000 laboratory tests, including 23.7% that were RSV positive, were evaluated over the three seasons, and RSV was detected within the state during all but three months of the study. Seasonal variation in the onset (October-November) of RSV activity and duration (six to seven months) of the RSV season according to the specified definition of seasonality was noted yearly within individual regions and among regions. On average over the study period, the greatest percentage of positive tests (33.8%) statewide occurred during January. Our data suggest the RSV season in North Carolina is longer than the national average, and RSV epidemics persist during months that fall outside of those in which RSV prophylaxis is given to high-risk children. Guidelines on the administration of RSV prophylaxis should ideally be based on results of local RSV test data.

  6. [Respiratory syncytial virus outbreak in a tertiary hospital Neonatal Intensive Care Unit].

    PubMed

    Moreno Parejo, Carlos; Morillo García, Aurea; Lozano Domínguez, Carmen; Carreño Ochoa, Concepción; Aznar Martín, Javier; Conde Herrera, Manuel

    2016-09-01

    Investigation and control of a respiratory syncytial virus (RSV) outbreak that affected the Neonatal Intensive Care Unit (NICU) of a university hospital from October to December 2012. Cohort study of children admitted to the NICU. The infection attack rate was calculated. A descriptive analysis of the cases and a multivariate analysis was performed using the variables that were shown to be risk factors for RSV infection. Preventive measures taken were: contact isolation; hand hygiene training and observation; exclusivity of a health team of nurses and physicians for positive cases, restrictions on visitor numbers; surveillance RSV testing, and palivizumab prophylaxis. The outbreak had three epidemic waves and 20 positive cases out of a total of 48 children admitted. The overall attack rate was 42%. Half of positive cases were children, with a median age of 36 days (p25=22, p75=58). The independent risk factors for RSV infection were birth weight below 1000 grams (OR=23.5; P=.002) and to have another nosocomial infection the week before the diagnosis of RSV infection (OR=19.98; P=.016). It was an outbreak with a high number of cases, due to the delay in notification, prolonged RSV carrier status, and low adherence to hand hygiene practice, which favoured the cross-transmission of infection. The most effective preventive measures were direct observation of hand hygiene and supervision of isolation measures. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Epidemiology of respiratory syncytial virus infection in rural and urban Kenya.

    PubMed

    Bigogo, Godfrey M; Breiman, Robert F; Feikin, Daniel R; Audi, Allan O; Aura, Barrack; Cosmas, Leonard; Njenga, M Kariuki; Fields, Barry S; Omballa, Victor; Njuguna, Henry; Ochieng, Peter M; Mogeni, Daniel O; Aol, George O; Olack, Beatrice; Katz, Mark A; Montgomery, Joel M; Burton, Deron C

    2013-12-15

    Information on the epidemiology of respiratory syncytial virus (RSV) infection in Africa is limited for crowded urban areas and for rural areas where the prevalence of malaria is high. At referral facilities in rural western Kenya and a Nairobi slum, we collected nasopharyngeal/oropharyngeal (NP/OP) swab specimens from patients with influenza-like illness (ILI) or severe acute respiratory illness (SARI) and from asymptomatic controls. Polymerase chain reaction assays were used for detection of viral pathogens. We calculated age-specific ratios of the odds of RSV detection among patients versus the odds among controls. Incidence was expressed as the number of episodes per 1000 person-years of observation. Between March 2007 and February 2011, RSV was detected in 501 of 4012 NP/OP swab specimens (12.5%) from children and adults in the rural site and in 321 of 2744 NP/OP swab specimens (11.7%) from those in the urban site. Among children aged <5 years, RSV was detected more commonly among rural children with SARI (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.3), urban children with SARI (OR, 8.5; 95% CI, 3.1-23.6), and urban children with ILI (OR, 3.4; 95% CI, 1.2-9.6), compared with controls. The incidence of RSV disease was highest among infants with SARI aged <1 year (86.9 and 62.8 episodes per 1000 person-years of observation in rural and urban sites, respectively). An effective RSV vaccine would likely substantially reduce the burden of respiratory illness among children in rural and urban areas in Africa.

  8. Risk factors for respiratory syncytial virus illness among patients with chronic obstructive pulmonary disease.

    PubMed

    Mehta, Jyotsna; Walsh, Edward E; Mahadevia, Parthiv J; Falsey, Ann R

    2013-06-01

    Respiratory syncytial virus (RSV), although not typically considered an important pathogen in adults, may cause acute exacerbation of chronic obstructive pulmonary disease (COPD). It is unclear which COPD patients are at highest risk for developing serious RSV illness. Our objective was to identify risk factors for RSV illness among adult patients with COPD. We conducted a pooled analysis of data from COPD patients in 2 previously published longitudinal studies that examined RSV infection in high risk adults for ≤ 2 RSV seasons. Risk factors for RSV illness studied included age, sex, race, smoking status, exposure to children, home oxygen use, inhaled or oral steroid use, instrumental activities of daily living scores, and co-morbid conditions. Outcomes studied included symptomatic and medically attended RSV illness. Logistic regression was used to identify significant risk factors for RSV illness among older adults with COPD. Among 379 patients with COPD, the rate of symptomatic RSV illness was 11.1% (42/379); almost half (20/42) of whom required medical attention. In multivariable analyses, congestive heart failure (odds ratio [OR] = 4.18; 95% CI: 1.38, 12.69) and exposure to children (OR = 2.38; 95% CI: 1.03, 5.51) were risk factors for symptomatic RSV illness. Congestive heart failure (OR = 4.16; 95% CI: 1.02, 17.01) was the only significant risk factor for developing medically attended RSV illness. Exposure to children and congestive heart failure are risk factors for RSV illness among adult patients with COPD. Future prospective, well-designed studies are needed to corroborate these findings and examine other risk factors, including history of exacerbations.

  9. Respiratory syncytial virus activity and climate parameters during a 12-year period.

    PubMed

    Sirimi, Natalia; Miligkos, Michael; Koutouzi, Foteini; Petridou, Evi; Siahanidou, Tania; Michos, Athanasios

    2016-06-01

    The epidemic pattern of respiratory syncytial virus (RSV) infection during long periods and the factors that determine seasonality are not well studied. In order to correlate the RSV epidemic activity with climate parameters, we conducted a retrospective study of children (0-14 year) who were hospitalized because of respiratory tract infection and had an RSV test performed in the major tertiary pediatric hospital of Greece during a 12-year period (2002-2013). Daily data regarding temperature and humidity were obtained from the Hellenic National Meteorological Service. A total of 2030/7516 (27%) children were tested positive for RSV infection. Among RSV positive children 1945/2030 (95.8%) were infants <1 year. A peak of RSV activity was measured in years 2002, 2003, and 2006 (>35% positive). The RSV season in our area spanned from December to April, with higher incidence during January through March. The peak monthly RSV incidence was observed during February with mean temperature 10.34 °C and mean relative humidity 69.16%. Regarding climate conditions, a statistically significant positive correlation was found between monthly RSV activity and mean monthly relative humidity (rho = 0.66, P-value = 0.02), whereas a negative correlation was found with mean monthly temperature (rho = -0.81, P-value = 0.002). However, in the multivariable analysis, only the effect of mean monthly temperature remained statistically significant (IRR = 0.72, 95% CI: 0.68, 0.80). Further understanding of RSV seasonality in different geographic areas would be important in order to timely implement preventing strategies with immunoprophylaxis or future RSV vaccines. © 2015 Wiley Periodicals, Inc.

  10. Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection.

    PubMed

    de Steenhuijsen Piters, Wouter A A; Heinonen, Santtu; Hasrat, Raiza; Bunsow, Eleonora; Smith, Bennett; Suarez-Arrabal, Maria-Carmen; Chaussabel, Damien; Cohen, Daniel M; Sanders, Elisabeth A M; Ramilo, Octavio; Bogaert, Debby; Mejias, Asuncion

    2016-11-01

    Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and hospitalizations in infants worldwide. Known risk factors, however, incompletely explain the variability of RSV disease severity, especially among healthy children. We postulate that the severity of RSV infection is influenced by modulation of the host immune response by the local bacterial ecosystem. To assess whether specific nasopharyngeal microbiota (clusters) are associated with distinct host transcriptome profiles and disease severity in children less than 2 years of age with RSV infection. We characterized the nasopharyngeal microbiota profiles of young children with mild and severe RSV disease and healthy children by 16S-rRNA sequencing. In parallel, using multivariable models, we analyzed whole-blood transcriptome profiles to study the relationship between microbial community composition, the RSV-induced host transcriptional response, and clinical disease severity. We identified five nasopharyngeal microbiota clusters characterized by enrichment of either Haemophilus influenzae, Streptococcus, Corynebacterium, Moraxella, or Staphylococcus aureus. RSV infection and RSV hospitalization were positively associated with H. influenzae and Streptococcus and negatively associated with S. aureus abundance, independent of age. Children with RSV showed overexpression of IFN-related genes, independent of the microbiota cluster. In addition, transcriptome profiles of children with RSV infection and H. influenzae- and Streptococcus-dominated microbiota were characterized by greater overexpression of genes linked to Toll-like receptor and by neutrophil and macrophage activation and signaling. Our data suggest that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially affecting clinical disease severity.

  11. Modelling the Seasonal Epidemics of Respiratory Syncytial Virus in Young Children

    PubMed Central

    Moore, Hannah C.; Jacoby, Peter; Hogan, Alexandra B.; Blyth, Christopher C.; Mercer, Geoffry N.

    2014-01-01

    Background Respiratory syncytial virus (RSV) is a major cause of paediatric morbidity. Mathematical models can be used to characterise annual RSV seasonal epidemics and are a valuable tool to assess the impact of future vaccines. Objectives Construct a mathematical model of seasonal epidemics of RSV and by fitting to a population-level RSV dataset, obtain a better understanding of RSV transmission dynamics. Methods We obtained an extensive dataset of weekly RSV testing data in children aged less than 2 years, 2000–2005, for a birth cohort of 245,249 children through linkage of laboratory and birth record datasets. We constructed a seasonally forced compartmental age-structured Susceptible-Exposed-Infectious-Recovered-Susceptible (SEIRS) mathematical model to fit to the seasonal curves of positive RSV detections using the Nelder-Mead method. Results From 15,830 specimens, 3,394 were positive for RSV. RSV detections exhibited a distinct biennial seasonal pattern with alternating sized peaks in winter months. Our SEIRS model accurately mimicked the observed data with alternating sized peaks using disease parameter values that remained constant across the 6 years of data. Variations in the duration of immunity and recovery periods were explored. The best fit to the data minimising the residual sum of errors was a model using estimates based on previous models in the literature for the infectious period and a slightly lower estimate for the immunity period. Conclusions Our age-structured model based on routinely collected population laboratory data accurately captures the observed seasonal epidemic curves. The compartmental SEIRS model, based on several assumptions, now provides a validated base model. Ranges for the disease parameters in the model that could replicate the patterns in the data were identified. Areas for future model developments include fitting climatic variables to the seasonal parameter, allowing parameters to vary according to age and implementing

  12. Modelling the seasonal epidemics of respiratory syncytial virus in young children.

    PubMed

    Moore, Hannah C; Jacoby, Peter; Hogan, Alexandra B; Blyth, Christopher C; Mercer, Geoffry N

    2014-01-01

    Respiratory syncytial virus (RSV) is a major cause of paediatric morbidity. Mathematical models can be used to characterise annual RSV seasonal epidemics and are a valuable tool to assess the impact of future vaccines. Construct a mathematical model of seasonal epidemics of RSV and by fitting to a population-level RSV dataset, obtain a better understanding of RSV transmission dynamics. We obtained an extensive dataset of weekly RSV testing data in children aged less than 2 years, 2000-2005, for a birth cohort of 245,249 children through linkage of laboratory and birth record datasets. We constructed a seasonally forced compartmental age-structured Susceptible-Exposed-Infectious-Recovered-Susceptible (SEIRS) mathematical model to fit to the seasonal curves of positive RSV detections using the Nelder-Mead method. From 15,830 specimens, 3,394 were positive for RSV. RSV detections exhibited a distinct biennial seasonal pattern with alternating sized peaks in winter months. Our SEIRS model accurately mimicked the observed data with alternating sized peaks using disease parameter values that remained constant across the 6 years of data. Variations in the duration of immunity and recovery periods were explored. The best fit to the data minimising the residual sum of errors was a model using estimates based on previous models in the literature for the infectious period and a slightly lower estimate for the immunity period. Our age-structured model based on routinely collected population laboratory data accurately captures the observed seasonal epidemic curves. The compartmental SEIRS model, based on several assumptions, now provides a validated base model. Ranges for the disease parameters in the model that could replicate the patterns in the data were identified. Areas for future model developments include fitting climatic variables to the seasonal parameter, allowing parameters to vary according to age and implementing a newborn vaccination program to predict the effect

  13. Burden of respiratory syncytial virus in hospitalized infants and young children in Amman, Jordan.

    PubMed

    Khuri-Bulos, Najwa; Williams, John V; Shehabi, Asem A; Faouri, Samir; Al Jundi, Ehsan; Abushariah, Omar; Chen, Qingxia; Ali, S Asad; Vermund, Sten; Halasa, Natasha B

    2010-05-01

    Acute respiratory infections (ARI) play a major role in hospitalizations in the Middle East, but the specific viral causes are unknown. We conducted prospective viral surveillance in children <5 y of age admitted with ARI and/or fever at 2 dissimilar hospitals in Amman, Jordan during peak respiratory syncytial virus (RSV) season. We collected prospective clinical and demographic data and obtained nose/throat swabs for testing for RSV by real-time polymerase chain reaction (RT-PCR). We obtained clinical and laboratory data for 728/743 (98%) subjects enrolled. The children's median age was 4.3 months, 58.4% were males, 87% were breastfed, 4% attended day care, 67% were exposed to smokers, 7% were admitted to the intensive care unit, and 0.7% died (n = 5). Out of 728 subjects, 467 (64%) tested positive by RT-PCR for RSV. Comparing RSV-positive with RSV-negative subjects, the RSV-positive subjects had lower median age (3.6 vs 6.4 months, p < 0.001) and fewer males (55% vs 64%, p = 0.02). RSV-positive children had higher rates of oxygen use (72% vs 42%, p < 0.001), a longer hospital stay (5 vs 4 days, p = 0.001), and higher hospital charges (US$538 vs US$431, p < 0.001) than RSV-negative children. In young hospitalized Jordanian infants, the medical and financial burden of RSV was found to be high. Effective preventive measures, such as an RSV vaccine, would have a significant beneficial impact.

  14. Burden of respiratory syncytial virus in hospitalized infants and young children in Amman, Jordan

    PubMed Central

    KHURI-BULOS, NAJWA; WILLIAMS, JOHN V.; SHEHABI, ASEM A.; FAOURI, SAMIR; JUNDI, EHSAN AL; ABUSHARIAH, OMAR; CHEN, QINGXIA; ALI, S. ASAD; VERMUND, STEN; HALASA, NATASHA B.

    2010-01-01

    Acute respiratory infections (ARI) play a major role in hospitalizations in the Middle East, but the specific viral causes are unknown. We conducted prospective viral surveillance in children <5 y of age admitted with ARI and/or fever at 2 dissimilar hospitals in Amman, Jordan during peak respiratory syncytial virus (RSV) season. We collected prospective clinical and demographic data and obtained nose/throat swabs for testing for RSV by real-time polymerase chain reaction (RT-PCR). We obtained clinical and laboratory data for 728/743 (98%) subjects enrolled. The children’s median age was 4.3 months, 58.4% were males, 87% were breastfed, 4% attended day care, 67% were exposed to smokers, 7% were admitted to the intensive care unit, and 0.7% died (n = 5). Out of 728 subjects, 467 (64%) tested positive by RT-PCR for RSV. Comparing RSV-positive with RSV-negative subjects, the RSV-positive subjects had lower median age (3.6 vs 6.4 months, p < 0.001) and fewer males (55% vs 64%, p = 0.02). RSV-positive children had higher rates of oxygen use (72% vs 42%, p < 0.001), a longer hospital stay (5 vs 4 days, p = 0.001), and higher hospital charges (US$538 vs US$431, p < 0.001) than RSV-negative children. In young hospitalized Jordanian infants, the medical and financial burden of RSV was found to be high. Effective preventive measures, such as an RSV vaccine, would have a significant beneficial impact. PMID:20100116

  15. [Clinical value of a rapid respiratory syncytial virus antigen detection in point-of-care testing].

    PubMed

    Ding, Y X; Tian, R; Qian, Y; Sun, Y; Deng, J; Wang, F; Zhu, R N; Zhao, L Q

    2017-02-02

    Objective: To evaluate the clinical value of a rapid respiratory syncytial virus (RSV) antigen detection in point-of-care testing (POCT). Method: A total of 209 specimens, including 78 throat swabs (TS) and 131 nasopharyngeal aspirates (NPAs), were collected from inpatients who visited the Children's Hospital Affiliated to the Capital Institute of Pediatrics and were diagnosed as acute respiratory infection from 5 January to 7 February, 2015. These specimens were tested for RSV by a rapid antigen detection kit which was compared with reverse transcription polymerase chain reaction (RT-PCR) and direct immunofluorescence assay (DFA) for RSV detection. Result: Compared with DFA for NPAs, the sensitivity and specificity of rapid antigen detection were 83.9% and 97.3%, respectively, with Kappa value of 0.86; Compared with RT-PCR, the sensitivity (NPAs, 74.2%; TS, 77.8%) and specificity (NPAs, 100.0%; TS, 92.0%) of rapid antigen detection were high, too, with Kappa value of 0.74 in NPAs and 0.62 in TS. However, the RSV positive rate of rapid antigen detection in TS (21.7%) from pediatric patients with acute lower respiratory tract infection was lower than that in NPAs (78.3%), as well as that of RT-PCR (7.3% in TS verse 78% in NPAs). The RSV rapid antigen detection kit can be finished in about 10 minutes. Conclusion: With characteristics of high specificity, high sensitivity, being rapid, efficient and easy to operate in comparison with DFA and RT-PCR, RSV rapid antigen detection in this study is suitable for POCT. For pediatric patients with acute respiratory tract infection, NPA was better than TS for RSV detection.

  16. Heliox reduces respiratory system resistance in respiratory syncytial virus induced respiratory failure.

    PubMed

    Kneyber, Martin C J; van Heerde, Marc; Twisk, Jos W R; Plötz, Frans B; Markhors, Dick G

    2009-01-01

    Respiratory syncytial virus (RSV) lower respiratory tract disease is characterised by narrowing of the airways resulting in increased airway resistance, air-trapping and respiratory acidosis. These problems might be overcome using helium-oxygen gas mixture. However, the effect of mechanical ventilation with heliox in these patients is unclear. The objective of this prospective cross-over study was to determine the effects of mechanical ventilation with heliox 60/40 versus conventional gas on respiratory system resistance, air-trapping and CO2 removal. Mechanically ventilated, sedated and paralyzed infants with proven RSV were enrolled within 24 hours after paediatric intensive care unit (PICU)admission. At T = 0, respiratory system mechanics including respiratory system compliance and resistance, and peak expiratory flow rate were measured with the AVEA ventilator. The measurements were repeated at each interval (after 30 minutes of ventilation with heliox, after 30 minutes of ventilation with nitrox and again after 30 minutes of ventilation with heliox). Indices of gas exchange (ventilation and oxygenation index) were calculated at each interval. Air-trapping (defined by relative change in end-expiratory lung volume) was determined by electrical impedance tomography (EIT) at each interval. Thirteen infants were enrolled. In nine, EIT measurements were performed. Mechanical ventilation with heliox significantly decreased respiratory system resistance. This was not accompanied by an improved CO2 elimination, decreased peak expiratory flow rate or decreased end-expiratory lung volume. Importantly, oxygenation remained unaltered throughout the experimental protocol. Respiratory system resistance is significantly decreased by mechanical ventilation with heliox (ISCRTN98152468).

  17. Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease.

    PubMed

    Cortjens, Bart; de Boer, Onno J; de Jong, Rineke; Antonis, Adriaan Fg; Sabogal Piñeros, Yanaika S; Lutter, René; van Woensel, Job Bm; Bem, Reinout A

    2016-02-01

    Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.