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1

Targeted silencing of anthrax toxin receptors protects against anthrax toxins.  

PubMed

Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax. PMID:24742682

Arévalo, Maria T; Navarro, Ashley; Arico, Chenoa D; Li, Junwei; Alkhatib, Omar; Chen, Shan; Diaz-Arévalo, Diana; Zeng, Mingtao

2014-05-30

2

Anthrax Toxin Receptor 2Dependent Lethal Toxin Killing In Vivo  

E-print Network

Anthrax Toxin Receptor 2­Dependent Lethal Toxin Killing In Vivo Heather M. Scobie1,2 , Darran J Jolla, California, United States of America Anthrax toxin receptors 1 and 2 (ANTXR1 and ANTXR2) have by residue D683 of the protective antigen (PA) subunit of anthrax toxin. The receptor-bound metal ion and PA

Sejnowski, Terrence J.

3

Probing interactions within anthrax toxin by electron paramagnetic resonance  

E-print Network

Probing interactions within anthrax toxin by electron paramagnetic resonance Laura D. Jennings of anthrax toxin forms oligomeric pores that translocate the enzymatic moieties of the toxin -- lethal factor

4

Human genetic variation altering anthrax toxin sensitivity  

E-print Network

Human genetic variation altering anthrax toxin sensitivity Mikhail Martchenkoa , Sophie I affecting capillary morphogenesis gene 2 (CMG2), which encodes a host membrane protein exploited by anthrax in sensitivity me- diated by the protective antigen (PA) moiety of anthrax toxin by more than four orders

Tang, Hua

5

Designing Inhibitors of Anthrax Toxin  

PubMed Central

Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination. PMID:24447197

Nestorovich, Ekaterina M.; Bezrukov, Sergey M.

2014-01-01

6

Anthrax lethal and edema toxins in anthrax pathogenesis.  

PubMed

The pathophysiological effects resulting from many bacterial diseases are caused by exotoxins released by the bacteria. Bacillus anthracis, a spore-forming bacterium, is such a pathogen, causing anthrax through a combination of bacterial infection and toxemia. B. anthracis causes natural infection in humans and animals and has been a top bioterrorism concern since the 2001 anthrax attacks in the USA. The exotoxins secreted by B. anthracis use capillary morphogenesis protein 2 (CMG2) as the major toxin receptor and play essential roles in pathogenesis during the entire course of the disease. This review focuses on the activities of anthrax toxins and their roles in initial and late stages of anthrax infection. PMID:24684968

Liu, Shihui; Moayeri, Mahtab; Leppla, Stephen H

2014-06-01

7

Receptor-specific requirements for anthrax toxin delivery into cells  

E-print Network

Receptor-specific requirements for anthrax toxin delivery into cells G. Jonah A. Rainey*, Darran J Contributed by R. John Collier, July 12, 2005 The three proteins that constitute anthrax toxin self marker 8 toxin entry Bacillus anthracis, the causative agent of anthrax, secretes a toxin

Sejnowski, Terrence J.

8

The roles of anthrax toxin in pathogenesis  

Microsoft Academic Search

Anthrax lethal toxin is a multi-functional virulence factor that has evolved to target multiple host functions to allow for optimal establishment of Bacillus anthracis infection. The toxin appears to play a role in all stages of infection, from germination to the induction of vascular collapse leading to host death. Early in infection, at sublethal doses, it acts to suppress immune

Mahtab Moayeri; Stephen H Leppla

2004-01-01

9

Anthrax toxin-induced rupture of artificial lipid bilayer membranes  

NASA Astrophysics Data System (ADS)

We demonstrate experimentally that anthrax toxin complexes rupture artificial lipid bilayer membranes when isolated from the blood of infected animals. When the solution pH is temporally acidified to mimic that process in endosomes, recombinant anthrax toxin forms an irreversibly bound complex, which also destabilizes membranes. The results suggest an alternative mechanism for the translocation of anthrax toxin into the cytoplasm.

Nablo, Brian J.; Panchal, Rekha G.; Bavari, Sina; Nguyen, Tam L.; Gussio, Rick; Ribot, Wil; Friedlander, Art; Chabot, Donald; Reiner, Joseph E.; Robertson, Joseph W. F.; Balijepalli, Arvind; Halverson, Kelly M.; Kasianowicz, John J.

2013-08-01

10

Anthrax toxin-induced rupture of artificial lipid bilayer membranes.  

PubMed

We demonstrate experimentally that anthrax toxin complexes rupture artificial lipid bilayer membranes when isolated from the blood of infected animals. When the solution pH is temporally acidified to mimic that process in endosomes, recombinant anthrax toxin forms an irreversibly bound complex, which also destabilizes membranes. The results suggest an alternative mechanism for the translocation of anthrax toxin into the cytoplasm. PMID:23947891

Nablo, Brian J; Panchal, Rekha G; Bavari, Sina; Nguyen, Tam L; Gussio, Rick; Ribot, Wil; Friedlander, Art; Chabot, Donald; Reiner, Joseph E; Robertson, Joseph W F; Balijepalli, Arvind; Halverson, Kelly M; Kasianowicz, John J

2013-08-14

11

Ratcheting up protein translocation with anthrax toxin.  

PubMed

Energy-consuming nanomachines catalyze the directed movement of biopolymers in the cell. They are found both dissolved in the aqueous cytosol as well as embedded in lipid bilayers. Inquiries into the molecular mechanism of nanomachine-catalyzed biopolymer transport have revealed that these machines are equipped with molecular parts, including adjustable clamps, levers, and adaptors, which interact favorably with substrate polypeptides. Biological nanomachines that catalyze protein transport, known as translocases, often require that their substrate proteins unfold before translocation. An unstructured protein chain is likely entropically challenging to bind, push, or pull in a directional manner, especially in a way that produces an unfolding force. A number of ingenious solutions to this problem are now evident in the anthrax toxin system, a model used to study protein translocation. Here we highlight molecular ratchets and current research on anthrax toxin translocation. A picture is emerging of proton-gradient-driven anthrax toxin translocation, and its associated ratchet mechanism likely applies broadly to other systems. We suggest a cyclical thermodynamic order-to-disorder mechanism (akin to a heat-engine cycle) is central to underlying protein translocation: peptide substrates nonspecifically bind to molecular clamps, which possess adjustable affinities; polypeptide substrates compress into helical structures; these clamps undergo proton-gated switching; and the substrate subsequently expands regaining its unfolded state conformational entropy upon translocation. PMID:22374876

Feld, Geoffrey K; Brown, Michael J; Krantz, Bryan A

2012-05-01

12

Ratcheting up protein translocation with anthrax toxin  

PubMed Central

Energy-consuming nanomachines catalyze the directed movement of biopolymers in the cell. They are found both dissolved in the aqueous cytosol as well as embedded in lipid bilayers. Inquiries into the molecular mechanism of nanomachine-catalyzed biopolymer transport have revealed that these machines are equipped with molecular parts, including adjustable clamps, levers, and adaptors, which interact favorably with substrate polypeptides. Biological nanomachines that catalyze protein transport, known as translocases, often require that their substrate proteins unfold before translocation. An unstructured protein chain is likely entropically challenging to bind, push, or pull in a directional manner, especially in a way that produces an unfolding force. A number of ingenious solutions to this problem are now evident in the anthrax toxin system, a model used to study protein translocation. Here we highlight molecular ratchets and current research on anthrax toxin translocation. A picture is emerging of proton-gradient-driven anthrax toxin translocation, and its associated ratchet mechanism likely applies broadly to other systems. We suggest a cyclical thermodynamic order-to-disorder mechanism (akin to a heat-engine cycle) is central to underlying protein translocation: peptide substrates nonspecifically bind to molecular clamps, which possess adjustable affinities; polypeptide substrates compress into helical structures; these clamps undergo proton-gated switching; and the substrate subsequently expands regaining its unfolded state conformational entropy upon translocation. PMID:22374876

Feld, Geoffrey K; Brown, Michael J; Krantz, Bryan A

2012-01-01

13

Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1  

PubMed Central

Anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (PA) with one of three reported cell surface toxin receptors (ANTXR). Receptor binding has been shown to influence host susceptibility to the toxins. Despite this crucial role for ANTXR in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about ANTXR expression on human leucocytes. We characterized the expression levels of ANTXR1 (TEM8) on human leucocytes using flow cytometry. In order to assess the effect of prior toxin exposure on ANTXR1 expression levels, leucocytes from individuals with no known exposure, those exposed to toxin through vaccination and convalescent individuals were analysed. Donors could be defined as either ‘low’ or ‘high’ expressers based on the percentage of ANTXR1-positive monocytes detected. Previous exposure to toxins appears to modulate ANTXR1 expression, exposure through active infection being associated with lower receptor expression. A significant correlation between low receptor expression and high anthrax toxin-specific interferon (IFN)-? responses was observed in previously infected individuals. We propose that there is an attenuation of ANTXR1 expression post-infection which may be a protective mechanism that has evolved to prevent reinfection. PMID:23607659

Ingram, R J; Harris, A; Ascough, S; Metan, G; Doganay, M; Ballie, L; Williamson, E D; Dyson, H; Robinson, J H; Sriskandan, S; Altmann, D M

2013-01-01

14

New insights into the biological effects of anthrax toxins: linking cellular to organismal responses  

E-print Network

Review New insights into the biological effects of anthrax toxins: linking cellular to organismal The anthrax toxins lethal toxin (LT) and edema toxin (ET) are essential virulence factors produced by Bacillus anthracis. These toxins act during two distinct phases of anthrax infection. During the first, prodromal

Nizet, Victor

15

Structure of heptameric protective antigen bound to an anthrax toxin receptor: A role for receptor  

E-print Network

Structure of heptameric protective antigen bound to an anthrax toxin receptor: A role for receptor of anthrax toxin forms a heptameric prepore. The prepore later undergoes pH-dependent conversion to a pore accomplishes this disruption by secreting a tripartite toxin­ anthrax toxin, consisting of two intracellularly

Harrison, Stephen C.

16

Anthrax  

MedlinePLUS

... Because plasmids often contain genes for toxins and antibiotic resistance, knowing the DNA sequence of such plasmids is ... than current therapies and shows promise against some antibiotic-resistant ... in three animal models. New anthrax therapies, such as monoclonal and ...

17

Genetically modified anthrax lethal toxin safely delivers whole HIV protein antigens into the  

E-print Network

Genetically modified anthrax lethal toxin safely delivers whole HIV protein antigens, 2000 (received for review January 24, 2000) Bacillus anthrax lethal toxin can be engineered to deliver compartment of mammalian cells. The engineered anthrax toxin vaccine appears unlikely to induce an antibody

Lieberman, Judy

18

Anthrax Toxin Induces Macrophage Death by p38 MAPK Inhibition but Leads to  

E-print Network

Immunity Article Anthrax Toxin Induces Macrophage Death by p38 MAPK Inhibition but Leads of the Gram-positive bacterial pathogen Bacillus anthracis, the causative agent of anthrax (Tournier et al. Anthrax patho- genesis depends on production of lethal toxin (LT) and edema toxin (ET) (Moayeri and Leppla

Nizet, Victor

19

Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor  

E-print Network

Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor Heather M. Scobie, G bipartite toxins thought to be involved in anthrax pathogenesis and resulting death of the host. The current-surface anthrax toxin receptors (ATRs), encoded by the tumor endothe- lial marker 8 (TEM8) gene. The ATR TEM8-PA

Sejnowski, Terrence J.

20

Identification of the cellular receptor for anthrax toxin  

NASA Astrophysics Data System (ADS)

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

Bradley, Kenneth A.; Mogridge, Jeremy; Mourez, Michael; Collier, R. John; Young, John A. T.

2001-11-01

21

Role of Toxin Functional Domains in Anthrax Pathogenesis  

Microsoft Academic Search

We investigated the role of the functional domains of anthrax toxins during infection. Three proteins produced by Bacillus anthracis, the protective antigen (PA), the lethal factor (LF), and the edema factor (EF), combine in pairs to produce the lethal (PA1LF) and edema (PA1EF) toxins. A genetic strategy was developed to introduce by allelic exchange specific point mutations or in-frame deletions

FABIEN BROSSIER; MARTINE WEBER-LEVY; MICHELE MOCK; JEAN-CLAUDE SIRARD

2000-01-01

22

A model of anthrax toxin lethal factor bound to protective antigen  

E-print Network

A model of anthrax toxin lethal factor bound to protective antigen D. Borden Lacy*, Henry C. Lin Contributed by R. John Collier, September 21, 2005 Anthrax toxin is made up of three proteins: the edema, the causative agent of anthrax, secretes three monomeric proteins, protective antigen (PA), edema factor (EF

Baker, David

23

Anthrax Lethal Toxin-Mediated Killing of Human and Murine Dendritic Cells Impairs  

E-print Network

Anthrax Lethal Toxin-Mediated Killing of Human and Murine Dendritic Cells Impairs the Adaptive anthracis interferes with host defenses by releasing anthrax lethal toxin (LT), which inactivates mitogen that anthrax LT impairs adaptive immunity by specifically targeting DCs. This may represent an immune- evasion

Brojatsch, Jürgen

24

Anthrax Toxin: Receptor Binding, Internalization, Pore Formation, and Translocation  

Microsoft Academic Search

Anthrax toxin consists of three nontoxic proteins that self-assemble at the surface of receptor-bearing mammalian cells or in solution, yielding a series of toxic complexes. Two of the proteins, called Lethal Factor (LF) and Edema Factor (EF), are enzymes that act on cytosolic substrates. The third, termed Protective Antigen (PA), is a multifunctional protein that binds to receptors, orchestrates the

John A. T. Young; R. John Collier

2007-01-01

25

Crystallographic studies of the Anthrax lethal toxin. Annual report  

SciTech Connect

The lethal form of Anthrax results from the inhalation of anthrax spores. Death is primarily due to the effects of the lethal toxin (Protective Antigen (PA) + Lethal Factor) from the causative agent, Bacillus anthracis. All the Anthrax vaccines currently in use or under development contain or produce PA, the major antigenic component of anthrax toxin, and there is a clear need for an improved vaccine for human use. In the previous report we described the first atomic resolution structure of PA, revealing that the molecule is composed largely of beta-sheets organized into four domains. This information can be used in the design. of recombinant PA vaccines. In this report we describe additional features of the full-length PA molecule derived from further crystallographic refinement and careful examination of the structure. We compare two crystal forms of PA grown at different pH values and discuss the functional implications. A complete definition of the function of each domain must await the crystal structure of the PA63 heptamer. We have grown crystals of the heptamer under both detergent and detergent-free conditions, and made substantial progress towards the crystal structure. The mechanism of anthrax intoxication in the light of our results is reviewed.

Frederick, C.A.

1996-07-01

26

Calpain-dependent cytoskeletal rearrangement exploited for anthrax toxin endocytosis  

PubMed Central

The protective antigen component of Bacillus anthracis toxins can interact with at least three distinct proteins on the host cell surface, capillary morphogenesis gene 2 (CMG2), tumor endothelial marker 8, and ?1-integrin, and, with the assistance of other host proteins, enters targeted cells by receptor-mediated endocytosis. Using an antisense-based phenotypic screen, we discovered the role of calpains in this process. We show that functions of a ubiquitous Ca2+-dependent cysteine protease, calpain-2, and of the calpain substrate talin-1 are exploited for association of anthrax toxin and its principal receptor, CMG2, with higher-order actin filaments and consequently for toxin entry into host cells. Down-regulated expression of calpain-2 or talin-1, or pharmacological interference with calpain action, did not affect toxin binding but reduced endocytosis and increased the survival of cells exposed to anthrax lethal toxin. Adventitious expression of wild-type talin-1 promoted toxin endocytosis and lethality, whereas expression of a talin-1 mutant (L432G) that is insensitive to calpain cleavage did not. Disruption of talin-1, which links integrin-containing focal adhesion complexes to the actin cytoskeleton, facilitated association of toxin bound to its principal cell-surface receptor, CMG2, with higher-order actin filaments undergoing dynamic disassembly and reassembly during endocytosis. Our results reveal a mechanism by which a bacterial toxin uses constitutively occurring calpain-mediated cytoskeletal rearrangement for internalization. PMID:24085852

Jeong, Sun-Young; Martchenko, Mikhail; Cohen, Stanley N.

2013-01-01

27

The role of antibodies to Bacillus anthracis and anthrax toxin components in inhibiting the early stages of infection by anthrax spores  

Microsoft Academic Search

Vaccines which are efficacious against anthrax, such as the human vaccine, Anthrax Vaccine Absorbed (AVA), contain the protective antigen (PA) component of the anthrax toxins as the major protective immunogen. Although AVA protects against inhalational anthrax, the immune responses to and role in protection of PA and possibly other antigens have yet to be fully elucidated. Sera from animals immunized

Susan Welkos; Stephen Little; Arthur Friedlander; David Fritz; Patricia Fellows

28

Polyvalent Recognition of Biopolymers:The Design of Potent Inhibitors of Anthrax Toxin  

NASA Astrophysics Data System (ADS)

Polyvalency -- the simultaneous binding of multiple ligands on one entity to multiple receptors on another -- is a phenomenon that is ubiquitous in nature. We are using a biomimetic approach, inspired by polyvalency, to design potent inhibitors of anthrax toxin. Since the major symptoms and death from anthrax are due primarily to the action of anthrax toxin, the toxin is a prime target for therapeutic intervention. We describe the design of potent polyvalent anthrax toxin inhibitors, and will discuss the role of pattern matching in polyvalent recognition. Pattern-matched polyvalent inhibitors can neutralize anthrax toxin in vivo, and may enable the successful treatment of anthrax during the later stages of the disease, when antibiotic treatment is ineffective.

Kane, Ravi

2007-03-01

29

Proteasomes Control Caspase-1 Activation in Anthrax Lethal Toxin-mediated Cell Killing*S  

E-print Network

Proteasomes Control Caspase-1 Activation in Anthrax Lethal Toxin-mediated Cell Killing*S Received York 10461 Activation of caspase-1 through the inflammasome protein Nalp1b controls anthrax lethal. The spore-forming bacterium Bacillus anthracis is the caus- ative agent of anthrax disease (1

Brojatsch, Jürgen

30

Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin  

Microsoft Academic Search

Anthrax poses a clear and present danger as an agent of biological terrorism. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that

Anshu Agrawal; Jai Lingappa; Stephen H. Leppla; Sudhanshu Agrawal; Abdul Jabbar; Conrad Quinn; Bali Pulendran

2003-01-01

31

LETTER doi:10.1038/nature09446 Anthrax toxins cooperatively inhibit endocytic  

E-print Network

LETTER doi:10.1038/nature09446 Anthrax toxins cooperatively inhibit endocytic recycling by the Rab Sorge2 *, Victor Nizet2,4 & Ethan Bier1 Bacillus anthracis is the causative agent of anthrax in humans and other mammals1,2 . In lethal systemic anthrax, proliferating bacilli secrete large quantities

Nizet, Victor

32

Standardized, mathematical model-based and validated in vitro analysis of anthrax lethal toxin neutralization  

Microsoft Academic Search

Quantification of anthrax lethal toxin (LTx) neutralization activity (TNA) is pivotal in assessing protective antibody responses to anthrax vaccines and for evaluation of immunotherapies for anthrax. We have adapted and redesigned the TNA assay to establish a unifying, standardized, quantitative and validated technology platform for LTx neutralization in the J774A.1 murine cell line. Critical design features of this platform are

Han Li; Stephen D. Soroka; Thomas H. Taylor Jr.; Karen L. Stamey; Kelly Wallace Stinson; Alison E. Freeman; Darbi R. Abramson; Rita Desai; Li X. Cronin; J. Wade Oxford; Joseph Caba; Cynthia Pleatman; Sonal Pathak; Daniel S. Schmidt; Vera A. Semenova; Sandra K. Martin; Patricia P. Wilkins; Conrad P. Quinn

2008-01-01

33

MICROBIOLOGY: Enhanced: Fighting Anthrax with a Mutant Toxin  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required: There is an urgent need to develop new therapeutics against the microbe causing anthrax, which has the potential to be used in biological warfare. In their Perspective, Olsnes and Wesche discuss a new therapeutic approach designed by Sellman and colleagues. In this approach, a mutant subunit of the toxin prevents correct assembly of wild-type subunits into a pore in the host cell membrane. In this way, lethal bacterial enzymes are prevented from translocating into the host cell.

Sjur Olsnes (Institute for Cancer Research; Department of Biochemistry)

2008-10-05

34

Enhancement of Anthrax Lethal Toxin Cytotoxicity: a Subset of Monoclonal Antibodies against Protective Antigen Increases Lethal Toxin-Mediated Killing of Murine Macrophages  

Microsoft Academic Search

We investigated the ability of using monoclonal antibodies (MAbs) against anthrax protective antigen (PA), an anthrax exotoxin component, to modulate exotoxin cytotoxic activity on target macrophage cell lines. An- thrax PA plays a critical role in the pathogenesis of Bacillus anthracis infection. PA is the cell-binding compo- nent of the two anthrax exotoxins: lethal toxin (LeTx) and edema toxin. Several

Nehal Mohamed; Juan Li; Claudia S. Ferreira; Stephen F. Little; Arthur M. Friedlander; George L. Spitalny; Leslie S. Casey

2004-01-01

35

A dually active anthrax vaccine that confers protection against both bacilli and toxins  

PubMed Central

Systemic anthrax is caused by unimpeded bacillar replication and toxin secretion. We developed a dually active anthrax vaccine (DAAV) that confers simultaneous protection against both bacilli and toxins. DAAV was constructed by conjugating capsular poly-?-d-glutamic acid (PGA) to protective antigen (PA), converting the weakly immunogenic PGA to a potent immunogen, and synergistically enhancing the humoral response to PA. PGA-specific antibodies bound to encapsulated bacilli and promoted the killing of bacilli by complement. PA-specific antibodies neutralized toxin activity and protected immunized mice against lethal challenge with anthrax toxin. Thus, DAAV combines both antibacterial and antitoxic components in a single vaccine against anthrax. DAAV introduces a vaccine design that may be widely applicable against infectious diseases and provides additional tools in medicine and biodefense. PMID:12960361

Rhie, Gi-Eun; Roehrl, Michael H.; Mourez, Michael; Collier, R. John; Mekalanos, John J.; Wang, Julia Y.

2003-01-01

36

The medicinal chemistry of botulinum, ricin and anthrax toxins.  

PubMed

The potential use of weapons of mass destruction (nuclear, biological or chemical) by terrorist organizations represents a major threat to world peace and safety. Only a limited number of vaccines are available to protect the general population from the medical consequences of these weapons. In addition there are major health concerns associated with a pre-exposure mass vaccination of the general population. To reduce or eliminate the impact of these terrible threats, new drugs must be developed to safely treat individuals exposed to these agents. A review of all therapeutic agents under development for the treatment of the illnesses and injuries that result from exposure to nuclear, biological or chemical warfare agents is beyond the scope of any single article. The intent here is to provide a focused review for medicinal and organic chemists of three widely discussed and easily deployed biological warfare agents, botulinum neurotoxin and ricin toxins and the bacteria Bacillus anthracis. Anthrax will be addressed because of its similarity in both structure and mechanism of catalytic activity with botulinum toxin. The common feature of these three agents is that they exhibit their biological activity via toxin enzymatic hydrolysis of a specific bond in their respective substrate molecules. A brief introduction to the history of each of the biological warfare agents is presented followed by a discussion on the mechanisms of action of each at the molecular level, and a review of current potential inhibitors under investigation. PMID:15790305

Hicks, Rickey P; Hartell, Mark G; Nichols, Daniel A; Bhattacharjee, Apurba K; van Hamont, John E; Skillman, Donald R

2005-01-01

37

From structure to solutions: the role of basic research in developing anthrax countermeasures: Microbiology Graduate Program Seminar: Anthrax toxin.  

PubMed

Dr. John Collier traced the discoveries that elucidated the structure and function of the anthrax toxin in his talk "Anthrax Toxin," which was part of the Microbiology Graduate Program Seminar Series at Yale School of Medicine on February 23, 2012. Dr. Collier, Professor of Microbiology and Immunobiology at Harvard University, began by noting the advantages to studying anthrax pathogenesis in a biosafety level-1 lab. This designation does not merely facilitate his research, but also reflects a larger trend of basic research being leveraged to develop translational applications. Basic research on toxin structure has led to the development of a vaccine by Dr. Collier's group. Next-generation prophylactics also may stem from recent discoveries uncovering a role for cellular cofactors that mediate toxin function. Finally, basic research into the toxin substructure has facilitated efforts to change the receptor tropism to target dysregulated cells for therapeutic purposes. The urgency around biodefense agents makes the choice of research priorities a salient issue. As such, this author submits that basic research occupies a unique and lucrative niche driving clinical applications. PMID:22737057

Hardiman, Camille A

2012-06-01

38

New insights into the biological effects of anthrax toxins: linking cellular to organismal responses  

PubMed Central

The anthrax toxins lethal toxin (LT) and edema toxin (ET), are essential virulence factors produced by B. anthracis. These toxins act during two distinct phases of anthrax infection. During the first, prodromal phase, which is often asymptomatic, anthrax toxins act on cells of the immune system to help the pathogen establish infection. Then, during the rapidly progressing (or fulminant) stage of the disease bacteria disseminate via a hematological route to various target tissues and organs, which are typically highly vascularized. As bacteria proliferate in the bloodstream LT and ET begin to accumulate rapidly reaching a critical threshold level that will cause death even when the bacterial proliferation is curtailed by antibiotics. During this final phase of infection the toxins cause an increase in vascular permeability and a decrease in function of target organs including the heart, spleen, kidney, adrenal gland, and brain. In this review, we examine the various biological effects of anthrax toxins, focusing on the fulminant stage of the disease and on mechanisms by which the two toxins may collaborate to cause cardiovascular collapse. We discuss normal mechanisms involved in maintaining vascular integrity and based on recent studies indicating that LT and ET cooperatively inhibit membrane trafficking to cell-cell junctions we explore several potential mechanisms by which the toxins may achieve their lethal effects. We also summarize the effects of other potential virulence factors secreted by B. anthracis and consider the role of toxic factors in the evolutionarily recent emergence of this devastating disease. PMID:21930233

Guichard, Annabel; Nizet, Victor; Bier, Ethan

2013-01-01

39

Antibodies to anthrax toxin in humans and guinea pigs and their relevance to protective immunity  

Microsoft Academic Search

A forerunning study on the relationship between antibodies to the protective antigen (PA) and lethal factor (LF) components of anthrax toxin and protective immunity has been expanded and extended to include the third toxin component, the edema factor (EF). It was found that protection against the “vaccine resistant” Ames strain was possible in the absence of detectable anti-LF and anti-EF

P. C. B. Turnbull; S. H. Leppla; M. G. Broster; C. P. Quinn; J. Malling

1988-01-01

40

Dominant-Negative Mutants of a Toxin Subunit: An Approach to Therapy of Anthrax  

Microsoft Academic Search

The protective antigen moiety of anthrax toxin translocates the toxin's enzymic moieties to the cytosol of mammalian cells by a mechanism that depends on its ability to heptamerize and insert into membranes. We identified dominant- negative mutants of protective antigen that co-assemble with the wild-type protein and block its ability to translocate the enzymic moieties across mem- branes. These mutants

Bret R. Sellman; Michael Mourez; R. John Collier

2001-01-01

41

Role of chondroitin sulfate C in the action of anthrax toxin.  

PubMed

Anthrax toxin is produced by Bacillus anthracis, the causative agent of anthrax, and is responsible for the majority of disease symptoms. The toxin consists of 3 proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF), which combine to form lethal and edema toxin. Glycosaminoglycans, which are present on the surface of cells, were investigated with regard to their role in toxicity resulting from anthrax toxin exposure. Lethal toxin-induced cytotoxicity of the RAW 264.7 cells was significantly inhibited by the addition of chondroitin sulfate C as determined by the MTT assay. By contrast, several other glycosaminoglycans, including heparin, heparan sulfate, and dermatan sulfate did not show significant levels of inhibition. Studies utilizing fluorescence-labeled PA demonstrated decreased PA binding to RAW 264.7 cells with the addition of chondroitin sulfate C. Formation of PA oligomers at the surface of cells after binding was also inhibited by chondroitin sulfate C. Interestingly, enzymatic degradation of endogenous chondroitin sulfate C from the cell surface with chondroitinase ABC was accompanied by increased sensitivity to the toxin. These findings were further confirmed by pretreating cells with sodium chlorate to reduce the degree of cell surface glycosaminoglycans sulfation. In addition, chondroitin sulfate C effectively inhibits edema toxin-induced cAMP accumulation in cells. Our results indicate that chondroitin sulfate C may play an important role in the toxicity of anthrax toxin. PMID:22503668

Ahn, Hyun Chan; Kim, Na Young; Hur, Gyeung Haeng; Yang, Jai Myung; Shin, Sungho

2012-07-16

42

Anthrax  

MedlinePLUS

Anthrax is a disease caused by Bacillus anthracis, a germ that lives in soil. Many people know ... bioterror attacks. In the attacks, someone purposely spread anthrax through the U.S. mail. This killed five people ...

43

ANTHRAX  

Microsoft Academic Search

Anthrax is an ancient bacterial infection capable of infecting nearly all warm-blooded animals. It has existed since early-recorded history as a disease of both human beings and their livestock. However, recent exposures to anthrax due to bioterrorism have turned anthrax and its mechanisms of infection into an important topic of inquiry. As new information is obtained, more effective treatments for

Michele Mock; Agnes Fouet

2001-01-01

44

Control of Anthrax Toxin Gene Expression by the Transition State Regulator abrB  

Microsoft Academic Search

Bacillus anthracis produces the anthrax toxin proteins protective antigen (PA), lethal factor (LF), and edema factor (EF) in a growth phase-dependent manner when cultured in liquid medium. Expression of the toxin genes pagA, lef, and cya peaks in late log phase, and steady-state levels of the toxin proteins are highest during the transition into stationary phase. Here we show that

Elke Saile; Theresa M. Koehler

2002-01-01

45

Protection against anthrax toxin by recombinant antibody fragments correlates with antigen affinity  

Microsoft Academic Search

The tripartite toxin produced by Bacillus anthracis is the key determinant in the etiology of anthrax. We have engineered a panel of toxin-neutralizing antibodies, including single-chain variable fragments (scFvs) and scFvs fused to a human constant ? domain (scAbs), that bind to the protective antigen subunit of the toxin with equilibrium dissociation constants (Kd) between 63 nM and 0.25 nM.

Jennifer A. Maynard; Catharina B. M. Maassen; Stephen H. Leppla; Kathleen Brasky; Jean L. Patterson; Brent L. Iverson; George Georgiou

2002-01-01

46

Tumor Endothelium Marker-8 Based Decoys Exhibit Superiority over Capillary Morphogenesis Protein-2 Based Decoys as Anthrax Toxin Inhibitors  

PubMed Central

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell-expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding-affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs. PMID:21674060

Xu, Long; Guo, Qiang; Kong, Yirong; Fu, Ling; Xu, Junjie; Cheng, Yuanguo; Chen, Wei

2011-01-01

47

Anthrax uses a receptor on the surface of cells to inject its lethal toxins. However, the physiological function of this receptor, named  

E-print Network

Anthrax uses a receptor on the surface of cells to inject its lethal toxins. However, the physiological function of this receptor, named Anthrax Toxin Receptor 2a (Antxr2a), remained unknown until now. Anthrax is a particularly virulent germ once a person is infected by inhaling its spores. The severity

Loewith, Robbie

48

Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax  

PubMed Central

The CDC recommend 60 days of oral antibiotics combined with a three-dose series of the anthrax vaccine for prophylaxis after potential exposure to aerosolized Bacillus anthracis spores. The anthrax vaccine is currently not licensed for anthrax postexposure prophylaxis and has to be made available under an Investigational New Drug protocol. Postexposure prophylaxis based on antibiotics can be problematic in cases where the use of antibiotics is contraindicated. Furthermore, there is a concern that an exposure could involve antibiotic-resistant strains of B. anthracis. Availability of alternate treatment modalities that are effective in prophylaxis of inhalation anthrax is therefore highly desirable. A major research focus toward this end has been on passive immunization using polyclonal and monoclonal antibodies against B. anthracis toxin components. Since 2001, significant progress has been made in isolation and commercial development of monoclonal and polyclonal antibodies that function as potent neutralizers of anthrax lethal toxin in both a prophylactic and therapeutic setting. Several new products have completed Phase I clinical trials and are slated for addition to the National Strategic Stockpile. These rapid advances were possible because of major funding made available by the US government through programs such as Bioshield and the Biomedical Advanced Research and Development Authority. Continued government funding is critical to support the development of a robust biodefense industry. PMID:19207098

Schneemann, Anette; Manchester, Marianne

2009-01-01

49

The Design of Potent Liposome-Based Inhibitors of Anthrax Toxin  

NASA Astrophysics Data System (ADS)

Several biological processes involve the recognition of a specific pattern of binding sites on a target surface. Theoreticians have predicted that endowing synthetic biomimetic structures with statistical pattern matching capabilities may impact the development of sensors and separation processes. We demonstrated for the first time that statistical pattern matching significantly enhances the potency of a polyvalent therapeutic -- an anthrax toxin inhibitor. We functionalized liposomes with an inhibitory peptide at different densities and observed a transition in potency at an inter-peptide separation that matches the distance between ligand-binding sites on the heptameric subunit of anthrax toxin. Pattern-matched polyvalent liposomes neutralized anthrax toxin in vitro at concentrations four orders of magnitude lower than the corresponding monovalent peptide. We also showed that polyvalent liposome-based inhibitors can neutralize a microbial toxin in vivo. Statistical pattern matching represents a facile strategy to enhance the potency of therapeutics targeting toxins or pathogens. Our results also illuminate other fundamental aspects of polyvalent recognition --specifically we found that the efficiency of polyvalent inhibition is influenced by the competition between the rates of ligand dissociation and diffusion.

Rai, Prakash; Padala, Chakradhar; Poon, Vincent; Saraph, Arundhati; Basha, Saleem; Kate, Sandesh; Tao, Kevin; Mogridge, Jeremy; Kane, Ravi

2006-03-01

50

Anthrax  

E-print Network

and Control Animals in areas where anthrax has previously occurred should be vaccinated against the disease. Vaccine should be given at least 2 to 4 weeks before the normal seasonal outbreak. In areas where anthrax often occurs, a veterinarian may recommend... giving a booster shot in 2 to 4 weeks. Normally an annual booster is adequate. Vaccinated animals may develop some swelling and fever that lasts several days. Dairy cattle may produce less milk and pregnant sows may abort after vaccination. Milk from...

Lawhorn, D. Bruce

2001-08-09

51

Anthrax  

Microsoft Academic Search

\\u000a Anthrax, a zoonotic disease of herbivorous animals transmissible from animals to man, occurs primarily in three forms: cutaneous,\\u000a inhalational, and gastrointestinal. Meningitis and septicemia occur but are secondary to one of the primary forms; occasionally,\\u000a cases of anthrax meningitis are reported in which a primary focus is not identified. The etiologic agent is Bacillus anthracis, a gram-positive organism that in

Philip S. Brachman; Arnold F. Kaufmann

52

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.  

PubMed

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

53

Cryo-electron microscopy study of bacteriophage T4 displaying anthrax toxin proteins  

SciTech Connect

The bacteriophage T4 capsid contains two accessory surface proteins, the small outer capsid protein (Soc, 870 copies) and the highly antigenic outer capsid protein (Hoc, 155 copies). As these are dispensable for capsid formation, they can be used for displaying proteins and macromolecular complexes on the T4 capsid surface. Anthrax toxin components were attached to the T4 capsid as a fusion protein of the N-terminal domain of the anthrax lethal factor (LFn) with Soc. The LFn-Soc fusion protein was complexed in vitro with Hoc{sup -}Soc{sup -}T4 phage. Subsequently, cleaved anthrax protective antigen heptamers (PA63){sub 7} were attached to the exposed LFn domains. A cryo-electron microscopy study of the decorated T4 particles shows the complex of PA63 heptamers with LFn-Soc on the phage surface. Although the cryo-electron microscopy reconstruction is unable to differentiate on its own between different proposed models of the anthrax toxin, the density is consistent with a model that had predicted the orientation and position of three LFn molecules bound to one PA63 heptamer.

Fokine, Andrei; Bowman, Valorie D.; Battisti, Anthony J. [Department of Biological Sciences, Purdue University, 915 W. State Street, West Lafayette, IN 47907-2054 (United States); Li Qin [Department of Biology, Catholic University of America, 620 Michigan Avenue NE, Washington, DC 20064 (United States); Chipman, Paul R. [Department of Biological Sciences, Purdue University, 915 W. State Street, West Lafayette, IN 47907-2054 (United States); Rao, Venigalla B. [Department of Biology, Catholic University of America, 620 Michigan Avenue NE, Washington, DC 20064 (United States); Rossmann, Michael G. [Department of Biological Sciences, Purdue University, 915 W. State Street, West Lafayette, IN 47907-2054 (United States)], E-mail: mr@purdue.edu

2007-10-25

54

Anthrax  

NSDL National Science Digital Library

This patient education program explains the causes and types of anthrax. It also reviews the symptoms, diagnosis, treatment, and prevention of anthrax through vaccination and awareness of bioterrorism. This resource is a MedlinePlus Interactive Health Tutorial from the National Library of Medicine, designed and developed by the Patient Education Institute. NOTE: This tutorial requires a special Flash plug-in, version 4 or above. If you do not have Flash, you will be prompted to obtain a free download of the software before you start the tutorial. You will also need an Acrobat Reader, available as a free download, in order to view the Reference Summary.

Patient Education Institute

55

Erythropoiesis Suppression Is Associated with Anthrax Lethal Toxin-Mediated Pathogenic Progression  

PubMed Central

Anthrax is a disease caused by the bacterium Bacillus anthracis, which results in high mortality in animals and humans. Although some of the mechanisms are already known such as asphyxia, extensive knowledge of molecular pathogenesis of this disease is deficient and remains to be further investigated. Lethal toxin (LT) is a major virulence factor of B. anthracis and a specific inhibitor/protease of mitogen-activated protein kinase kinases (MAPKKs). Anthrax LT causes lethality and induces certain anthrax-like symptoms, such as anemia and hypoxia, in experimental mice. Mitogen-activated protein kinases (MAPKs) are the downstream pathways of MAPKKs, and are important for erythropoiesis. This prompted us to hypothesize that anemia and hypoxia may in part be exacerbated by erythropoietic dysfunction. As revealed by colony-forming cell assays in this study, LT challenges significantly reduced mouse erythroid progenitor cells. In addition, in a proteolytic activity-dependent manner, LT suppressed cell survival and differentiation of cord blood CD34+-derived erythroblasts in vitro. Suppression of cell numbers and the percentage of erythroblasts in the bone marrow were detected in LT-challenged C57BL/6J mice. In contrast, erythropoiesis was provoked through treatments of erythropoietin, significantly ameliorating the anemia and reducing the mortality of LT-treated mice. These data suggested that suppressed erythropoiesis is part of the pathophysiology of LT-mediated intoxication. Because specific treatments to overcome LT-mediated pathogenesis are still lacking, these efforts may help the development of effective treatments against anthrax. PMID:23977125

Chang, Hsin-Hou; Wang, Tsung-Pao; Chen, Po-Kong; Lin, Yo-Yin; Liao, Chih-Hsien; Lin, Ting-Kai; Chiang, Ya-Wen; Lin, Wen-Bin; Chiang, Chih-Yu; Kau, Jyh-Hwa; Huang, Hsin-Hsien; Hsu, Hui-Ling; Liao, Chi-Yuan; Sun, Der-Shan

2013-01-01

56

Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions  

PubMed Central

Vascular leakage pathologies such as pleural effusion and hemorrhage are hallmarks of anthrax pathogenesis. We previously reported that anthrax lethal toxin (LT), the major virulence factor of anthrax, reduces barrier function in cultured primary human microvascular endothelial cells. Here, we show that LT-induced barrier dysfunction is accompanied by the reduced expression of the endothelial tight junction (TJ) protein claudin-5 but no change in the expression of other TJ components occludin, ZO-1, ZO-2, or the adherens junction (AJ) protein VE-cadherin. The downregulation of claudin-5 correlated temporally and dose-dependently with the reduction of transendothelial electrical resistance. LT-induced loss of claudin-5 was independent of cell death and preceded the appearance of actin stress fibers and altered AJ morphology. Pharmacological inhibition of MEK-1/2, two kinases that are proteolytically inactivated by LT, showed a similar reduction in claudin-5 expression. We found that LT reduced claudin-5 mRNA levels but did not accelerate the rate of claudin-5 degradation. Mice challenged with LT also showed significant reduction in claudin-5 expression. Together, these findings support a possible role for LT disruption of endothelial TJs in the vascular leakage pathologies of anthrax. PMID:23626836

D’Agnillo, Felice; Williams, Matthew C.; Moayeri, Mahtab; Warfel, Jason M.

2013-01-01

57

A microfluidic live cell assay to study anthrax toxin induced cell lethality assisted by conditioned medium  

PubMed Central

It is technically challenging to investigate the function of secreted protein in real time by supply of conditioned medium that contains secreted protein of interest. The internalization of anthrax toxin is facilitated by a secreted protein Dickkopf-1 (DKK1) and its receptor, and eventually leads to cell lethality. To monitor the dynamic interplay between these components in live cells, we use an integrated microfluidic device to perform the cell viability assays with real-time controlled culture microenvironment in parallel. Conditioned medium, which contains the secreted proteins from specific cell lines, can be continuously pumped towards the cells that exposed to toxin. The exogenous DKK1 secreted from distant cells is able to rescue the sensitivity to toxin for those DKK1-knocked-down cells. This high-throughput assay allows us to precisely quantify the dynamic interaction between key components that cause cell death, and provide independent evidence of the function of DKK1 in the complex process of anthrax toxin internalization. PMID:25731605

Shen, Jie; Cai, Changzu; Yu, Zhilong; Pang, Yuhong; Zhou, Ying; Qian, Lili; Wei, Wensheng; Huang, Yanyi

2015-01-01

58

A microfluidic live cell assay to study anthrax toxin induced cell lethality assisted by conditioned medium.  

PubMed

It is technically challenging to investigate the function of secreted protein in real time by supply of conditioned medium that contains secreted protein of interest. The internalization of anthrax toxin is facilitated by a secreted protein Dickkopf-1 (DKK1) and its receptor, and eventually leads to cell lethality. To monitor the dynamic interplay between these components in live cells, we use an integrated microfluidic device to perform the cell viability assays with real-time controlled culture microenvironment in parallel. Conditioned medium, which contains the secreted proteins from specific cell lines, can be continuously pumped towards the cells that exposed to toxin. The exogenous DKK1 secreted from distant cells is able to rescue the sensitivity to toxin for those DKK1-knocked-down cells. This high-throughput assay allows us to precisely quantify the dynamic interaction between key components that cause cell death, and provide independent evidence of the function of DKK1 in the complex process of anthrax toxin internalization. PMID:25731605

Shen, Jie; Cai, Changzu; Yu, Zhilong; Pang, Yuhong; Zhou, Ying; Qian, Lili; Wei, Wensheng; Huang, Yanyi

2015-01-01

59

Combination of two candidate subunit vaccine antigens elicits protective immunity to ricin and anthrax toxin in mice.  

PubMed

In an effort to develop combination vaccines for biodefense, we evaluated a ricin subunit antigen, RiVax, given in conjunction with an anthrax protective antigen, DNI. The combination led to high endpoint titer antibody response, neutralizing antibodies, and protective immunity against ricin and anthrax lethal toxin. This is a natural combination vaccine, since both antigens are recombinant subunit proteins that would be given to the same target population. PMID:25475957

Vance, David J; Rong, Yinghui; Brey, Robert N; Mantis, Nicholas J

2015-01-01

60

Monitoring of ELISA-reactive antibodies against anthrax protective antigen (PA), lethal factor (LF), and toxin-neutralising antibodies in serum of individuals vaccinated against anthrax with the PA-based UK anthrax vaccine  

Microsoft Academic Search

The human anthrax vaccines currently licensed contain the protective antigen (PA) of Bacillus anthracis as main antigen together with traces of some other bacillus components, e.g. lethal factor (LF). The present study aimed at monitoring the course of specific antibody titres against PA and LF by enzyme linked immunosorbent assays (ELISA), as well as the levels of toxin-neutralising antibodies, in

Roland Grunow; Mustafa Porsch-Özcürümez; Wolf Splettstoesser; Arno Buckendahl; Ulrike Hahn; Wolfgang Beyer; Reinhard Böhm; Maria Huber; Ulrich vd Esche; Wolfgang Bessler; Dimitrios Frangoulidis; Ernst-Jürgen Finke

2007-01-01

61

A Receptor-based Switch that Regulates Anthrax Toxin Pore Formation  

PubMed Central

Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the heptameric PA prepore that are required for pore conversion to an acidic endosomal compartment. The transfer cross-saturation (TCS) NMR approach was used to monitor changes in the heptameric PA-receptor contacts at different steps during prepore-to-pore conversion. These studies demonstrated that receptor contact with PA domain 2 is weakened prior to pore conversion, defining a novel intermediate in this pathway. Importantly, ANTXR2 remained bound to PA domain 4 following pore conversion, suggesting that the bound receptor might influence the structure and/or function of the newly formed pore. These studies provide new insights into the function of a receptor-based molecular switch that controls anthrax toxin entry into cells. PMID:22174672

Pilpa, Rosemarie M.; Bayrhuber, Monika; Marlett, John M.; Riek, Roland; Young, John A. T.

2011-01-01

62

Crystallographic studies of the anthrax lethal toxin. Final report, 1 July 1994-31 December 1996  

SciTech Connect

Protective Antigen (PA) is the central component of the three-part protein toxin secreted by Bacillus anthraces, the organism responsible for anthrax. Following proteolytic activation on the host cell surface, PA forms a membrane-inserting heptamer that translocates the toxic enzymes into the cytosol. We have solved the crystal structure of monomeric PA at 2.1 A resolution and the water-soluble heptamer at 4.5 A resolution. The monomer is organized mainly into antiparallel b-sheets and has four domains: an N-terminal domain containing two calcium ions; a heptamerization domain containing a large flexible loop implicated in membrane insertion; a small domain of unknown function; and a C-terminal receptor-binding domain. Removal of a 20 kDa fragment from the N-terminal domain permits assembly of the heptamer, a ring-shaped structure with a negatively charged lumen, and exposes a large hydrophobic surface for binding the toxic enzymes. We present a model of pH-dependent membrane insertion involving formation of a porin-like membrane-spanning b barrel. These studies greatly enhance current understanding of the mechanism of anthrax intoxication, and will be useful in the design of recombinant anthrax vaccines.

Frederick, C.A.

1997-01-01

63

Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy  

PubMed Central

Background Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Methods Wild type (WT) and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 ?g/g, intraperotineally (i.p.)). Cardiomyocyte contractile and intracellular Ca2+ properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination. Results Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca2+ handling), the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies. Conclusions Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca2+ anomalies, possibly through regulation of autophagy and mitochondrial function. PMID:23134810

2012-01-01

64

Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin  

PubMed Central

SUMMARY Anthrax Lethal Toxin is a classical AB-toxin comprised of two components, Protective Antigen (PA) and Lethal Factor (LF). Here we show that following assembly and endocytosis, PA forms a channel that translocates LF, not only into the cytosol, but also into the lumen of endosomal intraluminal vesicles (ILVs). These ILVs can fuse and release LF into the cytosol, where LF can proteolyze and disable host targets. We find that LF can persist in ILVs for days, fully sheltered from proteolytic degradation, both in vitro and in vivo. During this time ILV-localized LF can be transmitted to daughter cells upon cell division. In addition, LF-containing ILVs can be delivered to the extracellular medium as exosomes. These can deliver LF to the cytosol of naïve cells in a manner that is independent of the typical anthrax toxin-receptor trafficking pathway, while being sheltered from neutralizing extracellular factors of the immune system. PMID:24239351

Abrami, Laurence; Brandi, Lucia; Moayeri, Mahtab; Brown, Michael J.; Krantz, Bryan A.; Leppla, Stephen H.; van der Goot, F. G.

2013-01-01

65

Structure-based Inhibitor Discovery against Adenylyl Cyclase Toxins from Pathogenic Bacteria That Cause Anthrax and  

E-print Network

That Cause Anthrax and Whooping Cough* Received for publication, February 4, 2003, and in revised form, March bacteria that cause anthrax and whooping cough, respectively. Using the structure of the catalytic site pathogenesis and to fight against anthrax and whooping cough. The 2001 anthrax attacks in the United States

Mrksich, Milan

66

Anthrax lethal toxin paralyzes actin-based motility by blocking Hsp27 phosphorylation.  

PubMed

Inhalation of anthrax causes fatal bacteremia, indicating a meager host immune response. We previously showed that anthrax lethal toxin (LT) paralyzes neutrophils, a major component of innate immunity. Here, we have found that LT also inhibits actin-based motility of the intracellular pathogen Listeria monocytogenes. LT inhibition of actin assembly is mediated by blockade of Hsp27 phosphorylation, and can be reproduced by treating cells with the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580. Nonphosphorylated Hsp27 inhibits Listeria actin-based motility in cell extracts, and binds to and sequesters purified actin monomers. Phosphorylation of Hsp27 reverses these effects. RNA interference knockdown of Hsp27 blocks LT inhibition of Listeria actin-based motility. Rescue with wild-type Hsp27 accelerates Listeria speed in knockdown cells, whereas introduction of Hsp27 mutants incapable of phosphorylation or dephosphorylation causes slowing down. We propose that Hsp27 facilitates actin-based motility through a phosphorylation cycle that shuttles actin monomers to regions of new actin filament assembly. Our findings provide a previously unappreciated mechanism for LT virulence, and emphasize a central role for p38 MAP kinase-mediated phosphorylation of Hsp27 in actin-based motility and innate immunity. PMID:17446863

During, Russell L; Gibson, Bruce G; Li, Wei; Bishai, Ellen A; Sidhu, Gurjit S; Landry, Jacques; Southwick, Frederick S

2007-05-01

67

Expression of Nlrp1b Inflammasome Components in Human Fibroblasts Confers Susceptibility to Anthrax Lethal Toxin ?  

PubMed Central

Anthrax lethal toxin causes macrophages and dendritic cells from some mouse strains to undergo caspase-1-dependent cell death. Central to this process is the NOD-like receptor Nlrp1b (Nalp1b), which detects intoxication and then self-associates to form a complex, termed an inflammasome, that is capable of activating the procaspase-1 zymogen. The nature of the signal detected directly by Nlrp1b is not known, and the mechanisms of inflammasome assembly are poorly understood. Here, we demonstrate that transfection of human fibroblasts with plasmids encoding murine Nlrp1b and procaspase-1 was sufficient to confer susceptibility to lethal toxin-mediated death on the cells. As has been observed in murine macrophages, the enzymatic activities of lethal toxin and the proteasome were both required for activation of the Nlrp1b inflammasome and this activation led to prointerleukin-1? processing. Release of interleukin-1? from cells was not dependent on cell lysis, as its secretion was not affected by an osmoprotectant that prevented the appearance of lactate dehydrogenase in the culture medium. We generated constitutively active mutants of Nlrp1b by making amino-terminal deletions to the protein and observed that the ability to activate procaspase-1 was dependent on the CARD domain, which bound procaspase-1, and a region adjacent to the CARD domain that promoted self-association. Our results demonstrate that lethal toxin can activate Nlrp1b in a nonmyeloid cell line and are consistent with work that suggests that activation induces proximity of procaspase-1. PMID:19651869

Liao, Kuo-Chieh; Mogridge, Jeremy

2009-01-01

68

The anthrax toxin activator gene atxA is associated with CO2-enhanced non-toxin gene expression in Bacillus anthracis.  

PubMed Central

The Bacillus anthracis toxin genes, cya, lef, and pag, can be viewed as a regulon, in which transcription of all three genes is activated in trans by the same regulatory gene, atxA, in response to the same signal, CO2. In atxA+ strains, toxin gene expression is increased 5- to 20-fold in cells grown in 5% CO2 relative to cells grown in air. CO2-enhanced toxin gene transcription is not observed in atx4-null mutants. Here, we used two independent techniques to obtain evidence for additional CO2-induced atxA-regulated genes. First, total protein preparations from atxA4+ and atxA isolates grown in 5% CO2 and in air were examined by two-dimensional electrophoresis. Comparison of the resulting protein patterns indicated that synthesis of non-toxin proteins is influenced by growth in elevated CO2 and the toxin gene regulator, atxA. Second, we generated random transcriptional lacZ fusions in B. anthracis with transposon Tn917-LTV3. Transposon-insertion libraries were screened for mutants expressing CO2-enhanced atxA-dependent beta-galactosidase activity. DNA sequence analysis of transposon insertion sites in 17 mutants carrying CO2- and atxA-regulated fusions revealed 10 mutants carrying independent insertions on the 185-kb toxin plasmid pXO1 which did not map to the toxin genes. The tcr-lacZ fusion mutants (tcr for toxin coregulated) were Tox+, indicating that these genes may not be involved in anthrax toxin gene activation. Our data indicate a clear association of atxA with CO2-enhanced gene expression in B. anthracis and provide evidence that atxA regulates genes other than the structural genes for the anthrax toxin proteins. PMID:9234759

Hoffmaster, A R; Koehler, T M

1997-01-01

69

Protection against Anthrax Lethal Toxin Challenge by Genetic Immunization with a Plasmid Encoding the Lethal Factor Protein  

Microsoft Academic Search

The ability of genetic vaccination to protect against a lethal challenge of anthrax toxin was evaluated. BALB\\/c mice were immunized via gene gun inoculation with eucaryotic expression vector plasmids encoding either a fragment of the protective antigen (PA) or a fragment of lethal factor (LF). Plasmid pCLF4 contains the N-terminal region (amino acids (aa) 10 to 254) of Bacillus anthracis

BRIAN M. PRICE; ADRIANE L. LINER; STEPHEN H. LEPPLA; ALFRED MATECZUN; DARRELL R. GALLOWAY

2001-01-01

70

Polylysine-mediated translocation of the diphtheria toxin catalytic domain through the anthrax protective antigen pore.  

PubMed

The protective antigen (PA) moiety of anthrax toxin forms oligomeric pores in the endosomal membrane, which translocate the effector proteins of the toxin to the cytosol. Effector proteins bind to oligomeric PA via their respective N-terminal domains and undergo N- to C-terminal translocation through the pore. Earlier we reported that a tract of basic amino acids fused to the N-terminus of an unrelated effector protein (the catalytic domain diphtheria toxin, DTA) potentiated that protein to undergo weak PA-dependent translocation. In this study, we varied the location of the tract (N-terminal or C-terminal) and the length of a poly-Lys tract fused to DTA and examined the effects of these variations on PA-dependent translocation into cells and across planar bilayers in vitro. Entry into cells was most efficient with ?12 Lys residues (K12) fused to the N-terminus but also occurred, albeit 10-100-fold less efficiently, with a C-terminal tract of the same length. Similarly, K12 tracts at either terminus occluded PA pores in planar bilayers, and occlusion was more efficient with the N-terminal tag. We used biotin-labeled K12 constructs in conjunction with streptavidin to show that a biotinyl-K12 tag at either terminus is transiently exposed to the trans compartment of planar bilayers at 20 mV; this partial translocation in vitro was more efficient with an N-terminal tag than a C-terminal tag. Significantly, our studies with polycationic tracts fused to the N- and C-termini of DTA suggest that PA-mediated translocation can occur not only in the N to C direction but also in the C to N direction. PMID:25317832

Sharma, Onkar; Collier, R John

2014-11-11

71

Protein- and DNA-based anthrax toxin vaccines confer protection in guinea pigs against inhalational challenge with Bacillus cereus G9241.  

PubMed

In the past decade, several Bacillus cereus strains have been isolated from otherwise healthy individuals who succumbed to bacterial pneumonia presenting symptoms resembling inhalational anthrax. One strain was indistinguishable from B. cereus G9241, previously cultured from an individual who survived a similar pneumonia-like illness and which was shown to possess a complete set of plasmid-borne anthrax toxin-encoding homologs. The finding that B. cereus G9241 pathogenesis in mice is dependent on pagA1-derived protective antigen (PA) synthesis suggests that an anthrax toxin-based vaccine may be effective against this toxin-encoding B. cereus strain. Dunkin Hartley guinea pigs were immunized with protein- and DNA-based anthrax toxin-based vaccines, immune responses were evaluated and survival rates were calculated after lethal aerosol exposure with B. cereus G9241 spores. Each vaccine induced seroconversion with the protein immunization regimen eliciting significantly higher serum levels of antigen-specific antibodies at the prechallenge time-point compared with the DNA-protein prime-boost immunization schedule. Complete protection against lethal challenge was observed in all groups with a detectable prechallenge serum titer of toxin neutralizing antibodies. For the first time, we demonstrated that the efficacy of fully defined anthrax toxin-based vaccines was protective against lethal B. cereus G9241 aerosol challenge in the guinea pig animal model. PMID:25044336

Palmer, John; Bell, Matt; Darko, Christian; Barnewall, Roy; Keane-Myers, Andrea

2014-11-01

72

Differential Dependence on N-Glycosylation of Anthrax Toxin Receptors CMG2 and TEM8.  

PubMed

ANTXR 1 and 2, also known as TEM8 and CMG2, are two type I membrane proteins, which have been extensively studied for their role as anthrax toxin receptors, but with a still elusive physiological function. Here we have analyzed the importance of N-glycosylation on folding, trafficking and ligand binding of these closely related proteins. We find that TEM8 has a stringent dependence on N-glycosylation. The presence of at least one glycan on each of its two extracellular domains, the vWA and Ig-like domains, is indeed necessary for efficient trafficking to the cell surface. In the absence of any N-linked glycans, TEM8 fails to fold correctly and is recognized by the ER quality control machinery. Expression of N-glycosylation mutants reveals that CMG2 is less vulnerable to sugar loss. The absence of N-linked glycans in one of the extracellular domains indeed has little impact on folding, trafficking or receptor function of the wild type protein expressed in tissue culture cells. N-glycans do, however, seem required in primary fibroblasts from human patients. Here, the presence of N-linked sugars increases the tolerance to mutations in cmg2 causing the rare genetic disease Hyaline Fibromatosis Syndrome. It thus appears that CMG2 glycosylation provides a buffer towards genetic variation by promoting folding of the protein in the ER lumen. PMID:25781883

Friebe, Sarah; Deuquet, Julie; van der Goot, F Gisou

2015-01-01

73

Delivery of antibody mimics into mammalian cells via anthrax toxin protective antigen.  

PubMed

Antibody mimics have significant scientific and therapeutic utility for the disruption of protein-protein interactions inside cells; however, their delivery to the cell cytosol remains a major challenge. Here we show that protective antigen (PA), a component of anthrax toxin, efficiently transports commonly used antibody mimics to the cytosol of mammalian cells when conjugated to the N-terminal domain of LF (LFN). In contrast, a cell-penetrating peptide (CPP) was not able to deliver any of these antibody mimics into the cell cytosol. The refolding and binding of a transported tandem monobody to Bcr-Abl (its protein target) in chronic myeloid leukemia cells were confirmed by co-immunoprecipitation. We also observed inhibition of Bcr-Abl kinase activity and induction of apoptosis caused by the monobody. In a separate case, we show disruption of key interactions in the MAPK signaling pathway after PA-mediated delivery of an affibody binder that targets hRaf-1. We show for the first time that PA can deliver bioactive antibody mimics to disrupt intracellular protein-protein interactions. This technology adds a useful tool to expand the applications of these modern agents to the intracellular milieu. PMID:25250705

Liao, Xiaoli; Rabideau, Amy E; Pentelute, Bradley L

2014-11-01

74

Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding.  

PubMed

The secreted anthrax toxin consists of three components: the protective antigen (PA), edema factor (EF) and lethal factor (LF). LF, a zinc metalloproteinase, compromises the host immune system primarily by targeting mitogen-activated protein kinase kinases in macrophages. Peptide substrates and small-molecule inhibitors bind LF in the space between domains 3 and 4 of the hydrolase. Domain 3 is attached on a hinge to domain 2 via residues Ile300 and Pro385, and can move through an angular arc of greater than 35° in response to the binding of different ligands. Here, multiple LF structures including five new complexes with co-crystallized inhibitors are compared and three frequently populated LF conformational states termed `bioactive', `open' and `tight' are identified. The bioactive position is observed with large substrate peptides and leaves all peptide-recognition subsites open and accessible. The tight state is seen in unliganded and small-molecule complex structures. In this state, domain 3 is clamped over certain substrate subsites, blocking access. The open position appears to be an intermediate state between these extremes and is observed owing to steric constraints imposed by specific bound ligands. The tight conformation may be the lowest-energy conformation among the reported structures, as it is the position observed with no bound ligand, while the open and bioactive conformations are likely to be ligand-induced. PMID:25372673

Maize, Kimberly M; Kurbanov, Elbek K; De La Mora-Rey, Teresa; Geders, Todd W; Hwang, Dong Jin; Walters, Michael A; Johnson, Rodney L; Amin, Elizabeth A; Finzel, Barry C

2014-11-01

75

Ion Conductance of the Stem of the Anthrax Toxin Channel during Lethal Factor Translocation.  

PubMed

The tripartite anthrax toxin consists of protective antigen, lethal factor (LF), and edema factor. PA63 (the 63-kDa, C-terminal part of protective antigen) forms heptameric channels in cell membranes that allow for the transport of LF and edema factor into the cytosol. These channels are mushroom shaped, with a ring of seven phenylalanine residues (known as the phenylalanine clamp) lining the junction between the cap and the stem. It is known that when LF is translocated through the channel, the phenylalanine clamp creates a seal that causes an essentially complete block of conduction. In order to examine ion conductance in the stem of the channel, we used Venus yellow fluorescent protein as a molecular stopper to trap LFN (the 30-kDa, 263-residue N-terminal segment of LF), as well as various truncated constructs of LFN, in mutant channels in which the phenylalanine clamp residues were mutated to alanines. Here we present evidence that ion movement occurs within the channel stem (but is stopped, of course, at the phenylalanine clamp) during protein translocation. Furthermore, we also propose that the lower region of the stem plays an important role in securing peptide chains during translocation. PMID:24996036

Schiffmiller, Aviva; Finkelstein, Alan

2015-03-27

76

Differential Dependence on N-Glycosylation of Anthrax Toxin Receptors CMG2 and TEM8  

PubMed Central

ANTXR 1 and 2, also known as TEM8 and CMG2, are two type I membrane proteins, which have been extensively studied for their role as anthrax toxin receptors, but with a still elusive physiological function. Here we have analyzed the importance of N-glycosylation on folding, trafficking and ligand binding of these closely related proteins. We find that TEM8 has a stringent dependence on N-glycosylation. The presence of at least one glycan on each of its two extracellular domains, the vWA and Ig-like domains, is indeed necessary for efficient trafficking to the cell surface. In the absence of any N-linked glycans, TEM8 fails to fold correctly and is recognized by the ER quality control machinery. Expression of N-glycosylation mutants reveals that CMG2 is less vulnerable to sugar loss. The absence of N-linked glycans in one of the extracellular domains indeed has little impact on folding, trafficking or receptor function of the wild type protein expressed in tissue culture cells. N-glycans do, however, seem required in primary fibroblasts from human patients. Here, the presence of N-linked sugars increases the tolerance to mutations in cmg2 causing the rare genetic disease Hyaline Fibromatosis Syndrome. It thus appears that CMG2 glycosylation provides a buffer towards genetic variation by promoting folding of the protein in the ER lumen. PMID:25781883

Friebe, Sarah; Deuquet, Julie; van der Goot, F. Gisou

2015-01-01

77

High-sensitivity MALDI-TOF MS quantification of anthrax lethal toxin for diagnostics and evaluation of medical countermeasures.  

PubMed

Inhalation anthrax has a rapid progression and high fatality rate. Pathology and death from inhalation of Bacillus anthracis spores are attributed to the actions of secreted protein toxins. Protective antigen (PA) binds and imports the catalytic component lethal factor (LF), a zinc endoprotease, and edema factor (EF), an adenylyl cyclase, into susceptible cells. PA-LF is termed lethal toxin (LTx) and PA-EF, edema toxin. As the universal transporter for both toxins, PA is an important target for vaccination and immunotherapeutic intervention. However, its quantification has been limited to methods of relatively low analytic sensitivity. Quantification of LTx may be more clinically relevant than LF or PA alone because LTx is the toxic form that acts on cells. A method was developed for LTx-specific quantification in plasma using anti-PA IgG magnetic immunoprecipitation of PA and quantification of LF activity that co-purified with PA. The method was fast (<4 h total time to detection), sensitive at 0.033 ng/mL LTx in plasma for the fast analysis (0.0075 ng/mL LTx in plasma for an 18 h reaction), precise (6.3-9.9 % coefficient of variation), and accurate (0.1-12.7 %error; n???25). Diagnostic sensitivity was 100 % (n?=?27 animal/clinical cases). Diagnostic specificity was 100 % (n?=?141). LTx was detected post-antibiotic treatment in 6/6 treated rhesus macaques and 3/3 clinical cases of inhalation anthrax and as long as 8 days post-treatment. Over the course of infection in two rhesus macaques, LTx was first detected at 0.101 and 0.237 ng/mL at 36 h post-exposure and increased to 1147 and 12,107 ng/mL in late-stage anthrax. This demonstrated the importance of LTx as a diagnostic and therapeutic target. This method provides a sensitive, accurate tool for anthrax toxin detection and evaluation of PA-directed therapeutics. PMID:25673244

Boyer, Anne E; Gallegos-Candela, Maribel; Quinn, Conrad P; Woolfitt, Adrian R; Brumlow, Judith O; Isbell, Katherine; Hoffmaster, Alex R; Lins, Renato C; Barr, John R

2015-04-01

78

Identification of Novel Host-Targeted Compounds That Protect From Anthrax Lethal Toxin-Induced Cell Death  

PubMed Central

Studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. Bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. We conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function. We identified a structurally diverse set of small molecules that act at various points along the lethal toxin pathway, including inhibitors of endocytosis; natural product inhibitors of organelle acidification (e.g. the botulinum neurotoxin inhibitor, toosendanin); and a novel proteasome inhibitor, 4MNB (4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1-nitrosobenzene). Many of the compounds, including three drugs approved for use in humans, also protected against the related Clostridium difficile toxin TcdB, further demonstrating their value as novel tools for perturbation and study of toxin biology and host cellular processes, and highlighting potential new strategies for intervening on toxin-mediated diseases. PMID:23343607

Slater, Louise H.; Hett, Erik C.; Mark, Kevin; Chumbler, Nicole M.; Patel, Deepa; Lacy, D. Borden; Collier, R. John; Hung, Deborah T.

2013-01-01

79

Quantitative anti-PA IgG ELISA; assessment and comparability with the anthrax toxin neutralization assay in goats  

PubMed Central

Background Presently, few data exist on the level and duration of anti-protective antigen (PA) IgG in vaccinated livestock. Various adaptation of enzyme-linked immunosorbent assays (ELISAs) have been developed in studies to assess immune response following vaccination, albeit mostly in laboratory rodent models. The quantitative anti-anthrax IgG ELISA in this study describes a method of enumerating the concentration of anti-PA specific IgG present in sera of immunized goats, with the aid of an affinity-purified caprine polyclonal anti-anthrax PA-83 IgG standard. This was compared with the anthrax toxin neutralization assay (TNA) which measures a functional subset of toxin neutralizing anti-PA IgG. Results The measured concentrations obtained in the standard curve correlated with the known concentration at each dilution. Percentage recovery of the standard concentrations ranged from 89 to 98% (lower and upper asymptote respectively). Mean correlation coefficient (r2) of the standard curve was 0.998. Evaluation of the intra-assay coefficient of variation showed ranges of 0.23-16.90% and 0.40-12.46% for days 28 and 140 sera samples respectively, following vaccination. The mean inter-assay coefficient of variation for triplicate samples repeated on 5 different days was 18.53 and 12.17% for days 28 and 140 sera samples respectively. Spearman’s rank correlation of log-transformed IgG concentrations and TNA titres showed strong positive correlation (rs?=?0.942; p?=?0.01). Conclusion This study provides evidence that an indirect ELISA can be used for the quantification of anti-anthrax PA IgG in goats with the added advantage of using single dilutions to save time and resources. The use of such related immunoassays can serve as potential adjuncts to potency tests for Sterne and other vaccine types under development in ruminant species. This is the first report on the correlation of polyclonal anti-anthrax PA83 antibody with the TNA in goats. PMID:24373579

2013-01-01

80

Erythrocytic Mobilization Enhanced by the Granulocyte Colony-Stimulating Factor Is Associated with Reduced Anthrax-Lethal-Toxin-Induced Mortality in Mice  

PubMed Central

Anthrax lethal toxin (LT), one of the primary virulence factors of Bacillus anthracis, causes anthrax-like symptoms and death in animals. Experiments have indicated that levels of erythrocytopenia and hypoxic stress are associated with disease severity after administering LT. In this study, the granulocyte colony-stimulating factor (G-CSF) was used as a therapeutic agent to ameliorate anthrax-LT- and spore-induced mortality in C57BL/6J mice. We demonstrated that G-CSF promoted the mobilization of mature erythrocytes to peripheral blood, resulting in a significantly faster recovery from erythrocytopenia. In addition, combined treatment using G-CSF and erythropoietin tended to ameliorate B. anthracis-spore-elicited mortality in mice. Although specific treatments against LT-mediated pathogenesis remain elusive, these results may be useful in developing feasible strategies to treat anthrax. PMID:25384016

Chang, Hsin-Hou; Chiang, Ya-Wen; Lin, Ting-Kai; Lin, Guan-Ling; Lin, You-Yen; Kau, Jyh-Hwa; Huang, Hsin-Hsien; Hsu, Hui-Ling; Wang, Jen-Hung; Sun, Der-Shan

2014-01-01

81

Anthrax Toxins Inhibit Neutrophil Signaling Pathways in Brain Endothelium and Contribute to the Pathogenesis of Meningitis  

Microsoft Academic Search

BackgroundAnthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that

Nina M. van Sorge; Celia M. Ebrahimi; Shauna M. McGillivray; Darin Quach; Mojgan Sabet; Donald G. Guiney; Kelly S. Doran; Debbie Fox

2008-01-01

82

Affinity binding of antibodies to supermacroporous cryogel adsorbents with immobilized protein A for removal of anthrax toxin protective antigen.  

PubMed

Polymeric cryogels are efficient carriers for the immobilization of biomolecules because of their unique macroporous structure, permeability, mechanical stability and different surface chemical functionalities. The aim of the study was to demonstrate the potential use of macroporous monolithic cryogels for biotoxin removal using anthrax toxin protective antigen (PA), the central cell-binding component of the anthrax exotoxins, and covalent immobilization of monoclonal antibodies. The affinity ligand (protein A) was chemically coupled to the reactive hydroxyl and epoxy-derivatized monolithic cryogels and the binding efficiencies of protein A, monoclonal antibodies to the cryogel column were determined. Our results show differences in the binding capacity of protein A as well as monoclonal antibodies to the cryogel adsorbents caused by ligand concentrations, physical properties and morphology of surface matrices. The cytotoxicity potential of the cryogels was determined by an in vitro viability assay using V79 lung fibroblast as a model cell and the results reveal that the cryogels are non-cytotoxic. Finally, the adsorptive capacities of PA from phosphate buffered saline (PBS) were evaluated towards a non-glycosylated, plant-derived human monoclonal antibody (PANG) and a glycosylated human monoclonal antibody (Valortim(®)), both of which were covalently attached via protein A immobilization. Optimal binding capacities of 108 and 117 mg/g of antibody to the adsorbent were observed for PANG attached poly(acrylamide-allyl glycidyl ether) [poly(AAm-AGE)] and Valortim(®) attached poly(AAm-AGE) cryogels, respectively, This indicated that glycosylation status of Valortim(®) antibody could significantly increase (8%) its binding capacity relative to the PANG antibody on poly(AAm-AGE)-protien-A column (p < 0.05). The amounts of PA which remained in the solution after passing PA spiked PBS through PANG or Valortim bound poly(AAm-AGE) cryogel were significantly (p < 0.05) decreased relative to the amount of PA remained in the solution after passing through unmodified as well as protein A modified poly(AAm-AGE) cryogel columns, indicates efficient PA removal from spiked PBS over 60 min of circulation. The high adsorption capacity towards anthrax toxin PA of the cryogel adsorbents indicated potential application of these materials for treatment of Bacillus anthracis infection. PMID:25736504

Ingavle, Ganesh C; Baillie, Les W J; Zheng, Yishan; Lis, Elzbieta K; Savina, Irina N; Howell, Carol A; Mikhalovsky, Sergey V; Sandeman, Susan R

2015-05-01

83

A Heterodimer of a VHH (Variable Domains of Camelid Heavy Chain-only) Antibody That Inhibits Anthrax Toxin Cell Binding Linked to a VHH Antibody That Blocks Oligomer Formation Is Highly Protective in an Anthrax Spore Challenge Model.  

PubMed

Anthrax disease is caused by a toxin consisting of protective antigen (PA), lethal factor, and edema factor. Antibodies against PA have been shown to be protective against the disease. Variable domains of camelid heavy chain-only antibodies (VHHs) with affinity for PA were obtained from immunized alpacas and screened for anthrax neutralizing activity in macrophage toxicity assays. Two classes of neutralizing VHHs were identified recognizing distinct, non-overlapping epitopes. One class recognizes domain 4 of PA at a well characterized neutralizing site through which PA binds to its cellular receptor. A second neutralizing VHH (JKH-C7) recognizes a novel epitope. This antibody inhibits conversion of the PA oligomer from "pre-pore" to its SDS and heat-resistant "pore" conformation while not preventing cleavage of full-length 83-kDa PA (PA83) by cell surface proteases to its oligomer-competent 63-kDa form (PA63). The antibody prevents endocytosis of the cell surface-generated PA63 subunit but not preformed PA63 oligomers formed in solution. JKH-C7 and the receptor-blocking VHH class (JIK-B8) were expressed as a heterodimeric VHH-based neutralizing agent (VNA2-PA). This VNA displayed improved neutralizing potency in cell assays and protected mice from anthrax toxin challenge with much better efficacy than the separate component VHHs. The VNA protected virtually all mice when separately administered at a 1:1 ratio to toxin and protected mice against Bacillus anthracis spore infection. Thus, our studies show the potential of VNAs as anthrax therapeutics. Due to their simple and stable nature, VNAs should be amenable to genetic delivery or administration via respiratory routes. PMID:25564615

Moayeri, Mahtab; Leysath, Clinton E; Tremblay, Jacqueline M; Vrentas, Catherine; Crown, Devorah; Leppla, Stephen H; Shoemaker, Charles B

2015-03-01

84

Reductive Methylation and Mutation of an Anthrax Toxin Fusion Protein Modulates its Stability and Cytotoxicity  

PubMed Central

We characterized an anti-cancer fusion protein consisting of anthrax lethal factor (LF) and the catalytic domain of Pseudomonas exotoxin A by (i) mutating the N-terminal amino acids and by (ii) reductive methylation to dimethylate all lysines. Dimethylation of lysines was achieved quantitatively and specifically without affecting binding of the fusion protein to PA or decreasing the enzymatic activity of the catalytic moiety. Ubiquitination in vitro was drastically decreased for both the N-terminally mutated and dimethylated variants, and both appeared to be slightly more stable in the cytosol of treated cells. The dimethylated variant showed greatly reduced neutralization by antibodies to LF. The two described modifications offer unique advantages such as increased cytotoxic activity and diminished antibody recognition, and thus may be applicable to other therapeutic proteins that act in the cytosol of cells. PMID:24755540

Bachran, Christopher; Gupta, Pradeep K.; Bachran, Silke; Leysath, Clinton E.; Hoover, Benjamin; Fattah, Rasem J.; Leppla, Stephen H.

2014-01-01

85

Biophysical characterization and immunization studies of dominant negative inhibitor (DNI), a candidate anthrax toxin subunit vaccine  

PubMed Central

Dominant negative inhibitor (DNI) is a translocation-deficient homolog of recombinant protective antigen of Bacillus anthracis that is a candidate for a next generation anthrax vaccine. This study demonstrates that the biophysical characteristics of the DNI protein stored in lyophilized form at 4 °C for 8 y were similar to recombinant protective antigen (rPA). To provide information on the accelerated stability of DNI, samples in the lyophilized form were subjected to thermal stress (40 and 70 °C for up to 4 weeks) and thoroughly evaluated using various biophysical and chemical characterization techniques. Results demonstrate preserved structural stability of the DNI protein under extreme conditions, suggesting long-term stability can be achieved for a vaccine that employs DNI, as desired for a biodefense countermeasure. Furthermore, the biological activity of the stressed DNI bound to the adjuvant Alhydrogel® was evaluated in mice and it was found that the immunogenicity DNI was not affected by thermal stress. PMID:23925275

Iyer, Vidyashankara; Hu, Lei; Schanté, Carole E; Vance, David; Chadwick, Chrystal; Jain, Nishant Kumar; Brey, Robert N; Joshi, Sangeeta B; Volkin, David B; Andra, Kiran K; Bann, James G; Mantis, Nicholas J; Middaugh, C. Russell

2013-01-01

86

Biophysical characterization and immunization studies of dominant negative inhibitor (DNI), a candidate anthrax toxin subunit vaccine.  

PubMed

Dominant Negative Inhibitor (DNI) is a translocation-deficient homolog of recombinant protective antigen of Bacillus anthracis that is a candidate for a next generation anthrax vaccine. This study demonstrates that the biophysical characteristics of the DNI protein stored in lyophilized form at 4°C for 8 y were similar to recombinant Protective Antigen (rPA). To provide information on the accelerated stability of DNI, samples in the lyophilized form were subjected to thermal stress (40°C and 70°C for up to 4 weeks) and thoroughly evaluated using various biophysical and chemical characterization techniques. Results demonstrate preserved structural stability of the DNI protein under extreme conditions, suggesting long-term stability can be achieved for a vaccine that employs DNI, as desired for a biodefense countermeasure. Furthermore, the biological activity of the stressed DNI bound to the adjuvant Alhydrogel (®) was evaluated in mice and it was found that the immunogenicity DNI was not affected by thermal stress. PMID:23925275

Iyer, Vidyashankara; Hu, Lei; Schanté, Carole E; Vance, David; Chadwick, Chrystal; Jain, Nishant Kumar; Brey, Robert N; Joshi, Sangeeta B; Volkin, David B; Andra, Kiran K; Bann, James G; Mantis, Nicholas J; Middaugh, C Russell

2013-11-01

87

HDAC8-mediated epigenetic reprogramming plays a key role in resistance to anthrax lethal toxin-induced pyroptosis in macrophages*  

PubMed Central

Macrophages pre-exposed to a sub-lethal dose of anthrax lethal toxin (LeTx) are refractory to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). A small population of TIR cells (2–4%) retains TIR characteristics for up to 5 to 6 weeks. Through studying these long-term TIR cells, we found that a high level of histone deacetylase (HDAC)8 expression was crucial for TIR. Knocking down or inhibition of HDAC8 by siRNAs or the HDAC8-specific inhibitor PCI-34051, respectively, induced expression of the mitochondrial death genes Bcl2 Adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like (BNIP3L) and Metastatic Lymph Node (MLN)64, and re-sensitized TIR cells to LeTx. Among multiple histone acetylations, histone H3 lysine 27 acetylation (H3K27Ac) was most significantly decreased in TIR cells in an HDAC8-dependent manner, and the association of H3K27Ac with the genomic regions of BNIP3 and MLN64, where HDAC8 was recruited to, was diminished in TIR cells. Furthermore, over-expression of HDAC8 or knocking down the histone acetyltransferase CREB-binding protein (CBP)/p300, known to target H3K27, rendered wild-type cells resistant to LeTx. As in RAW264.7 cells, primary bone marrow-derived macrophages exposed to a sub-lethal dose of LeTx were resistance to LeTx in an HDAC8-dependent manner. Collectively, this study demonstrates that epigenetic reprogramming mediated by HDAC8 plays a key role in determining the susceptibility of LeTx-induced pyroptosis in macrophages. PMID:24973453

Ha, Soon-Duck; Han, Chae Young; Reid, Chantelle; Kim, Sung Ouk

2014-01-01

88

Anthrax lethal toxin inhibits translation of hypoxia-inducible factor 1? and causes decreased tolerance to hypoxic stress.  

PubMed

Hypoxia is considered to be a contributor to the pathology associated with administration of anthrax lethal toxin (LT). However, we report here that serum lactate levels in LT-treated mice are reduced, a finding inconsistent with the anaerobic metabolism expected to occur during hypoxia. Reduced lactate levels are also observed in the culture supernatants of LT-treated cells. LT inhibits the accumulation of hypoxia-inducible factor (HIF)-1?, a subunit of HIF-1, the master regulator directing cellular responses to hypoxia. The toxin has no effect on the transcription or protein turnover of HIF-1?, but instead it acts to inhibit HIF-1? translation. LT treatment diminishes phosphorylation of eIF4B, eIF4E, and rpS6, critical components of the intracellular machinery required for HIF-1? translation. Moreover, blockade of MKK1/2-ERK1/2, but not p38 or JNK signaling, lowers HIF-1? protein levels in both normoxic and hypoxic conditions, consistent with a role for MKK1 and MKK2 as the major targets of LT responsible for the inhibition of HIF-1? translation. The physiological importance of the LT-induced translation blockade is demonstrated by the finding that LT treatment decreases the survival of hepatocyte cell lines grown in hypoxic conditions, an effect that is overcome by preinduction of HIF-1?. Taken together, these data support a role for LT in dysregulating HIF-1? and thereby disrupting homeostatic responses to hypoxia, an environmental characteristic of certain tissues at baseline and/or during disseminated infection with Bacillus anthracis. PMID:24366872

Ouyang, Weiming; Torigoe, Chikako; Fang, Hui; Xie, Tao; Frucht, David M

2014-02-14

89

Anthrax toxin receptor 2 is expressed in murine and tumor vasculature and functions in endothelial proliferation and morphogenesis.  

PubMed

The Capillary Morphogenesis Gene 2 (CMG2) gene encodes an Anthrax toxin receptor (ANTXR2), but the normal physiological function is not known. ANTXR2/CMG2 was originally identified as a result of up-regulation during capillary morphogenesis of endothelial cells (ECs) cultured in vitro. We explored the hypothesis that key steps of the angiogenic process are either dependent or are influenced by ANTXR2/CMG2 activity. We describe the expression pattern of ANTXR2/CMG2 in several murine tissues and in normal breast and breast tumors. Endothelial expression was found in all of the tissues analyzed, in cultured ECs and in breast tumor vessels; however, ANTXR2/CMG2 expression was not restricted to this cell type. To assess potential angiogenic function, we used RNA interference to achieve significant reduction of ANTXR2/CMG2 expression in cultured human umbilical venous endothelial cells (HUVECs). Reduced ANTXR2/CMG2 expression resulted in significant inhibition of proliferation and reduced capacity of ECs to form capillary-like networks in vitro, whereas overexpression of ANTXR2/CMG2 in HUVEC increased proliferation and capillary-like network formation. Little change in migration of ECs was observed on knockdown or overexpression. We conclude that ANTXR2/CMG2 functions to promote endothelial proliferation and morphogenesis during sprouting angiogenesis, consistent with the endothelial expression of ANTXR2/CMG2 in several vascular beds. PMID:19901963

Reeves, C V; Dufraine, J; Young, J A T; Kitajewski, J

2010-02-11

90

Matrix metalloproteinase-activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis.  

PubMed

Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal-regulated kinase 1/2, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH(2)-terminal kinase and p38, but not extracellular signal-regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors. PMID:19372576

Alfano, Randall W; Leppla, Stephen H; Liu, Shihui; Bugge, Thomas H; Meininger, Cynthia J; Lairmore, Terry C; Mulne, Arlynn F; Davis, Samuel H; Duesbery, Nicholas S; Frankel, Arthur E

2009-04-01

91

Anthrax Vaccine  

MedlinePLUS

What is anthrax?Anthrax is a serious disease that can affect both animals and humans. It is caused by bacteria called Bacillus anthracis. People can get anthrax from contact with infected animals, wool, meat, or ...

92

The structure of tumor endothelial marker 8 (TEM8) extracellular domain and implications for its receptor function for recognizing anthrax toxin.  

PubMed

Anthrax toxin, which is released from the gram-positive bacterium Bacillus anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA binds a receptor on the surface of the target cell and further assembles into a homo-heptameric pore through which EF and LF translocate into the cytosol. Two distinct cellular receptors for anthrax toxin, TEM8/ANTXR1 and CMG2/ANTXR2, have been identified, and it is known that their extracellular domains bind PA with low and high affinities, respectively. Here, we report the crystal structure of the TEM8 extracellular vWA domain at 1.7 A resolution. The overall structure has a typical integrin fold and is similar to that of the previously published CMG2 structure. In addition, using structure-based mutagenesis, we demonstrate that the putative interface region of TEM8 with PA (consisting of residues 56, 57, and 154-160) is responsible for the PA-binding affinity differences between the two receptors. In particular, Leu56 was shown to be a key factor for the lower affinity of TEM8 towards PA compared with CMG2. Because of its high affinity for PA and low expression in normal tissues, an isolated extracellular vWA domain of the L56A TEM8 variant may serve as a potent antitoxin and a potential therapeutic treatment for anthrax infection. Moreover, as TEM8 is often over-expressed in tumor cells, our TEM8 crystal structure may provide new insights into how to design PA mutants that preferentially target tumor cells. PMID:20585457

Fu, Sheng; Tong, Xiaohang; Cai, Chenguang; Zhao, Ying; Wu, Yang; Li, Yuanyuan; Xu, Junjie; Zhang, Xuejun C; Xu, Long; Chen, Wei; Rao, Zihe

2010-01-01

93

The Structure of Tumor Endothelial Marker 8 (TEM8) Extracellular Domain and Implications for Its Receptor Function for Recognizing Anthrax Toxin  

PubMed Central

Anthrax toxin, which is released from the Gram-positive bacterium Bacillus anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA binds a receptor on the surface of the target cell and further assembles into a homo-heptameric pore through which EF and LF translocate into the cytosol. Two distinct cellular receptors for anthrax toxin, TEM8/ANTXR1 and CMG2/ANTXR2, have been identified, and it is known that their extracellular domains bind PA with low and high affinities, respectively. Here, we report the crystal structure of the TEM8 extracellular vWA domain at 1.7 Å resolution. The overall structure has a typical integrin fold and is similar to that of the previously published CMG2 structure. In addition, using structure-based mutagenesis, we demonstrate that the putative interface region of TEM8 with PA (consisting of residues 56, 57, and 154–160) is responsible for the PA-binding affinity differences between the two receptors. In particular, Leu56 was shown to be a key factor for the lower affinity of TEM8 towards PA compared with CMG2. Because of its high affinity for PA and low expression in normal tissues, an isolated extracellular vWA domain of the L56A TEM8 variant may serve as a potent antitoxin and a potential therapeutic treatment for anthrax infection. Moreover, as TEM8 is often over-expressed in tumor cells, our TEM8 crystal structure may provide new insights into how to design PA mutants that preferentially target tumor cells. PMID:20585457

Cai, Chenguang; Zhao, Ying; Wu, Yang; Li, Yuanyuan; Xu, Junjie; Zhang, Xuejun C.; Xu, Long; Chen, Wei; Rao, Zihe

2010-01-01

94

Specific, Sensitive, and Quantitative Enzyme-Linked Immunosorbent Assay for Human Immunoglobulin G Antibodies to Anthrax Toxin Protective Antigen  

Microsoft Academic Search

The bioterrorism-associated human anthrax epidemic in the fall of 2001 highlighted the need for a sensi- tive, reproducible, and specific laboratory test for the confirmatory diagnosis of human anthrax. The Cen- ters for Disease Control and Prevention developed, optimized, and rapidly qualified an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) antibodies to Bacillus anthracis protective anti- gen (PA) in

Conrad P. Quinn; Vera A. Semenova; Cheryl M. Elie; Sandra Romero-Steiner; Carolyn Greene; Han Li; Karen Stamey; Evelene Steward-Clark; Daniel S. Schmidt; Elizabeth Mothershed; Janet Pruckler; Stephanie Schwartz; Robert F. Benson; Leta O. Helsel; Patricia F. Holder; Scott E. Johnson; Molly Kellum; Trudy Messmer; W. Lanier Thacker; Lilah Besser; Brian D. Plikaytis; Thomas H. Taylor; Alison E. Freeman; Kelly J. Wallace; Peter Dull; Jim Sejvar; Erica Bruce; Rosa Moreno; Anne Schuchat; Jairam R. Lingappa; Nina Marano; Sandra K. Martin; John Walls; Melinda Bronsdon; George M. Carlone; Mary Bajani-Ari; David A. Ashford; David S. Stephens; Bradley A. Perkins

95

MICROBIOLOGY: A Binding Contract for Anthrax  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. As the anthrax bioterrorism attacks demonstrated last year, individuals infected with the causative organism, Bacillus anthracis, may still die even after successful antibiotic treatment because of the production of large amounts of the anthrax toxin. In their Perspective, Bull and Parrish discuss new work published elsewhere that identifies an antitoxin antibody that could be used to passively immunize infected individuals and neutralize the anthrax toxin.

James J. Bull (University of Texas; Section of Integrative Biology and Institute for Cellular and Molecular Biology)

2002-07-12

96

Prophylaxis and Therapy of Inhalational Anthrax by a Novel Monoclonal Antibody to Protective Antigen That Mimics Vaccine-Induced Immunity  

Microsoft Academic Search

The neutralizing antibody response to the protective antigen (PA) component of anthrax toxin elicited by approved anthrax vaccines is an accepted correlate for vaccine-mediated protection against anthrax. We reasoned that a human anti-PA monoclonal antibody (MAb) selected on the basis of superior toxin neutral- ization activity might provide potent protection against anthrax. The fully human MAb (also referred to as

Laura Vitale; Diann Blanset; Israel Lowy; Thomas O'Neill; Joel Goldstein; Stephen F. Little; Gerard P. Andrews; Gary Dorough; Ronald K. Taylor; Tibor Keler

2006-01-01

97

Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma  

PubMed Central

Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMPs). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated Anthrax Lethal Toxin (LeTx), a novel recombinant protein toxin combination, demonstrates potent MAPK pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic anti-tumor activity against xenografts that did not show significant anti-proliferative responses to the LeTx in vitro. Here we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable to that produced by the multi-kinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo anti-tumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC, but potentially in any solid tumor. PMID:20053778

Alfano, Randall W.; Leppla, Stephen H.; Liu, Shihui; Bugge, Thomas H.; Ortiz, Janelle M.; Lairmore, Terry C.; Duesbery, Nicholas S.; Mitchell, Ian C.; Nwariaku, Fiemu; Frankel, Arthur E.

2009-01-01

98

Anthrax Spores Make an Essential Contribution to Vaccine Efficacy  

Microsoft Academic Search

Anthrax is caused by Bacillus anthracis, a gram-positive spore-forming bacterium. Septicemia and toxemia rapidly lead to death in infected mammal hosts. Currently used acellular vaccines against anthrax consist of protective antigen (PA), one of the anthrax toxin components. However, in experimental animals such vaccines are less protective than live attenuated strains. Here we demonstrate that the addition of formaldehyde- inactivated

Fabien Brossier; Martine Levy; Michèle Mock

2002-01-01

99

Nano Aptasensor for Protective Antigen Toxin of Lakshmi N. Cella,,,|  

E-print Network

Nano Aptasensor for Protective Antigen Toxin of Anthrax Lakshmi N. Cella,,,| Pablo Sanchez of California, Riverside, California 92521 We demonstrate a highly sensitive nano aptasensor for anthrax toxin, demonstrating it as a potential tool for rapid and point-of-care diagnosis for anthrax. Anthrax is a disease

Chen, Wilfred

100

Interactions of anthrax lethal factor with protective antigen defined by site-directed spin labeling  

E-print Network

Interactions of anthrax lethal factor with protective antigen defined by site-directed spin, 2010 (sent for review October 29, 2010) The protective antigen (PA) moiety of anthrax toxin forms oligo the PA pore. Anthrax toxin, in addition to its importance in regard to the pathogenesis of Bacillus

McQuade, D. Tyler

101

Regulation of anthrax toxin activator gene (atxA) expression in Bacillus anthracis: temperature, not CO2/bicarbonate, affects AtxA synthesis.  

PubMed Central

Anthrax toxin gene expression in Bacillus anthracis is dependent on the presence of atxA, a trans-acting regulatory gene located on the resident 185-kb plasmid pXO1. In atxA+ strains, expression of the toxin genes (pag, lef, and cya) is enhanced by two physiologically significant signals: elevated CO2/bicarbonate and temperature. To determine whether increased toxin gene expression in response to these signals is associated with increased atxA expression, we monitored steady-state levels of atxA mRNA and AtxA protein in cells cultured in different conditions. We purified histidine-tagged AtxA [AtxA(His)] from Escherichia coli and used anti-AtxA(His) serum to detect AtxA in protein preparations from B. anthracis cells. AtxA was identified as a protein with an apparent size of 56 kDa in cytoplasmic fractions of B. anthracis cells. Our data indicate that atxA expression is not influenced by CO2/bicarbonate levels. However, the steady-state level of atxA mRNA in cells grown in elevated CO2/bicarbonate at 37 degrees C is five- to sixfold higher than that observed in cells grown in the same conditions at 28 degrees C. A corresponding difference in AtxA protein was also seen at the different growth temperatures. When atxA was cloned on a multicopy plasmid in B. anthracis, AtxA levels corresponding to the atxA gene copy number were observed. However, this strain produced significantly less pag mRNA and protective antigen protein than the parental strain harboring atxA in single copy on pXO1. These results indicate that increased AtxA expression does not lead to a corresponding increase in pag expression. Our data strongly suggest that an additional factor(s) is involved in regulation of pag and that the relative amounts of such a factor(s) and AtxA are important for optimal toxin gene expression. PMID:9199422

Dai, Z; Koehler, T M

1997-01-01

102

Anthrax Attacks  

NSDL National Science Digital Library

This Science NetLinks lesson focuses on the bacterial disease known as Anthrax. Anthrax has always been identified as a disease that infects cattle, but there are known cases of people contracting this disease directly from handling infected cattle. In this online lesson the students will research the disease and its impact on human health.

Science Netlinks

2002-05-05

103

Anthrax Lethal Toxin Impairs IL-8 Expression in Epithelial Cells through Inhibition of Histone H3 Modification  

E-print Network

are taken up by macrophages and/or dendritic cells, and subsequently migrate in the draining lymph nodes Abstract Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis, the etiological agent, instillation of a B. anthracis strain expressing active LT represses lung inflammation. The inhibitory effects

Paris-Sud XI, Université de

104

Cutaneous anthrax (image)  

MedlinePLUS

Anthrax is caused by the bacteria Bacillus anthracis . While anthrax commonly affects hoofed animals such as sheep and goats, humans may get sick from anthrax, too. The most common type of anthrax infection ...

105

Cytotoxicity of Anthrax Lethal Toxin to Human Acute Myeloid Leukemia Cells Is Nonapoptotic and Dependent on Extracellular Signal-Regulated Kinase 1/2 Activity1  

PubMed Central

In this study, we attempt to target the mitogen-activated protein kinase (MAPK) pathway in acute myeloid leukemia (AML) cells using a recombinant anthrax lethal toxin (LeTx). LeTx consists of protective antigen (PrAg) and lethal factor (LF). PrAg binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of LF, and undergoes endocytosis, releasing LF into the cytosol. LF cleaves MAPK kinases, inhibiting the MAPK pathway. We tested potency of LeTx on a panel of 11 human AML cell lines. Seven cell lines showed cytotoxic responses to LeTx. Cytotoxicity of LeTx was mimicked by the specific mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126, indicating that LeTx-induced cell death is mediated through the MEK1/2-extracellular signal-regulated kinase (ERK1/2) branch of the MAPK pathway. The four LeTx-resistant cell lines were sensitive to the phosphatidylinositol 3-kinase inhibitor LY294002. Co-treatment of AML cells with both LeTx and LY294002 did not lead to increased sensitivity, showing a lack of additive/synergistic effects when both pathways are inhibited. Flow cytometry analysis of MAPK pathway activation revealed the presence of phospho-ERK1/2 only in LeTx-sensitive cells. Staining for Annexin V/propidium iodide and active caspases showed an increase in double-positive cells and the absence of caspase activation following treatment, indicating that LeTx-induced cell death is caspase-independent and nonapoptotic. We have shown that a majority of AML cell lines are sensitive to the LF-mediated inhibition of the MAPK pathway. Furthermore, we have demonstrated that LeTx-induced cytotoxicity in AML cells is nonapoptotic and dependent on phospho-ERK1/2 levels. PMID:23418614

Kassab, Elias; Darwish, Manal; Timsah, Zahra; Liu, ShiHui; Leppla, Stephen H; Frankel, Arthur E; Abi-Habib, Ralph J

2013-01-01

106

Cutaneous Anthrax  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

107

Anthrax: Prevention  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

108

Inhalation Anthrax  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

109

Gastrointestinal Anthrax  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

110

Injection Anthrax  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

111

Anthrax: Diagnosis  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

112

Anthrax: Symptoms  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

113

Anthrax: Treatment  

MedlinePLUS

... supported by your browser. For this reason, some items on this page will be unavailable. For more information about this ... several options for treating patients with anthrax, including antibiotics and antitoxin. Patients with serious cases of ...

114

Anthrax: pre-publication and special issue  

NSDL National Science Digital Library

This special topics Webpage from Nature contains two pre-publication research papers and a collection of articles, news stories, and commentary from Nature's archive. The two pre-pubs, Bradley et al.'s "Identification of the cellular receptor for anthrax toxin" and "Crystal structure of the anthrax lethal factor" by Pannifer et al., should be useful to researchers and scientists working on treatments for anthrax. The two other feature articles here, "Designing a polyvalent inhibitor of anthrax toxin" by Mourez et al. and "Genomics and future biological weapons: the need for preventive action by the biomedical community," by Fraser et al., come from October issues of Nature Biotechnology and Nature Genetics respectively. Interested members of the general public should find the collection of Nature news stories, which cover a range of issues related to bioweapons and defense, a worthwhile read. All material is available in HTML or .pdf formats.

2001-01-01

115

STRUCTURE BASED DESIGN OF PROTEIN LIGANDS: A STUDY OF ANTIBODY-LIKE SCAFFOLDS TARGETED AGAINST THE ANTHRAX TOXIN  

SciTech Connect

We have adopted structure-based approaches to enhance the affinities of two single chain antibodies, scFv1 and scFv4, that bind to two different epitopes on the Protective Antigen (PA), a toxin from Bacillus anthracis. In one approach, we have modified scFv4 and re-engineered a novel antibody-like scaffold in which we have placed V{sub L} on the N terminus and V{sub H} on the C-terminus and joined them by a 10 amino-acid-long linker. This scaffold preserves the native V{sub L}-V{sub H} contact interface and the dispositions of the CDR loops. It binds to PA with 10 fold higher affinity than scFv4. In a second approach, we have created a bispecific ligand by covalently joining scFv1 and scFv4 by a flexible linker that supports simultaneous and synergistic binding of the two scFvs to PA. This bispecific scFv1-linker-scFv4 binds to PA with 10 fold higher affinity than the individual scFvs. The newly re-engineered antibody-like scaffold of scFv4 and scFv1-linker-scFv4 are expected to be potent inhibitors of PA binding to the host cells.

P. SHIFLETT; E. HONG-GELLER; ET AL

2000-12-01

116

Pathophysiology of anthrax  

PubMed Central

Infection by Bacillus anthracis in animals and humans results from accidental or intentional exposure, by oral, cutaneous or pulmonary routes, to spores, which are normally present in the soil. Treatment includes administration of antibiotics, vaccination or treatment with antibody to the toxin. A better understanding of the molecular basis of the processes involved in the pathogenesis of anthrax namely, spore germination in macrophages and biological effects of the secreted toxins on heart and blood vessels will lead to improved management of infected animals and patients. Controlling germination will be feasible by inhibiting macrophage paralysis and cell death. On the other hand, the control of terminal hypotension might be achieved by inhibition of cardiomyocyte mitogen-activated protein kinase and stimulation of vessel cAMP. PMID:19273366

Frankel, Arthur E.; Kuo, Shu-Ru; Dostal, David; Watson, Linley; Duesbery, Nicholas S.; Cheng, Che-Ping; Cheng, Heng Jie; Tang, Wei-Jen; Leppla, Stephen H.

2014-01-01

117

Effective antiprotease-antibiotic treatment of experimental anthrax  

Microsoft Academic Search

BACKGROUND: Inhalation anthrax is characterized by a systemic spread of the challenge agent, Bacillus anthracis. It causes severe damage, including multiple hemorrhagic lesions, to host tissues and organs. It is widely believed that anthrax lethal toxin secreted by proliferating bacteria is a major cause of death, however, the pathology of intoxication in experimental animals is drastically different from that found

Serguei G Popov; Taissia G Popova; Svetlana Hopkins; Raymond S Weinstein; Rebecca MacAfee; Karl J Fryxell; Vikas Chandhoke; Charles Bailey; Ken Alibek

2005-01-01

118

Anthrax Antibodies  

NSDL National Science Digital Library

This Science Update, from Science NetLinks, features an interview with George Georgiou about efforts to make a better vaccine against anthrax. Science Updates are audio interviews with scientists and are accompanied by a set of questions as well as links to related Science NetLink lessons and other related resources.

Science Update

2002-10-27

119

Anthrax - blood test  

MedlinePLUS

Anthrax serology test; Antibody test for anthrax; Serologic test for B. anthracis ... A normal result means no antibodies to the anthrax bacteria was seen in your blood sample. However, during the early stages of infection, your body may only ...

120

What Is Anthrax?  

MedlinePLUS

... How the Body Works Main Page What Is Anthrax? KidsHealth > Kids > Health Problems > Infections > What Is Anthrax? Print A A A Text Size You may have heard about anthrax and wondered what it is. Some people are ...

121

Bioterrorism Preparedness--Anthrax  

E-print Network

This publication explains how people can prepare for a terrorist attack that uses anthrax. It discusses the reasons anthrax might be used in a bioterrorist attack and lists symptoms of anthrax infection in people and signs in animals....

Lawhorn, D. Bruce

2002-04-24

122

Neutron-based sterilization of anthrax contamination.  

PubMed

With the anthrax threat becoming a reality, it is very important to have an effective way to sterilize areas contaminated by anthrax. Anthrax spores are the dormant form of the anthrax bacteria. They can germinate in tissues, producing new bacteria that release lethal toxins. Neutrons can be a powerful tool in our defense against anthrax contamination. Neutrons are elementary particles that have no charge, which allows them to be very penetrating, killing the anthrax spores on the surface and inside the containers. So neutrons have an advantage over other forms of radiation if deep penetration is required to kill biological organisms. A Cf neutron source allows for a low cost method of decontamination. It emits most neutrons in the 100 keV to 2 MeV energy regions, and a neutron in this energy region is 20 times more deadly than electrons or gamma rays in killing anthrax spores. If we just consider the first neutron collision with anthrax spores and that all the anthrax spores will not survive at the dose level above 2.0 x 10 Gy, our calculations show that a 0.5-g Cf neutron source within 20 min can generate 1.11 x 10 m fluence neutrons, which is good enough to kill the anthrax spores on the sample. An experimental confirmation of the above results may prove that to achieve 1.11 x 10 m fluence neutrons on the anthrax spore sample, the neutron irradiation time may be reduced dramatically or the Cf neutron source reduced to 0.1 g level or even less. The aim of this paper is to evaluate a feasible way to sterilize the anthrax contamination by using a Cf neutron source. Presently, we are mainly concentrating on the theoretical estimation of neutron fluence to see if the Cf neutron source can deliver enough neutron irradiation dose to kill the anthrax spores. Our future work will focus on experimental confirmation and Monte Carlo simulation by using Geant4 or MCNP codes. At that time, we will consider the effects of the real experimental setup, the shielding materials, the exact chemical components, and the biological structures of anthrax spores. We also need to consider the ways of carrying the anthrax spores, and this includes surface contamination, inside an envelope, or hidden in sealed metal containers and luggage. PMID:16607173

Liu, Bin; Wang, Qingfei

2006-05-01

123

ForPeerReview Modeling the structure of mAb 14B7 bound to the anthrax protective  

E-print Network

ForPeerReview Modeling the structure of mAb 14B7 bound to the anthrax protective antigen Journal, Department of Chemical Engineering and Materials Science Key Words: affinity maturation, anthrax toxin to the Anthrax Protective Antigen Arvind Sivasubramanian,1 Jennifer A. Maynard2 and Jeffrey J. Gray1, 3, 4* 1

Gray, Jeffrey J.

124

ANTHRAX TECHNICAL ASSISTANCE DOCUMENT  

EPA Science Inventory

The Anthrax TAD was developed as an Interim Draft Final technical resource in November 2003. It is specifically for response to an actual or suspected terrorist release of anthrax (i.e., it is not intended for response to anthrax in agricultural settings.). The TAD was provided ...

125

Anthrax lethal factor inhibition  

PubMed Central

The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) ?50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit “point of no return” model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax. PMID:15911756

Shoop, W. L.; Xiong, Y.; Wiltsie, J.; Woods, A.; Guo, J.; Pivnichny, J. V.; Felcetto, T.; Michael, B. F.; Bansal, A.; Cummings, R. T.; Cunningham, B. R.; Friedlander, A. M.; Douglas, C. M.; Patel, S. B.; Wisniewski, D.; Scapin, G.; Salowe, S. P.; Zaller, D. M.; Chapman, K. T.; Scolnick, E. M.; Schmatz, D. M.; Bartizal, K.; MacCoss, M.; Hermes, J. D.

2005-01-01

126

Molecular Analysis of the Interaction of Anthrax Adenylyl Cyclase Toxin, Edema Factor, with 2?(3?)-O-(N-(methyl)anthraniloyl)-Substituted Purine and Pyrimidine Nucleotides  

PubMed Central

Bacillus anthracis causes anthrax disease and exerts its deleterious effects by the release of three exotoxins: lethal factor, protective antigen, and edema factor (EF), a highly active calmodulin-dependent adenylyl cyclase (AC). However, conventional antibiotic treatment is ineffective against either toxemia or antibiotic-resistant strains. Thus, more effective drugs for anthrax treatment are needed. Previous studies from our laboratory showed that mammalian membranous AC (mAC) exhibits broad specificity for purine and pyrimidine nucleotides (Mol Pharmacol 70 878-886,200616766715). Here, we investigated structural requirements for EF inhibition by natural purine and pyrimidine nucleotides and nucleotides modified with N-methylanthraniloyl (MANT)- or anthraniloyl groups at the 2?(3?)-O-ribosyl position. MANT-CTP was the most potent EF inhibitor (Ki, 100 nM) among 16 compounds studied. MANT-nucleotides inhibited EF competitively. Activation of EF by calmodulin resulted in effective fluorescence resonance energy transfer (FRET) from tryptophan and tyrosine residues located in the vicinity of the catalytic site to MANT-ATP, but FRET to MANT-CTP was only small. Mutagenesis studies revealed that Phe586 is crucial for FRET to MANT-ATP and MANT-CTP and that the mutations N583Q, K353A, and K353R differentially alter the inhibitory potencies of MANT-ATP and MANT-CTP. Docking approaches relying on crystal structures of EF indicate similar binding modes of the MANT nucleotides with subtle differences in the region of the nucleobases. In conclusion, like mAC, EF accommodates both purine and pyrimidine nucleotides. The unique preference of EF for the base cytosine offers an excellent starting point for the development of potent and selective EF inhibitors. PMID:19056899

Taha, Hesham M.; Schmidt, Jennifer; Göttle, Martin; Suryanarayana, Srividya; Shen, Yuequan; Tang, Wei-Jen; Gille, Andreas; Geduhn, Jens; König, Burkhard; Dove, Stefan; Seifert, Roland

2009-01-01

127

Observations on Experimental Anthrax: Demonstration of a Specific Lethal Factor produced in vivo by Bacillus anthracis  

Microsoft Academic Search

AN enigma in the study of the cause of death in anthrax has been that no lethal endo- or exo-toxin has been found in cultures of the organism1-3. Recently, we have been able to demonstrate a factor in the plasma of guinea pigs dying of anthrax which is not only lethal but also specifically neutralized by anthrax antiserum. This communication

H. Smith; J. Keppie

1954-01-01

128

Development of a simple method for the rapid identification of organisms causing anthrax by coagglutination test.  

PubMed

A protective antigen (PA) based coagglutination test was optimized in the present study for the specific and sensitive identification of bacteria causing anthrax in a cost effective and less risky manner. The test showed 100% specificity and sensitivity up to 9 × 10(3) formalinized vegetative cells or 11 ng of PA. The optimized test also detected anthrax toxin directly from the serum as well as blood of anthrax infected animals indicating the potential application for direct diagnosis of anthrax under field conditions. PMID:25151655

Sumithra, T G; Chaturvedi, V K; Gupta, P K; Siju, S J; Susan, C; Bincy, J; Laxmi, U; Sunita, S C; Rai, A K

2014-11-01

129

Lethal factor, but not edema factor, is required to cause fatal anthrax in cynomolgus macaques after pulmonary spore challenge.  

PubMed

Inhalational anthrax is caused by inhalation of Bacillus anthracis spores. The ability of B. anthracis to cause anthrax is attributed to the plasmid-encoded A/B-type toxins, edema toxin (edema factor and protective antigen) and lethal toxin (lethal factor and protective antigen), and a poly-d-glutamic acid capsule. To better understand the contribution of these toxins to the disease pathophysiology in vivo, we used B. anthracis Ames strain and isogenic toxin deletion mutants derived from the Ames strain to examine the role of lethal toxin and edema toxin after pulmonary spore challenge of cynomolgus macaques. Lethal toxin, but not edema toxin, was required to induce sustained bacteremia and death after pulmonary challenge with spores delivered via bronchoscopy. After intravenous challenge with bacilli to model the systemic phase of infection, lethal toxin contributed to bacterial proliferation and subsequent host death to a greater extent than edema toxin. Deletion of protective antigen resulted in greater loss of virulence after intravenous challenge with bacilli than deletion of lethal toxin or edema toxin alone. These findings are consistent with the ability of anti-protective antigen antibodies to prevent anthrax and suggest that lethal factor is the dominant toxin that contributes to the escape of significant numbers of bacilli from the thoracic cavity to cause anthrax after inhalation challenge with spores. PMID:25285720

Hutt, Julie A; Lovchik, Julie A; Drysdale, Melissa; Sherwood, Robert L; Brasel, Trevor; Lipscomb, Mary F; Lyons, C Rick

2014-12-01

130

Identification of Residues Lining the Anthrax Protective Antigen Channel †  

Microsoft Academic Search

In its activated 63 kDa form, the protective antigen (PA) component of anthrax toxin forms a heptameric prepore, which converts to a pore (channel) in endosomal membranes at low pH and mediates translocation of the toxin's enzymic moieties to the cytosol. It has been proposed that the prepore-to- pore conversion involves a conformational rearrangement of a disordered amphipathic loop (D2L2;

Ericka L. Benson; Paul D. Huynh; Alan Finkelstein; R. John Collier

1998-01-01

131

Development of novel vaccines against anthrax in man  

Microsoft Academic Search

It has been shown that antianthrax immunity induced by the novel vaccine proposed has not only antitoxic, but also antispore character. The whole complex of antigens, namely surface spore antigens, surface antigens of cell wall and toxin components is required for the induction of strong and stable immunity against anthrax. The STI-1 vaccine strain with introduced resistance to several antibiotics

A. V. Stepanov; L. I. Marinin; A. P. Pomerantsev; N. A. Staritsin

1996-01-01

132

Molecular Motions as a Drug Target: Mechanistic Simulations of Anthrax Toxin Edema Factor Function Led to the Discovery of Novel Allosteric Inhibitors  

PubMed Central

Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavities at the surface of EF were determined for each path intermediate to identify potential sites where the binding of a ligand could block activation. A non-catalytic cavity (allosteric) was found to shrink rapidly at early stages of the path and was chosen to perform virtual screening. Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars. PMID:23012649

Laine, Élodie; Martínez, Leandro; Ladant, Daniel; Malliavin, Thérèse; Blondel, Arnaud

2012-01-01

133

Purification of tritium-labeled cholera toxin.  

PubMed Central

Cholera toxin was labeled with tritium by the Wilzbach technique, and highly purified radiolabeled toxin was obtained by Sephadex column chromatography and disc gel electrophoresis. 3H-labeled cholera toxin retained its biological activity and chemical stability and had a specific activity of 405.9 muCi/mumol. The methods utilized in extraction and purification of 3H-labeled toxin may be advantageous for preparation of other biologically active radiolabeled proteins. Images PMID:689738

Banwell, J G; Hanke, D W; Diedrich, D

1978-01-01

134

ANTHRAX REMEDIATION RESEARCH NEEDS  

EPA Science Inventory

The Environmental Protection Agency has initiated a research program to respond to the immediate needs arising from the recent Bacillus anthracis bioterrorism events. Although the program has a strong emphasis on anthrax, other pathogens and chemical agents, including toxic indu...

135

Anthrax vaccination strategies  

PubMed Central

The biological attack conducted through the U.S. postal system in 2001 broadened the threat posed by anthrax from one pertinent mainly to soldiers on the battlefield to one understood to exist throughout our society. The expansion of the threatened population placed greater emphasis on the reexamination of how we vaccinate against Bacillus anthracis. The currently-licensed Anthrax Vaccine, Adsorbed (AVA) and Anthrax Vaccine, Precipitated (AVP) are capable of generating a protective immune response but are hampered by shortcomings that make their widespread use undesirable or infeasible. Efforts to gain U.S. Food and Drug Administration (FDA) approval for licensure of a second generation recombinant protective antigen (rPA)-based anthrax vaccine are ongoing. However, this vaccine's reliance on the generation of a humoral immune response against a single virulence factor has led a number of scientists to conclude that the vaccine is likely not the final solution to optimal anthrax vaccine design. Other vaccine approaches, which seek a more comprehensive immune response targeted at multiple components of the B. anthracis organism, are under active investigation. This review seeks to summarize work that has been done to build on the current PA-based vaccine methodology and to evaluate the search for future anthrax prophylaxis strategies. PMID:19729034

Cybulski, Robert J.; Sanz, Patrick; O'Brien, Alison D.

2009-01-01

136

Deletion modification enhances anthrax specific immunity and protective efficacy of a hepatitis B core particle-based anthrax epitope vaccine.  

PubMed

Protective antigen (PA) is one of the major virulence factors of anthrax and is also the major constituent of the current anthrax vaccine. Previously, we found that the 2?2-2?3 loop of PA contains a dominant neutralizing epitope, the SFFD. We successfully inserted the 2?2-2?3 loop of PA into the major immunodominant region (MIR) of hepatitis B virus core (HBc) protein. The resulting fusion protein, termed HBc-N144-PA-loop2 (HBcL2), can effectively produce anthrax specific protective antibodies in an animal model. However, the protective immunity caused by HBcL2 could still be improved. In this research, we removed amino acids 79-81 from the HBc MIR of the HBcL2. This region was previously reported to be the major B cell epitope of HBc, and in keeping with this finding, we observed that the short deletion in the MIR not only diminished the intrinsic immunogenicity of HBc but also stimulated a higher titer of anthrax specific immunity. Most importantly, this deletion led to the full protection of the immunized mice against a lethal dose anthrax toxin challenge. We supposed that the conformational changes which occurred after the short deletion and foreign insertion in the MIR of HBc were the most likely reasons for the improvement in the immunogenicity of the HBc-based anthrax epitope vaccine. PMID:24054942

Yin, Ying; Zhang, Sheng; Cai, Chenguang; Zhang, Jun; Dong, Dayong; Guo, Qiang; Fu, Ling; Xu, Junjie; Chen, Wei

2014-02-01

137

New Treatment for Anthrax Approved  

MedlinePLUS

... this page, please enable JavaScript. New Treatment for Anthrax Approved FDA cites preparedness for intentional release of ... Roberts Wednesday, March 25, 2015 Related MedlinePlus Pages Anthrax Biodefense and Bioterrorism WEDNESDAY, March 25, 2015 (HealthDay ...

138

Methods for neutralizing anthrax or anthrax spores  

DOEpatents

The present invention concerns methods, compositions and apparatus for neutralizing bioagents, wherein bioagents comprise biowarfare agents, biohazardous agents, biological agents and/or infectious agents. The methods comprise exposing the bioagent to an organic semiconductor and exposing the bioagent and organic semiconductor to a source of energy. Although any source of energy is contemplated, in some embodiments the energy comprises visible light, ultraviolet, infrared, radiofrequency, microwave, laser radiation, pulsed corona discharge or electron beam radiation. Exemplary organic semiconductors include DAT and DALM. In certain embodiments, the organic semiconductor may be attached to one or more binding moieties, such as an antibody, antibody fragment, or nucleic acid ligand. Preferably, the binding moiety has a binding affinity for one or more bioagents to be neutralized. Other embodiments concern an apparatus comprising an organic semiconductor and an energy source. In preferred embodiments, the methods, compositions and apparatus are used for neutralizing anthrax spores.

Sloan, Mark A; Vivekandanda, Jeevalatha; Holwitt, Eric A; Kiel, Johnathan L

2013-02-26

139

Pediatric anthrax clinical management.  

PubMed

Anthrax is a zoonotic disease caused by Bacillus anthracis, which has multiple routes of infection in humans, manifesting in different initial presentations of disease. Because B anthracis has the potential to be used as a biological weapon and can rapidly progress to systemic anthrax with high mortality in those who are exposed and untreated, clinical guidance that can be quickly implemented must be in place before any intentional release of the agent. This document provides clinical guidance for the prophylaxis and treatment of neonates, infants, children, adolescents, and young adults up to the age of 21 (referred to as "children") in the event of a deliberate B anthracis release and offers guidance in areas where the unique characteristics of children dictate a different clinical recommendation from adults. PMID:24777226

Bradley, John S; Peacock, Georgina; Krug, Steven E; Bower, William A; Cohn, Amanda C; Meaney-Delman, Dana; Pavia, Andrew T

2014-05-01

140

Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax.  

PubMed

Although antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P = 0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n = 39) than for LVX alone (13 deaths; n = 37), and the survival time was prolonged for the combination (P = 0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course. PMID:25487792

Migone, Thi-Sau; Bolmer, Sally; Zhong, John; Corey, Al; Vasconcelos, Daphne; Buccellato, Matthew; Meister, Gabriel

2015-02-01

141

Anthrax Spores under a microscope  

NASA Technical Reports Server (NTRS)

Anthrax spores are inactive forms of Bacillus anthracis. They can survive for decades inside a spore's tough protective coating; they become active when inhaled by humans. A result of NASA- and industry-sponsored research to develop small greenhouses for space research is the unique AiroCide TiO2 system that kills anthrax spores and other pathogens.

2003-01-01

142

Three eyelid localized cutaneous anthrax cases.  

PubMed

Anthrax is primarily seen in the developing countries, but it can be a worldwide medical concern due to bioterrorism threats. Palpebral anthrax is a rare form of cutaneous anthrax. Untreated cutaneous anthrax can be lethal. Patients with palpebral anthrax can develop complications including cicatrisation and ectropion. Thus, anthrax should be considered in differential diagnosis for patients presenting with preseptal cellulitis in high-risk regions. Herein, we report three anthrax cases (with different age) involving eyelids that were cured without any complications due to early diagnosis and treatment. PMID:24641116

Esmer, Oktay; Karadag, Remzi; Bilgili, Serap Gunes; Gultepe, Bilge; Bayramlar, Huseyin; Karadag, Ayse Serap

2014-12-01

143

A fragment of anthrax lethal factor delivers proteins to the cytosol without requiring protective antigen  

E-print Network

of entering the cytosol indepen- dently of PA. To investigate this further, the intracellular trafficking. Bacillus anthracis is the causative agent of anthrax in animals and humans. It produces two bipartite animals. LF is a 796-aa polypeptide, and the functional toxin domain is located between amino acids 383

Lieberman, Judy

144

Two capsular polysaccharides enable Bacillus cereus G9241 to cause anthrax-like disease  

PubMed Central

Summary Bacillus cereus G9241 causes an anthrax-like respiratory illness in humans, however the molecular mechanisms of disease pathogenesis are not known. Genome sequencing identified two putative virulence plasmids proposed to provide for anthrax toxin (pBCXO1) and/or capsule expression (pBC218). We report here that B. cereus G9241 causes anthrax-like disease in immune-competent mice, which is dependent on each of the two virulence plasmids. pBCXO1 encodes pagA1, the homolog of anthrax protective antigen, as well as hasACB, providing for hyaluronic acid capsule formation, two traits that each contribute to disease pathogenesis. pBC218 harbors bpsX-H, Bacillus cereus exo-polysaccharide, which produce a second capsule. During infection, B. cereus G9241 elaborates both hasACB and bpsX-H capsules, which together are essential for the establishment of anthrax-like disease and the resistance of bacilli to phagocytosis. A single nucleotide deletion causes premature termination of hasA translation in B. anthracis, which is known to escape phagocytic killing by its pXO2 encoded poly-D-?-glutamic acid (PDGA) capsule. Thus, multiple different gene clusters endow pathogenic bacilli with capsular material, provide for escape from innate host immune responses and aid in establishing the pathogenesis of anthrax-like disease. PMID:21371137

Oh, So-Young; Budzik, Jonathan M.; Garufi, Gabriella; Schneewind, Olaf

2012-01-01

145

An outbreak of anthrax meningoencephalitis.  

PubMed

We report a common-source outbreak of anthrax meningoencephalitis in Chittoor district in Andhra Pradesh, southern India, in October 1990. The source of infection was the carcass of a sheep. Of 5 persons who skinned and cut up its meat for human consumption, 4 developed anthrax meningoencephalitis and one a malignant pustule. Another person who wrapped the meat in a cloth and carried it home on his head developed a malignant pustule on his forehead and also meningoencephalitis. All subjects with anthrax meningoencephalitis died, but the one with only a malignant pustule recovered. A large number of people who cooked or ate the cooked meat of the dead sheep remained well. The medical, public health and veterinary authorities were alerted and sheep, goats and cattle in the locality were immunized with anthrax vaccine. Although rules against consumption of meat of dead animals exist, their violation shows a lack of public awareness. Health education should be undertaken to correct this situation. PMID:8036676

George, S; Mathai, D; Balraj, V; Lalitha, M K; John, T J

1994-01-01

146

Anthrax: Who Is at Risk  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

147

Laboratory Testing for Anthrax: Frequently Asked Questions  

MedlinePLUS

... Questions Which laboratories can test specimens for the bacteria that cause anthrax? Laboratories that are a part ... patient specimens for Bacillus anthracis , the type of bacteria that causes anthrax. LRN labs are strategically located ...

148

Anthrax vaccine and public health policy.  

PubMed

The Centers for Disease Control and Prevention has classified Bacillus anthracis, the causative organism of anthrax, as a category A potential bioterrorism agent. There are critical shortcomings in the US anthrax vaccine program. Rather than depending on the private sector, the government must assume direct production of anthrax vaccine. The development of a capacity capable of preemptive immunization of the public against anthrax should be considered. PMID:17901434

Weiss, Martin Meyer; Weiss, Peter D; Weiss, Joseph B

2007-11-01

149

Anthrax Vaccine and Public Health Policy  

PubMed Central

The Centers for Disease Control and Prevention has classified Bacillus anthracis, the causative organism of anthrax, as a category A potential bioterrorism agent. There are critical shortcomings in the US anthrax vaccine program. Rather than depending on the private sector, the government must assume direct production of anthrax vaccine. The development of a capacity capable of preemptive immunization of the public against anthrax should be considered. PMID:17901434

Weiss, Martin Meyer; Weiss, Peter D.; Weiss, Joseph B.

2007-01-01

150

Investigation of Inhalation Anthrax Case, United States  

PubMed Central

Inhalation anthrax occurred in a man who vacationed in 4 US states where anthrax is enzootic. Despite an extensive multi-agency investigation, the specific source was not detected, and no additional related human or animal cases were found. Although rare, inhalation anthrax can occur naturally in the United States. PMID:24447835

Blaney, David; Shadomy, Sean; Lehman, Mark; Pesik, Nicki; Tostenson, Samantha; Delaney, Lisa; Tiller, Rebekah; DeVries, Aaron; Gomez, Thomas; Sullivan, Maureen; Blackmore, Carina; Stanek, Danielle; Lynfield, Ruth

2014-01-01

151

LIST OF CONTRACTORS TO SUPPORT ANTHRAX REMEDIATION  

E-print Network

LIST OF CONTRACTORS TO SUPPORT ANTHRAX REMEDIATION May 2010 Prepared for the Interagency Biological by the Northwest Regional Technology Center for Homeland Security List of Contractors to Support Anthrax of Contractors to Support Anthrax Remediation During August 2008, the Pacific Northwest National Laboratory (PNNL

152

Anthrax: A Guide for Biology Teachers.  

ERIC Educational Resources Information Center

Presents facts about anthrax so that biology teachers can communicate them to others. Defines anthrax and the nature of bacterial spores. Discusses transmission and clinical presentation as well as prevention, diagnosis, and treatment. Explores the use of anthrax as a biological warfare agent. (Contains 27 references.) (DDR)

Simon, Eric J.

2002-01-01

153

WASTE DISPOSAL WORKSHOPS: ANTHRAX CONTAMINATED WASTE  

E-print Network

WASTE DISPOSAL WORKSHOPS: ANTHRAX CONTAMINATED WASTE January 2010 Prepared for the Interagency DE-AC05-76RL01830 Waste Disposal Workshops: Anthrax-Contaminated Waste AM Lesperance JF Upton SL #12;#12;PNNL-SA-69994 Waste Disposal Workshops: Anthrax- Contaminated Waste AM Lesperance JF Upton SL

154

Airing Out Anthrax  

NASA Technical Reports Server (NTRS)

The AiroCide TiO2 is an air-purifier that kills 93.3 percent of airborne pathogens that pass through it, including Bacillus anthraci, more commonly known as anthrax. It is essentially a spinoff of KES Science & Technology, Inc.'s Bio-KES system, a highly effective device used by the produce industry for ethylene gas removal to aid in preserving the freshness of fruits, vegetables, and flowers. The TiO2-based ethylene removal technology that is incorporated into the company's AiroCide TiO2 and Bio-KES products was first integrated into a pair of plant-growth chambers known as ASTROCULTURE(TM) and ADVANCED ASTROCULTURE(TM). Both chambers have housed commercial plant growth experiments in space on either the Space Shuttle or the International Space Station. The AiroCide TiO2 also has a proven record of destroying 98 percent of other airborne pathogens, such as microscopic dust mites, molds, and fungi. Moreover, the device is a verified killer of Influenza A (flu), E. coli, Staphylococcus aureas, Streptococcus pyogenes, and Mycoplasma pneumoniae, among many other harmful viruses.

2002-01-01

155

Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase  

NASA Astrophysics Data System (ADS)

Lethal factor, the principal virulence factor of Bacillus anthracis, inhibits mitogen-activated protein kinase (MAPK) signaling by proteolytically cleaving MAPK kinases. Edema factor, another component of anthrax toxin, is an adenylate cyclase, which increases intracellular cAMP. Inhibition of MAPK signaling with either anthrax lethal toxin (LeTx) or small molecule MAPK kinase inhibitors triggers apoptosis in human melanoma cells. Normal melanocytes do not undergo apoptosis in response to MAPK inhibition but arrest in the G1 phase of the cell cycle. Importantly, in vivo treatment of human melanoma xenograft tumors in athymic nude mice with LeTx results in significant or complete tumor regression without apparent side effects, suggesting that inhibiting the MAPK signaling pathway may be a useful strategy for treating melanoma. Additionally, interrupting MAPK signaling with LeTx and elevating cAMP with anthrax edema toxin in both melanoma cells and melanocytes lead to dramatic melanin production, perhaps explaining the formation of blackened eschars in cutaneous anthrax.

Koo, Han-Mo; Vanbrocklin, Matt; McWilliams, Mary Jane; Leppla, Stephan H.; Duesbery, Nicholas S.; Vande Woude, George F.

2002-03-01

156

Clinical impressions of anthrax from the 2006 outbreak in Saskatchewan  

PubMed Central

Clinical signs and carcass traits observed during the 2006 Saskatchewan anthrax outbreak were largely consistent with those previously published, except for cutaneous anthrax and anthrax mastitis in cows, and subcutaneous edema in bulls and horses. Failure of blood to clot was the most reliable indicator of anthrax in carcasses. PMID:19436482

Himsworth, Chelsea G.; Argue, Connie K.

2009-01-01

157

Clinical impressions of anthrax from the 2006 outbreak in Saskatchewan.  

PubMed

Clinical signs and carcass traits observed during the 2006 Saskatchewan anthrax outbreak were largely consistent with those previously published, except for cutaneous anthrax and anthrax mastitis in cows, and subcutaneous edema in bulls and horses. Failure of blood to clot was the most reliable indicator of anthrax in carcasses. PMID:19436482

Himsworth, Chelsea G; Argue, Connie K

2009-03-01

158

SUSPICIOUS MAIL OR PARCELS: ANTHRAX, RICIN, CHEMICAL, BIOLOGICAL INFORMATION  

E-print Network

04/19/2013 SUSPICIOUS MAIL OR PARCELS: ANTHRAX, RICIN, CHEMICAL, BIOLOGICAL INFORMATION Threats of exposure to ricin and previously anthrax have caused an increase in anxiety over the possibility to threaten persons with harm. ANTHRAX Effective dispersal of anthrax is difficult due to the processes

159

Treatment of Anthrax Disease Frequently Asked Questions  

SciTech Connect

This document provides a summary of Frequently Asked Questions (FAQs) on the treatment of anthrax disease caused by a wide-area release of Bacillus anthracis spores as an act bioterrorism. These FAQs are intended to provide the public health and medical community, as well as others, with guidance and communications to support the response and long-term recovery from an anthrax event.

Judd, Kathleen S.; Young, Joan E.; Lesperance, Ann M.; Malone, John D.

2010-05-14

160

Anthrax vaccine associated deaths in miniature horses.  

PubMed

During a widespread anthrax outbreak in Canada, miniature horses were vaccinated using a live spore anthrax vaccine. Several of these horses died from an apparent immune-mediated vasculitis temporally associated with this vaccination. During the course of the outbreak, other miniature horses from different regions with a similar vaccination history, clinical signs, and necropsy findings were found. PMID:25829553

Wobeser, Bruce K

2015-04-01

161

Serum adenosine deaminase activity in cutaneous anthrax  

PubMed Central

Background Adenosine deaminase (ADA) activity has been discovered in several inflammatory conditions; however, there are no data associated with cutaneous anthrax. The aim of this study was to investigate serum ADA activity in patients with cutaneous anthrax. Material/Methods Sixteen patients with cutaneous anthrax and 17 healthy controls were enrolled. We measured ADA activity; peripheral blood leukocyte, lymphocyte, neutrophil, and monocyte counts; erythrocyte sedimentation rate; and C reactive protein levels. Results Serum ADA activity was significantly higher in patients with cutaneous anthrax than in the controls (p<0.001). A positive correlation was observed between ADA activity and lymphocyte counts (r=0.589, p=0.021) in the patient group. Conclusions This study suggests that serum ADA could be used as a biochemical marker in cutaneous anthrax. PMID:24997584

Sunnetcioglu, Mahmut; Karadas, Sevdegul; Aslan, Mehmet; Ceylan, Mehmet Resat; Demir, Halit; Oncu, Mehmet Resit; Karahocagil, Mustafa Kas?m; Sunnetcioglu, Aysel; Aypak, Cenk

2014-01-01

162

Purification and biophysical characterization of the core protease domain of anthrax lethal factor  

SciTech Connect

Anthrax lethal toxin (LeTx) stands for the major virulence factor of the anthrax disease. It comprises a 90 kDa highly specific metalloprotease, the anthrax lethal factor (LF). LF possesses a catalytic Zn{sup 2+} binding site and is highly specific against MAPK kinases, thus representing the most potent native biomolecule to alter and inactivate MKK [MAPK (mitogen-activated protein kinase) kinases] signalling pathways. Given the importance of the interaction between LF and substrate for the development of anti-anthrax agents as well as the potential treatment of nascent tumours, the analysis of the structure and dynamic properties of the LF catalytic site are essential to elucidate its enzymatic properties. Here we report the recombinant expression and purification of a C-terminal part of LF (LF{sub 672-776}) that harbours the enzyme's core protease domain. The biophysical characterization and backbone assignments ({sup 1}H, {sup 13}C, {sup 15}N) of the polypeptide revealed a stable, well folded structure even in the absence of Zn{sup 2+}, suitable for high resolution structural analysis by NMR.

Gkazonis, Petros V.; Dalkas, Georgios A.; Chasapis, Christos T. [Department of Pharmacy, University of Patras, GR-26504 Patras (Greece)] [Department of Pharmacy, University of Patras, GR-26504 Patras (Greece); Vlamis-Gardikas, Alexios [Department of Biochemistry, Foundation for Biomedical Research (BRFAA), Academy of Athens, GR-11527 Athens (Greece)] [Department of Biochemistry, Foundation for Biomedical Research (BRFAA), Academy of Athens, GR-11527 Athens (Greece); Bentrop, Detlef [Institute of Physiology II, University of Freiburg, D-79108 Freiburg (Germany)] [Institute of Physiology II, University of Freiburg, D-79108 Freiburg (Germany); Spyroulias, Georgios A., E-mail: G.A.Spyroulias@upatras.gr [Department of Pharmacy, University of Patras, GR-26504 Patras (Greece)

2010-06-04

163

Stable Dry Powder Formulation for Nasal Delivery of Anthrax Vaccine  

PubMed Central

There is a current biodefense interest in protection against Anthrax. Here we developed a new generation of stable and effective anthrax vaccine. We studied the immune response elicited by rPA delivered intranasally with a novel mucosal adjuvant, a mast cell activator Compound 48/80. The vaccine formulation was prepared in a powder form by spray-freeze-drying (SFD) under optimized conditions to produce particles with a target size of D50=25?m, suitable for delivery to the rabbit nasal cavity. Physicochemical properties of the powder vaccines were characterized to assess their delivery and storage potential. Structural stability of rPA was confirmed by CD and ATR-FTIR, while functional stability of rPA and C48/80 was monitored by cell-based assays. Animal study was performed using a unitdose powder device for direct nasal application. Results showed that C48/80 provided effective mucosal adjuvant activity in rabbits. Freshly prepared SFD powder vaccine formulations or powders stored for over two years at room temperature elicited significantly elevated serum PA-specific and lethal toxin neutralization antibody titers that were comparable to that induced by IM immunization with rPA. Nasal delivery of this vaccine formulation may be a viable alternative to the currently licensed vaccine, or an attractive vaccine platform for other mucosally transmitted diseases. PMID:21905034

Wang, Sheena H.; Kirwan, Shaun M.; Abraham, Soman N.; Staats, Herman F.; Hickey, Anthony J.

2013-01-01

164

Adenovirus-based prime-boost immunization for rapid vaccination against anthrax.  

PubMed

Prime-boost vaccination using plasmid DNA and replication-defective adenovirus vectors has emerged as a highly effective strategy for vaccinating against viral pathogens. However, its ability to provide protection against bacterial disease has never been assessed. Here we evaluate prime-boost vaccination approaches for immunizing against anthrax. We show that mice primed with DNA and boosted with an adenovirus vector, both expressing domain four of Bacillus anthracis protective antigen (PA), have higher antibody and toxin-neutralizing titers than mice immunized with either single modality alone. DNA-primed/adenovirus-boosted mice also had significantly higher antibody and toxin-neutralizing titers than mice immunized with Anthrax Vaccine Adsorbed. High levels of antigen-specific interferon-gamma-secreting cells were present in vaccinated mice indicating that a cell-mediated immune response had also been stimulated. Both DNA-primed/adenovirus-boosted and adenovirus-primed/adenovirus-boosted mice were fully protected from Sterne strain spore challenge. We also show that a single injection with an adenovirus vector-expressing domain four of PA can provide partial protection from spore challenge 2 weeks after immunization and full protection 3 weeks after immunization. These results demonstrate that adenovirus-based prime-boost vaccination can provide rapid protection from anthrax and that this approach may be an effective strategy for immunizing against bacterial as well as viral pathogens. PMID:17164792

McConnell, Michael J; Hanna, Philip C; Imperiale, Michael J

2007-01-01

165

[Molecular aspects of anthrax pathogenesis].  

PubMed

A model of anthrax infection with the role determined for main pathogenicity factors of Bacillus anthracis exotoxin and capsule is presented. After spore phagocytosis by macrophages, synthesis of the main exotoxin component begins - a protective antigen that in oligomeric form disrupts phagosome membrane. This accelerates the transition of the pathogen from phagosome into the macrophage cytoplasm. Poly-D-glutamine capsule synthesized by the pathogen triggers the exit (exocytosis) of vegetative cells from macrophages and protects them from re-phagocytosis in lymphatic node lumen. The vegetative cells, that actively and freely replicate in lymphatic node, secret an exotoxin that disrupts endothelial septum between lymph and blood due to cytotoxic activity. As a result the vegetative cells get into blood and bacteremia develops. Pathogenetic pattern during anthrax (multiple hemorrhages in various organs etc.) is associated with local microcirculation disorders of various organs caused by the effect of bacterial exoproteases via activation of Willebrand factor. This results in a rapid local increase of microbial mass and consequent powerful cytotoxic effect of exotoxin on the tissue cells of the affected organ. Death of the infected organism takes place at the final stage of infec- tion due to toxic shock caused by the exotoxin. A reduction of body temperature takes place after death and the process of spore formation begins in the dead animal: capsule depolymerization, chain shortening, peptidoglycan cortex formation. Spores in this form are the prolonged source of infectious agent conservation and spread of infection in nature. PMID:25286538

Noskov, A N

2014-01-01

166

Effects of dynamin inactivation on pathways of anthrax toxin uptake  

E-print Network

-mediated transferrin uptake in cells expressing dynamints . A long-term endocytic block (days) can be obtained by over) but in only incomplete blockage of transferrin uptake . Thus, it appears that transferrin can enter

Kirchhausen, Tomas

167

Small Molecule Inhibitors of Anthrax Lethal Factor Toxin  

PubMed Central

This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds. PMID:24290062

Williams, John D.; Khan, Atiyya R.; Cardinale, Steven C.; Butler, Michelle M.; Bowlin, Terry L.; Peet, Norton P.

2014-01-01

168

Comprehensive analysis and selection of anthrax vaccine adsorbed immune correlates of protection in rhesus macaques.  

PubMed

Humoral and cell-mediated immune correlates of protection (COP) for inhalation anthrax in a rhesus macaque (Macaca mulatta) model were determined. The immunological and survival data were from 114 vaccinated and 23 control animals exposed to Bacillus anthracis spores at 12, 30, or 52 months after the first vaccination. The vaccinated animals received a 3-dose intramuscular priming series (3-i.m.) of anthrax vaccine adsorbed (AVA) (BioThrax) at 0, 1, and 6 months. The immune responses were modulated by administering a range of vaccine dilutions. Together with the vaccine dilution dose and interval between the first vaccination and challenge, each of 80 immune response variables to anthrax toxin protective antigen (PA) at every available study time point was analyzed as a potential COP by logistic regression penalized by least absolute shrinkage and selection operator (LASSO) or elastic net. The anti-PA IgG level at the last available time point before challenge (last) and lymphocyte stimulation index (SI) at months 2 and 6 were identified consistently as a COP. Anti-PA IgG levels and lethal toxin neutralization activity (TNA) at months 6 and 7 (peak) and the frequency of gamma interferon (IFN-?)-secreting cells at month 6 also had statistically significant positive correlations with survival. The ratio of interleukin 4 (IL-4) mRNA to IFN-? mRNA at month 6 also had a statistically significant negative correlation with survival. TNA had lower accuracy as a COP than did anti-PA IgG response. Following the 3-i.m. priming with AVA, the anti-PA IgG responses at the time of exposure or at month 7 were practicable and accurate metrics for correlating vaccine-induced immunity with protection against inhalation anthrax. PMID:25185577

Chen, Ligong; Schiffer, Jarad M; Dalton, Shannon; Sabourin, Carol L; Niemuth, Nancy A; Plikaytis, Brian D; Quinn, Conrad P

2014-11-01

169

Clostridial toxins.  

PubMed

Clostridia produce the highest number of toxins of any type of bacteria and are involved in severe diseases in humans and other animals. Most of the clostridial toxins are pore-forming toxins responsible for gangrenes and gastrointestinal diseases. Among them, perfringolysin has been extensively studied and it is the paradigm of the cholesterol-dependent cytolysins, whereas Clostridium perfringens epsilon-toxin and Clostridium septicum alpha-toxin, which are related to aerolysin, are the prototypes of clostridial toxins that form small pores. Other toxins active on the cell surface possess an enzymatic activity, such as phospholipase C and collagenase, and are involved in the degradation of specific cell-membrane or extracellular-matrix components. Three groups of clostridial toxins have the ability to enter cells: large clostridial glucosylating toxins, binary toxins and neurotoxins. The binary and large clostridial glucosylating toxins alter the actin cytoskeleton by enzymatically modifying the actin monomers and the regulatory proteins from the Rho family, respectively. Clostridial neurotoxins proteolyse key components of neuroexocytosis. Botulinum neurotoxins inhibit neurotransmission at neuromuscular junctions, whereas tetanus toxin targets the inhibitory interneurons of the CNS. The high potency of clostridial toxins results from their specific targets, which have an essential cellular function, and from the type of modification that they induce. In addition, clostridial toxins are useful pharmacological and biological tools. PMID:19824793

Popoff, Michel R; Bouvet, Philippe

2009-10-01

170

Anthrax: Exposure to Hides/Drums  

MedlinePLUS

... Confirming Anthrax Through the Laboratory Response Network Laboratory Testing - FAQs Collecting Specimens Recommended Specimens Information for Specific Groups Laboratory Professionals People Who Work with Animal Products Exposure to Hides/Drums Treatment of Products ...

171

Anthrax Vaccine: What You Need to Know  

MedlinePLUS

... some people handling animals or animal products • some military personnel, as determined by the Department of Defense ... and are at risk of developing inhalation disease. Nursing mothers may safely be given anthrax vaccine. 5 ...

172

List of Contractors to Support Anthrax Remediation  

SciTech Connect

This document responds to a need identified by private sector businesses for information on contractors that may be qualified to support building remediation efforts following a wide-area anthrax release.

Judd, Kathleen S.; Lesperance, Ann M.

2010-05-14

173

Anthrax vaccines: present status and future prospects.  

PubMed

The management of anthrax remains a top priority among the biowarfare/bioterror agents. It was the Bacillus anthracis spore attack through the US mail system after the September 11, 2001, terrorist attacks in the USA that highlighted the potential of B. anthracis as a bioterrorism agent and the threat posed by its deliberate dissemination. These attacks invigorated the efforts toward understanding the anthrax pathogenesis and development of more comprehensive medical intervention strategies for its containment in case of both natural disease and manmade, accidental or deliberate infection of a non-suspecting population. Currently, efforts are directed toward the development of safe and efficacious vaccines as well as intervention tools for controlling the disease in the advanced fulminant stage when toxemia has already developed. This work presents an overview of the current understanding of anthrax pathogenesis and recent advances made, particularly after 2001, for the successful management of anthrax and outlines future perspectives. PMID:23984963

Kaur, Manpreet; Singh, Samer; Bhatnagar, Rakesh

2013-08-01

174

Radiolabeled oligonucleotides for antisense imaging  

PubMed Central

Oligonucleotides radiolabeled with isotopes emitting ?-rays (for SPECT imaging) or positrons (for PET imaging) can be useful for targeting messenger RNA (mRNA) thereby serving as non-invasive imaging tools for detection of gene expression in vivo (antisense imaging). Radiolabeled oligonucleotides may also be used for monitoring their in vivo fate, thereby helping us better understand the barriers to its delivery for antisense targeting. These developments have led to a new area of molecular imaging and targeting, utilizing radiolabeled antisense oligonucleotides. However, the success of antisense imaging relies heavily on overcoming the barriers for its targeted delivery in vivo. Furthermore, the low ability of the radiolabeled antisense oligonucleotide to subsequently internalize into the cell and hybridize with its target mRNA poses additional challenges in realizing its potentials. This review covers the advances in the antisense imaging probe development for PET and SPECT, with an emphasis on radiolabeling strategies, stability, delivery and in vivo targeting. PMID:21822406

Iyer, Arun K; He, Jiang

2011-01-01

175

Anthrax: memorandum from a WHO meeting.  

PubMed Central

The risk of anthrax can be reduced through international collaboration in health education and training, promotion of research, and provision of scientific and technical advice. These issues were discussed by a WHO Working Group on Anthrax in September 1995, and this Memorandum presents their priority concerns and recommendations in several areas: surveillance, epidemiology, diagnosis in humans and in animals, prevention and control, and international cooperation. PMID:9002326

1996-01-01

176

Cutaneous anthrax in Southeast Anatolia of Turkey.  

PubMed

Abstract Context: Anthrax is a rare disease cause by Bacillus anthracis, a Gram-positive, rod-shaped endospore-forming capsuled bacterium. Anthrax is manifest in three primary forms: cutaneous, respiratory, and gastrointestinal. Cutaneous anthrax accounts for approximately 95% of all cases of anthrax in humans. Objective: In the present study, we evaluated the clinical diagnosis and treatment of cutaneous anthrax, a rare disease that nonetheless remains a serious healthcare problem in developing countries. Methods: The complete medical records of patients diagnosed with cutaneous anthrax between January 2001 and December 2012 were examined in a retrospective manner. Cutaneous anthrax was diagnosed by the identification of typical antrax lesions and/or the presence of Gram-positive-capsuled bacillus after staining with Gram stain and methylen blue in pathology samples obtained from these lesions and the presence of characteristic scarring with a history of severe swelling, black eschar, and positive response to treatment form the basis of diagnosis in cases where cultures were negative for the presence of bacillus. Results: A total of 58 patients were admitted to the hospital with cutaneous anthrax between January 2001 and December 2012. This included 32 (55.2%) males and 26 (44.8%) females, with an age range of 15-82 years and a mean age of 38?±?13.8 years. The incubation period for the infection ranged between 1 and 20?d (mean 3.7?±?1.4?d). The most common symptoms at the time of hospital referral were swelling, redness, and black eschar of the skin. The most common lesion site was the hand and fingers (41.3%). Isolated of bacteria was used to diagnose the disease in six cases (23.8%), detection of Gram-positive bacillus in samples of characteristic lesion material was used in seven (28.5%) cases, and the presence of a characteristic lesion was the sole diagnositc criteria in 45 (77.6%) cases. Treatment consisted of penicillin G (12 cases), ampicillin-sulbactam (30 cases), Cefazolin (12 cases), or ciprofloxacin (4 cases). Conclusion: Although the prevalence of anthrax is a decreasing worldwide, it remains a significant problem in developing countries. Rapid identification of the signs and symptoms of cutaneous anthrax is essential for effective treatment. Early supportive treatment and appropriate antimicrobial measures are necessary to address this potentially life-threatening disease. PMID:24678748

Tekin, Recep; Sula, Bilal; Devec?, Ozcan; Tekin, Alicem; Bozkurt, Fatma; Ucmak, Derya; Kaya, Safak; Bekcibasi, Muhammed; Erkan, Mehmet Emin; Ayaz, Celal; Hosoglu, Salih

2014-03-31

177

Laboratories Face Crackdown in Wake of Anthrax Scare.  

ERIC Educational Resources Information Center

Explores the after-effects on college laboratories of the anthrax mail scare; scientists say the anthrax scare justifies tougher rules on biological agents, but some fear that Congress may go too far. (EV)

Southwick, Ron

2001-01-01

178

Delayed-type hypersensitivity reaction to anthrax vaccine.  

PubMed

The Anthrax Vaccine Immunization Program is a Department of Defense initiative to protect military personnel against the threat of anthrax. Surveillance for adverse events associated with anthrax vaccination has shown that mild local reactions are not uncommon while systemic reactions are extremely rare. We present a case of 26-year-old male with delayed-type hypersensitivity after two doses of anthrax vaccine. PMID:11799819

Greidanus, Thomas G; Honl, Beth A

2002-01-01

179

Anthrax  

MedlinePLUS

... potential to be used as a weapon of bioterrorism; this occurred in 2001 with an attack on ... Animal shearers Tanners In the case of a bioterrorism attack, anyone exposed to B. anthracis is at ...

180

Public health vaccination policies for containing an anthrax outbreak  

Microsoft Academic Search

Concern about biological weapons has raised questions about the most effective public health policies to contain an anthrax outbreak. We developed a probability model to predict the impact of different anthrax antibiotic and vaccination policies. An anthrax outbreak can be significantly contained by minimizing the delay until initiation of antibiotic prophylaxis. However, even if mass distribution of antibiotics is completed

Ron Brookmeyer; Elizabeth Johnson; Robert Bollinger

2004-01-01

181

Emergency response to an anthrax attack Lawrence M. Wein*  

E-print Network

Emergency response to an anthrax attack Lawrence M. Wein* , David L. Craft , and Edward H. Kaplan of an airborne anthrax attack. The system consists of an atmospheric dispersion model, an age- dependent dose, the bacterium that causes anthrax, via the United States mail in 2001 (1) and the dire warnings about

Li, Fei-Fei

182

Anthrax: has the clinical milieu changed since 2001?  

PubMed Central

Since the anthrax attacks of 2001 (Amerithrax), several important improvements in the knowledge of Bacillus anthracis and the clinical condition it causes have occurred. While much remains to be known about the optimal management of anthrax patients, several approaches that were not widely utilized, available, or known in 2001 would be used in the treatment of critically ill anthrax patients in 2012. PMID:23882372

Adalja, Amesh A.

2012-01-01

183

Exoproteome analysis of a novel strain of Bacillus cereus implicated in disease resembling cutaneous anthrax.  

PubMed

Bacillus cereus belongs to B. cereus sensu lato group, shared by six other related species including Bacillus anthracis. B. anthracis is the causative agent for serious illness affecting a wide range of animals as well as humans and is a category A Biological and Toxin Warfare (BTW) agent. Recent studies indicate that a Bacillus species other than B. anthracis can cause anthrax-like disease and role of anthrax virulence plasmids (pXO1 and pXO2) on the pathogenicity of B. cereus has been documented. B. cereus strain TF5 was isolated from the tissue fluid of cutaneous anthrax-like skin lesions of a human patient from an anthrax endemic area in India. The strain harboured a PA gene, however, presence of pXO1 or pXO2-like plasmids could not be ascertained using reported primers. Abundant exoproteome of the strain in the early stationary phase was elucidated using a 2-DE MS approach and compared with that from a reference B. cereus strain. Analysis of proteins showing qualitative and quantitative differences between the two strains indicated an altered regulatory mechanism and putative role of S-layer protein and sphingomyelinase in the pathogenesis of strain TF5. Phylogenetic analysis of the S-layer protein indicated close affiliation of the strain with anthracis-like B. cereus strains such as B. cereus var. anthracis strain CI; whereas sphingomyelinase exhibited specific relationship with all the strains of B. anthracis apart from that with anthracis-like B. cereus strains. PMID:24412723

Ghosh, Neha; Goel, Ajay Kumar; Alam, Syed Imteyaz

2014-03-01

184

Acceleration of epithelial cell syndecan-1 shedding by anthrax hemolytic virulence factors  

PubMed Central

Background It has been recently reported that major pathogens Staphylococcus aureus and Pseudomonas aeruginosa accelerate a normal process of cell surface syndecan-1 (Synd1) ectodomain shedding as a mechanism of host damage due to the production of shedding-inducing virulence factors. We tested if acceleration of Synd1 shedding takes place in vitro upon treatment of epithelial cells with B. anthracis hemolysins, as well as in vivo during anthrax infection in mice. Results The isolated anthrax hemolytic proteins AnlB (sphingomyelinase) and AnlO (cholesterol-binding pore-forming factor), as well as ClnA (B. cereus homolog of B. anthracis phosphatidyl choline-preferring phospholipase C) cause accelerated shedding of Synd1 and E-cadherin from epithelial cells and compromise epithelial barrier integrity within a few hours. In comparison with hemolysins in a similar range of concentrations, anthrax lethal toxin (LT) also accelerates shedding albeit at slower rate. Individual components of LT, lethal factor and protective antigen are inactive with regard to shedding. Inhibition experiments favor a hypothesis that activities of tested bacterial shedding inducers converge on the stimulation of cytoplasmic tyrosine kinases of the Syk family, ultimately leading to activation of cellular sheddase. Both LT and AnlO modulate ERK1/2 and p38 MAPK signaling pathways, while JNK pathway seems to be irrelevant to accelerated shedding. Accelerated shedding of Synd1 also takes place in DBA/2 mice challenged with Bacillus anthracis (Sterne) spores. Elevated levels of shed ectodomain are readily detectable in circulation after 24 h. Conclusion The concerted acceleration of shedding by several virulence factors could represent a new pathogenic mechanism contributing to disruption of epithelial or endothelial integrity, hemorrhage, edema and abnormal cell signaling during anthrax infection. PMID:16464252

Popova, Taissia G; Millis, Bryan; Bradburne, Chris; Nazarenko, Svetlana; Bailey, Charles; Chandhoke, Vikas; Popov, Serguei G

2006-01-01

185

Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers  

PubMed Central

The protein transporter, anthrax lethal toxin, is comprised of protective antigen (PA), a transmembrane translocase, and lethal factor (LF), a cytotoxic enzyme. Following assembly into holotoxin complexes, PA forms an oligomeric channel that unfolds LF and translocates it into the host cell. We report the crystal structure of the core of a lethal toxin complex to 3.1-Å resolution; the structure contains a PA octamer bound to four LF PA-binding domains (LFN). The first ? helix and ? strand of each LFN unfold and dock into a deep amphipathic cleft on the surface of the PA octamer, which we call the ? clamp. The ? clamp possesses nonspecific polypeptide binding activity and is functionally relevant to efficient holotoxin assembly, PA octamer formation, and LF unfolding and translocation. This structure provides insight on the mechanism of translocation-coupled protein unfolding. PMID:21037566

Feld, Geoffrey K.; Thoren, Katie L.; Kintzer, Alexander F.; Sterling, Harry J.; Tang, Iok I.; Greenberg, Shoshana G.; Williams, Evan R.; Krantz, Bryan A.

2011-01-01

186

Generation of protective immune response against anthrax by oral immunization with protective antigen plant-based vaccine.  

PubMed

In concern with frequent recurrence of anthrax in endemic areas and inadvertent use of its spores as biological weapon, the development of an effective anthrax vaccine suitable for both human and veterinary needs is highly desirable. A simple oral delivery through expression in plant system could offer promising alternative to the current methods that rely on injectable vaccines extracted from bacterial sources. In the present study, we have expressed protective antigen (PA) gene in Indian mustard by Agrobacterium-mediated transformation and in tobacco by plastid transformation. Putative transgenic lines were verified for the presence of transgene and its expression by molecular analysis. PA expressed in transgenic lines was biologically active as evidenced by macrophage lysis assay. Intraperitoneal (i.p.) and oral immunization with plant PA in murine model indicated high serum PA specific IgG and IgA antibody titers. PA specific mucosal immune response was noted in orally immunized groups. Further, antibodies indicated lethal toxin neutralizing potential in-vitro and conferred protection against in-vivo toxin challenge. Oral immunization experiments demonstrated generation of immunoprotective response in mice. Thus, our study examines the feasibility of oral PA vaccine expressed in an edible plant system against anthrax. PMID:24548460

Gorantala, Jyotsna; Grover, Sonam; Rahi, Amit; Chaudhary, Prerna; Rajwanshi, Ravi; Sarin, Neera Bhalla; Bhatnagar, Rakesh

2014-04-20

187

Efficacy of ETI-204 Monoclonal Antibody as an Adjunct Therapy in a New Zealand White Rabbit Partial Survival Model for Inhalational Anthrax.  

PubMed

Inhalational anthrax is characterized by extensive bacteremia and toxemia as well as nonspecific to mild flu-like symptoms, until the onset of hypotension, shock, and mortality. Without treatment, the mortality rate approaches 100%. Antibiotic treatment is not always effective, and alternative treatments are needed, such as monotherapy for antibiotic-resistant inhalational anthrax or as an adjunct therapy in combination with antibiotics. The Bacillus anthracis antitoxin monoclonal antibody (MAb) ETI-204 is a high-affinity chimeric deimmunized antibody which targets the anthrax toxin protective antigen (PA). In this study, a partial protection New Zealand White (NZW) rabbit model was used to evaluate the protective efficacy of the adjunct therapy with the MAb. Following detection of PA in the blood, NZW rabbits were administered either an antibiotic (doxycycline) alone or the antibiotic in conjunction with ETI-204. Survival was evaluated to compare the efficacy of the combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals. PMID:25645849

Biron, Bethany; Beck, Katie; Dyer, David; Mattix, Marc; Twenhafel, Nancy; Nalca, Aysegul

2015-04-01

188

Substrate Recognition of Anthrax Lethal Factor Examined by Combinatorial and Pre-steady-state Kinetic Approaches*  

PubMed Central

Lethal factor (LF), a zinc-dependent protease of high specificity produced by Bacillus anthracis, is the effector component of the binary toxin that causes death in anthrax. New therapeutics targeting the toxin are required to reduce systemic anthrax-related fatalities. In particular, new insights into the LF catalytic mechanism will be useful for the development of LF inhibitors. We evaluated the minimal length required for formation of bona fide LF substrates using substrate phage display. Phage-based selection yielded a substrate that is cleaved seven times more efficiently by LF than the peptide targeted in the protein kinase MKK6. Site-directed mutagenesis within the metal-binding site in the LF active center and within phage-selected substrates revealed a complex pattern of LF-substrate interactions. The elementary steps of LF-mediated proteolysis were resolved by the stopped-flow technique. Pre-steady-state kinetics of LF proteolysis followed a four-step mechanism as follows: initial substrate binding, rearrangement of the enzyme-substrate complex, a rate-limiting cleavage step, and product release. Examination of LF interactions with metal ions revealed an unexpected activation of the protease by Ca2+ and Mn2+. Based on the available structural and kinetic data, we propose a model for LF-substrate interaction. Resolution of the kinetic and structural parameters governing LF activity may be exploited to design new LF inhibitors. PMID:19359249

Zakharova, Maria Yu.; Kuznetsov, Nikita A.; Dubiley, Svetlana A.; Kozyr, Arina V.; Fedorova, Olga S.; Chudakov, Dmitry M.; Knorre, Dmitry G.; Shemyakin, Igor G.; Gabibov, Alexander G.; Kolesnikov, Alexander V.

2009-01-01

189

The Sverdlovsk Anthrax Outbreak of 1979  

Microsoft Academic Search

In April and May 1979, an unusual anthrax epidemic occurred in Sverdlovsk, Union of Soviet Socialist Republics. Soviet officials attributed it to consumption of contaminated meat. U.S. agencies attributed it to inhalation of spores accidentally released at a military microbiology facility in the city. Epidemiological data show that most victims worked or lived in a narrow zone extending from the

Matthew Meselson; Jeanne Guillemin; Martin Hugh-Jones; Alexander Langmuir; Ilona Popova; Alexis Shelokov; Olga Yampolskaya

1994-01-01

190

Anthrax Attack! A Case on Bioterrorism  

NSDL National Science Digital Library

This case study presents a fictitious bio-terrorist plan to release anthrax in the United States. Students are assigned character roles and, through research, role-playing, and teamwork, develop a plan to minimize or avert the attack. The case is appropriate for courses designed for health professionals, general biology courses, and social science courses.

Kari A. Mergenhagen

2003-01-01

191

Crystal structure of the anthrax lethal factor  

Microsoft Academic Search

Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways. Here we describe the crystal structure of LF and its

Andrew D. Pannifer; Thiang Yian Wong; Robert Schwarzenbacher; Martin Renatus; Carlo Petosa; Jadwiga Bienkowska; D. Borden Lacy; R. John Collier; Stephen H. Leppla; Philip Hanna; Robert C. Liddington

2001-01-01

192

Guidelines for Pregnant Women Who Have Been Exposed to Anthrax but Do Not Have Symptoms  

MedlinePLUS

... Who Have Been Exposed to Anthrax But Do Not Have Symptoms Recommend on Facebook Tweet Share Compartir ... have been exposed to anthrax, but who do not have symptoms of anthrax disease. For CDC guidelines ...

193

Application Track: Emerging Application Title: Optimizing Anthrax Outbreak Detection Methods Using Reinforcement Learning  

E-print Network

Application Track: Emerging Application Title: Optimizing Anthrax Outbreak Detection Methods Using makes developing effective detection methods essential for public health. In the case of anthrax attack Processes (POMDPs) on outbreak detection mechanism for improving alarm function in anthrax outbreak

Verbrugge, Clark

194

Histopathological effects of anthrax lethal factor on rat liver.  

PubMed

Bacillus anthracis, the causative agent of anthrax, has become an increasingly important scientific topic due to its potential role in bioterrorism. The lethal toxin (LT) of B. anthracis consists of lethal factor (LF) and a protective antigen (PA). This study investigated whether only lethal factor was efficient as a hepatotoxin in the absence of the PA. To achieve this aim, LF (100 µg/kg body weight, dissolved in sterile distilled water) or distilled water vehicle were intraperitoneally injected once into adult rats. At 24 h post-injection, the hosts were euthanized and their livers removed and tissue samples examined under light and electron microscopes. As a result of LF application, hepatic injury - including cytoplasmic and nuclear damage in hepatocytes, sinusoidal dilatation, and hepatocellular lysis - became apparent. Further, light microscopic analyses of liver sections from the LF-injected rats revealed ballooning degeneration and cytoplasmic loss within hepatocytes, as well as peri-sinusoidal inflammation. Additionally, an increase in the numbers of Kupffer cells was evident. Common vascular injuries were also found in the liver samples; these injuries caused hypoxia and pathological changes. In addition, some cytoplasmic and nuclear changes were detected within the liver ultrastructure. The results of these studies allow one to suggest that LF could be an effective toxicant alone and that PA might act in situ to modify the effect of this agent (or the reverse situation wherein LF modifies effects of PA) such that lethality results. PMID:24344743

Altunkaynak, Berrin Zuhal; Ozbek, Elvan

2015-01-01

195

Platelet-activating Factor Contributes to Bacillus anthracis Lethal Toxin-associated Damage*  

PubMed Central

The lethal toxin (LeTx) of Bacillus anthracis plays a central role in the pathogenesis of anthrax-associated shock. Platelet-activating factor (PAF) is a potent lipid mediator that has been implicated in endotoxin-associated shock. In this study, we examined the contribution of PAF to the manifestations of lethal toxin challenge in WT mice. LeTx challenge resulted in transient increase in serum PAF levels and a concurrent decrease in PAF acetylhydrolase activity. Inhibition of PAF activity using PAF antagonists or toxin challenge of PAF receptor negative mice reversed or ameliorated many of the pathologic features of LeTx-induced damage, including changes in vascular permeability, hepatic necrosis, and cellular apoptosis. In contrast, PAF inhibition had minimal effects on cytokine levels. Findings from these studies support the continued study of PAF antagonists as potential adjunctive agents in the treatment of anthrax-associated shock. PMID:24478317

Rivera, Johanna; Sellers, Rani S.; Zeng, Wangyong; van Rooijen, Nico; Casadevall, Arturo; Goldman, David L.

2014-01-01

196

Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor.  

PubMed

Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera. PMID:23202316

Schein, Catherine H; Chen, Deliang; Ma, Lili; Kanalas, John J; Gao, Jian; Jimenez, Maria Estrella; Sower, Laurie E; Walter, Mary A; Gilbertson, Scott R; Peterson, Johnny W

2012-11-01

197

Anthrax as an example of the One Health concept.  

PubMed

Anthrax is a peracute, acute or subacute multispecies bacterial infection that occurs on many continents. It is one of the oldest infectious diseases known; the biblical fifth and sixth plagues (Exodus chapters 7 to 9) that affected first livestock and then humans were probably anthrax. From the earliest historical records until development of an effective vaccine midway through the 20th Century, anthrax was one of the foremost causes of uncontrolled mortality in cattle, sheep, goats, horses and pigs, with 'spill over' into humans, worldwide. With the development of the Sterne spore vaccine, a sharp decline in anthrax outbreaks in livestock occurred during the 1930-1980 era. There were successful national vaccination programmes in many countries during this period, complemented by the liberal use of antibiotics and the implementation of quarantine regulations and carcass disposal. However, a resurgence of this disease in livestock has been reported recently in some regions, where complacency and a false sense of security have hindered vaccination programmes. The epidemiology of anthrax involves an environmental component, as well as livestock, wildlife and human components. This makes anthrax an ideal example for discussion in the One Health context. Many outbreaks of anthrax in wildlife are undetected or unreported, owing to surveillance inadequacies and difficulties. Human disease is generally acquired accidentally during outbreaks of anthrax in domestic livestock and wildlife. The exception is deliberate targeting of humans with anthrax in the course of biowarfare or bioterrorism. PMID:25707186

Bengis, R G; Frean, J

2014-08-01

198

Clinical microbiologists facing an anthrax alert.  

PubMed

Microbiological war and terrorist attacks are made to weaken populations by transmitting pathogenic and epidemic microorganisms. These bacteria or viruses are often difficult to diagnose. Anthrax alerts following September 2001 showed that most clinical microbiology laboratories were not adequately prepared, using obsolete diagnostic methods or being too slow to use accurate tools when facing a major threat. Following this period, most microbiology laboratories were prepared for bioterrorism alerts, in order to provide accurate and rapid results, although such events are rare and unexpected. In this review, we describe the organization and preparedness of our clinical microbiology laboratory regarding bioterrorism risk, although its main task is to perform routine diagnostic microbiology tests. To illustrate the difficulties, we briefly describe an anthrax alert. PMID:24845109

Jaton, K; Greub, G

2014-06-01

199

Challenges in Disposing of Anthrax Waste  

SciTech Connect

Disasters often create large amounts of waste that must be managed as part of both immediate response and long-term recovery. While many federal, state, and local agencies have debris management plans, these plans often do not address chemical, biological, and radiological contamination. The Interagency Biological Restoration Demonstration’s (IBRD) purpose was to holistically assess all aspects of an anthrax incident and assist the development of a plan for long-term recovery. In the case of wide-area anthrax contamination and the follow-on response and recovery activities, a significant amount of material will require decontamination and disposal. Accordingly, IBRD facilitated the development of debris management plans to address contaminated waste through a series of interviews and workshops with local, state, and federal representatives. The outcome of these discussion was the identification of three primary topical areas that must be addressed: 1) Planning; 2) Unresolved research questions, and resolving regulatory issues.

Lesperance, Ann M.; Stein, Steven L.; Upton, Jaki F.; Toomey, Christopher

2011-09-01

200

Unusual cause of fatal anthrax meningitis.  

PubMed

We report the case of fatal anthrax meningoencephalitis in the province of Mu? located in eastern Anatolia, Turkey. The organism isolated from cerebrospinal fluid was identified as Bacillus anthracis. The patient was treated with crystallized penicillin G (24 MU/day IV) and ciprofloxacin (2?×?400/day IV), but died 5 days after hospitalization. Although it is a rare case, we consider that the patients who have skin, respiratory and neurological systems might also have hemorrhagic meningitis. PMID:24678752

Parlak, Emine; Parlak, Mehmet; Atli, Seval Bilgiç

2015-03-01

201

Anthrax phylogenetic structure in Northern Italy  

PubMed Central

Background Anthrax has almost disappeared from mainland Europe, except for the Mediterranean region where cases are still reported. In Central and South Italy, anthrax is enzootic, but in the North there are currently no high risk areas, with only sporadic cases having been registered in the last few decades. Regional genetic and molecular characterizations of anthrax in these regions are still lacking. To investigate the potential molecular diversity of Bacillus anthracis in Northern Italy, canonical Single nucleotide polymorphism (canSNP) and Multilocus variable number tandem repeat analysis (MLVA) genotyping was performed against all isolates from animal outbreaks registered in the last twenty years in the region. Findings Six B. anthracis strains were analyzed. The canSNP analysis indicates the presence of three sublineages/subgroups each of which belong to one of the 12 worldwide CanSNP genotypes: B.Br.CNEVA (3 isolates), A.Br.005/006 (1 isolates) and A.008/009 (2 isolate). The latter is the dominant canSNP genotype in Italy. The 15-loci MLVA analysis revealed five different genotypes among the isolates. Conclusions The major B branch and the A.Br.005/006 were recovered in the Northeast region. The genetic structure of anthrax discovered in this area differs from the rest of the country, suggesting the presence of a separate and independent B. anthracis molecular evolution niche. Although the isolates analyzed in this study are limited in quantity and representation, these results indicate that B. anthracis genetic diversity changes around the Alps. PMID:21801397

2011-01-01

202

Radiolabelled peptides for oncological diagnosis.  

PubMed

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The (111)In-labelled somatostatin analogue octreotide (OctreoScan) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. PMID:22388627

Laverman, Peter; Sosabowski, Jane K; Boerman, Otto C; Oyen, Wim J G

2012-02-01

203

BOTULINUM TOXIN  

PubMed Central

Botulinum toxin, one of the most poisonous biological substances known, is a neurotoxin produced by the bacterium Clostridium botulinum. C. botulinum elaborates eight antigenically distinguishable exotoxins (A, B, C1, C2, D, E, F and G). All serotypes interfere with neural transmission by blocking the release of acetylcholine, the principal neurotransmitter at the neuromuscular junction, causing muscle paralysis. The weakness induced by injection with botulinum toxin A usually lasts about three months. Botulinum toxins now play a very significant role in the management of a wide variety of medical conditions, especially strabismus and focal dystonias, hemifacial spasm, and various spastic movement disorders, headaches, hypersalivation, hyperhidrosis, and some chronic conditions that respond only partially to medical treatment. The list of possible new indications is rapidly expanding. The cosmetological applications include correction of lines, creases and wrinkling all over the face, chin, neck, and chest to dermatological applications such as hyperhidrosis. Injections with botulinum toxin are generally well tolerated and side effects are few. A precise knowledge and understanding of the functional anatomy of the mimetic muscles is absolutely necessary to correctly use botulinum toxins in clinical practice. PMID:20418969

Nigam, P K; Nigam, Anjana

2010-01-01

204

Catastrophic Incident Recovery: Long-Term Recovery from an Anthrax Event Symposium  

E-print Network

Anthrax Symposium Catastrophic Incident Recovery: Long-Term Recovery from an Anthrax Event. The Catastrophic Incident Recovery: Long-Term Recovery from an Anthrax Event Symposium was held on March 19, 2008. To increase the knowledge of anthrax as an agent of bioterrorism, three nationally recognized experts

205

AHDC FACT SHEET 1 DL-1050 5/12 Anthrax Sample Collection and Shipping Guidelines  

E-print Network

AHDC FACT SHEET 1 DL-1050 5/12 Anthrax Sample Collection and Shipping Guidelines Animal Health-mail: diagcenter@cornell.edu AHDC FACT SHEET Guidelines for Diagnosis and Sample Collection of Anthrax Suspect of North America sporadically experience natural anthrax outbreaks, natural exposure to anthrax is uncommon

Keinan, Alon

206

Epidemiologic Investigations of Bioterrorism-Related Anthrax, New Jersey, 2001  

Microsoft Academic Search

At least four Bacillus anthracis-containing envelopes destined for New York City and Washington, D.C. were processed at the Trenton Processing and Distribution Center (PDC) on September 18 and October 9, 2001. When cutaneous anthrax was confirmed in a Trenton postal worker, the PDC was closed. Four cutaneous and two inhalational anthrax cases were identified. Five patients were hospitalized; none died.

Carolyn M. Greene; Jennita Reefhuis; Christina Tan; Anthony E. Fiore; Susan Goldstein; Michael J. Beach; Stephen C. Redd; David Valiante; Gregory Burr; James Buehler; Robert W. Pinner; Eddy Bresnitz; Beth P. Bell

2002-01-01

207

Pathology of Inhalation Anthrax in Cynomolgus Monkeys (Macaca fascicularis)  

Microsoft Academic Search

Anthrax is considered a serious biowarfare and bioterrorism threat because of its high lethality, especially by the inhalation route. Rhesus macaques (Macaca mulatta) are the most commonly used nonhuman primate model of human inhalation anthrax exposure. The nonavailability of rhesus macaques necessitated development of an alternate model for vaccine testing and immunologic studies. This report describes the median lethal dose

Daphne Vasconcelos; Roy Barnewall; Michael Babin; Robert Hunt; James Estep; Carl Nielsen; Robert Carnes; John Carney

2003-01-01

208

Bacillus cereus G9241 S-Layer Assembly Contributes to the Pathogenesis of Anthrax-Like Disease in Mice  

PubMed Central

Bacillus cereus G9241, the causative agent of anthrax-like disease, harbors virulence plasmids encoding anthrax toxins as well as hyaluronic acid (HA) and B. cereus exopolysaccharide (BPS) capsules. B. cereus G9241 also harbors S-layer genes, including homologs of Bacillus anthracis surface array protein (Sap), extractable antigen 1 (EA1), and the S-layer-associated proteins (BSLs). In B. anthracis, S-layer proteins and BSLs attach via their S-layer homology domains (SLH) to the secondary cell wall polysaccharide (SCWP) in a manner requiring csaB, a predicted ketalpyruvate transferase. Here we used a genetic approach to analyze B. cereus G9241 S-layer assembly and function. Variants lacking the csaB gene synthesized SCWP but failed to retain Sap, EA1, and BSLs in the bacterial envelope. The B. cereus G9241 csaB mutant assembled capsular polysaccharides but displayed an increase in chain length relative to the wild-type strain. This phenotype is likely due to its inability to deposit BslO murein hydrolase at divisional septa. During growth under capsule-inducing conditions, B. cereus G9241 assembled BSLs (BslA and BslO) and the Sap S-layer protein, but not EA1, in the envelope. Finally, csaB-mediated assembly of S-layer proteins and BSLs in B. cereus G9241 contributes to the pathogenesis of anthrax-like disease in mice. PMID:23204457

Wang, Ya-Ting; Oh, So-Young; Hendrickx, Antoni P. A.; Lunderberg, J. M.

2013-01-01

209

Bacillus anthracis’ lethal toxin induces broad transcriptional responses in human peripheral monocytes  

PubMed Central

Background Anthrax lethal toxin (LT), produced by the Gram-positive bacterium Bacillus anthracis, is a highly effective zinc dependent metalloprotease that cleaves the N-terminus of mitogen-activated protein kinase kinases (MAPKK or MEKs) and is known to play a role in impairing the host immune system during an inhalation anthrax infection. Here, we present the transcriptional responses of LT treated human monocytes in order to further elucidate the mechanisms of LT inhibition on the host immune system. Results Western Blot analysis demonstrated cleavage of endogenous MEK1 and MEK3 when human monocytes were treated with 500?ng/mL LT for four hours, proving their susceptibility to anthrax lethal toxin. Furthermore, staining with annexin V and propidium iodide revealed that LT treatment did not induce human peripheral monocyte apoptosis or necrosis. Using Affymetrix Human Genome U133 Plus 2.0 Arrays, we identified over 820 probe sets differentially regulated after LT treatment at the p <0.001 significance level, interrupting the normal transduction of over 60 known pathways. As expected, the MAPKK signaling pathway was most drastically affected by LT, but numerous genes outside the well-recognized pathways were also influenced by LT including the IL-18 signaling pathway, Toll-like receptor pathway and the IFN alpha signaling pathway. Multiple genes involved in actin regulation, signal transduction, transcriptional regulation and cytokine signaling were identified after treatment with anthrax LT. Conclusion We conclude LT directly targets human peripheral monocytes and causes multiple aberrant gene responses that would be expected to be associated with defects in human monocyte’s normal signaling transduction pathways and function. This study provides further insights into the mechanisms associated with the host immune system collapse during an anthrax infection, and suggests that anthrax LT may have additional downstream targets outside the well-known MAPK pathway. PMID:22747600

2012-01-01

210

Cutaneous anthrax in the Artibonite Valley of Haiti: 1992-2002.  

PubMed

More cutaneous anthrax cases were noted at Hospital Albert Schweitzer (HAS) in the Artibonite Valley of Haiti. We examine the incidence of anthrax in the Artibonite between 1992 and 2002, describe the clinical presentation of cutaneous anthrax, and determine risk factors for anthrax. In 1992 HAS reported 1 case of anthrax for an incidence of 4 cases per million persons/year. In 2002, there were 20 cases of anthrax for an incidence of 72 cases per million persons/year. This is a 17-fold increase (P = 0.0002). Causes of death from anthrax included asphyxiation from edema of the neck with tracheal compression and concurrent gastrointestinal anthrax. Butchering cattle that had died of illness was identified as a risk factor. The incidence of human anthrax has increased in the Artibonite Valley and is a cause of significant mortality. Control of anthrax in humans depends on improved animal vaccination programs. PMID:17984330

Peck, Robert N; Fitzgerald, Daniel W

2007-11-01

211

Rapid generation of an anthrax immunotherapeutic from goats using a novel non-toxic muramyl dipeptide adjuvant  

PubMed Central

Background There is a clear need for vaccines and therapeutics for potential biological weapons of mass destruction and emerging diseases. Anthrax, caused by the bacterium Bacillus anthracis, has been used as both a biological warfare agent and bioterrorist weapon previously. Although antibiotic therapy is effective in the early stages of anthrax infection, it does not have any effect once exposed individuals become symptomatic due to B. anthracis exotoxin accumulation. The bipartite exotoxins are the major contributing factors to the morbidity and mortality observed in acute anthrax infections. Methods Using recombinant B. anthracis protective antigen (PA83), covalently coupled to a novel non-toxic muramyl dipeptide (NT-MDP) derivative we hyper-immunized goats three times over the course of 14 weeks. Goats were plasmapheresed and the IgG fraction (not affinity purified) and F(ab')2 derivatives were characterized in vitro and in vivo for protection against lethal toxin mediated intoxication. Results Anti-PA83 IgG conferred 100% protection at 7.5 ?g in a cell toxin neutralization assay. Mice exposed to 5 LD50 of Bacillus anthracis Ames spores by intranares inoculation demonstrated 60% survival 14 d post-infection when administered a single bolus dose (32 mg/kg body weight) of anti-PA83 IgG at 24 h post spore challenge. Anti-PA83 F(ab')2 fragments retained similar neutralization and protection levels both in vitro and in vivo. Conclusion The protection afforded by these GMP-grade caprine immunotherapeutics post-exposure in the pilot murine model suggests they could be used effectively to treat post-exposure, symptomatic human anthrax patients following a bioterrorism event. These results also indicate that recombinant PA83 coupled to NT-MDP is a potent inducer of neutralizing antibodies and suggest it would be a promising vaccine candidate for anthrax. The ease of production, ease of covalent attachment, and immunostimulatory activity of the NT-MDP indicate it would be a superior adjuvant to alum or other traditional adjuvants in vaccine formulations. PMID:17953756

Kelly, Cassandra D; O'Loughlin, Chris; Gelder, Frank B; Peterson, Johnny W; Sower, Laurie E; Cirino, Nick M

2007-01-01

212

Anthrax Protective Antigen Delivered by Salmonella enterica Serovar Typhi Ty21a Protects Mice from a Lethal Anthrax Spore Challenge  

Microsoft Academic Search

Bacillus anthracis, the etiological agent of anthrax disease, is a proven weapon of bioterrorism. Currently, the only licensed vaccine against anthrax in the United States is AVA Biothrax, which, although efficacious, suffers from several limitations. This vaccine requires six injectable doses over 18 months to stimulate protective immunity, requires a cold chain for storage, and in many cases has been

Manuel Osorio; Yanping Wu; Sunil Singh; Tod J. Merkel; Siba Bhattacharyya; Milan S. Blake; Dennis J. Kopecko

2009-01-01

213

Intramuscular delivery of adenovirus serotype 5 vector expressing humanized protective antigen induces rapid protection against anthrax that may bypass intranasally originated preexisting adenovirus immunity.  

PubMed

Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 10? infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD??) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax. PMID:24307239

Wu, Shipo; Zhang, Zhe; Yu, Rui; Zhang, Jun; Liu, Ying; Song, Xiaohong; Yi, Shaoqiong; Liu, Ju; Chen, Jianqin; Yin, Ying; Xu, Junjie; Hou, Lihua; Chen, Wei

2014-02-01

214

Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques  

Microsoft Academic Search

The authors examined the efficacy of Bacillus anthracis protective antigen (PA) combined with adjuvants as vaccines against an aerosol challenge of virulent anthrax spores in rhesus macaques. Adjuvants tested included i) aluminum hydroxide (Alhydrogel), ii) saponin QS-21 and iii) monophosphoryl lipid A (MPL) in squalene\\/ lecithin\\/Tween 80 emulsion (SLT). Animals were immunized once with either 50 ?g of recombinant PA

B. E. Ivins; M. L. M. Pitt; P. F. Fellows; J. W. Farchaus; G. E. Benner; D. M. Waag; S. F. Little; G. W. Anderson; P. H. Gibbs; A. M. Friedlander

1998-01-01

215

Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives.  

PubMed

Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme. PMID:24102525

Antonelli, Anthony C; Zhang, Yu; Golub, Lorne M; Johnson, Francis; Simon, Sanford R

2014-10-01

216

Further Insights into Brevetoxin Metabolism by de Novo Radiolabeling  

PubMed Central

The toxic dinoflagellate Karenia brevis, responsible for early harmful algal blooms in the Gulf of Mexico, produces many secondary metabolites, including potent neurotoxins called brevetoxins (PbTx). These compounds have been identified as toxic agents for humans, and they are also responsible for the deaths of several marine organisms. The overall biosynthesis of these highly complex metabolites has not been fully ascertained, even if there is little doubt on a polyketide origin. In addition to gaining some insights into the metabolic events involved in the biosynthesis of these compounds, feeding studies with labeled precursors helps to discriminate between the de novo biosynthesis of toxins and conversion of stored intermediates into final toxic products in the response to environmental stresses. In this context, the use of radiolabeled precursors is well suited as it allows working with the highest sensitive techniques and consequently with a minor amount of cultured dinoflagellates. We were then able to incorporate [U-14C]-acetate, the renowned precursor of the polyketide pathway, in several PbTx produced by K. brevis. The specific activities of PbTx-1, -2, -3, and -7, identified by High-Resolution Electrospray Ionization Mass Spectrometer (HRESIMS), were assessed by HPLC-UV and highly sensitive Radio-TLC counting. We demonstrated that working at close to natural concentrations of acetate is a requirement for biosynthetic studies, highlighting the importance of highly sensitive radiolabeling feeding experiments. Quantification of the specific activity of the four, targeted toxins led us to propose that PbTx-1 and PbTx-2 aldehydes originate from oxidation of the primary alcohols of PbTx-7 and PbTx-3, respectively. This approach will open the way for a better comprehension of the metabolic pathways leading to PbTx but also to a better understanding of their regulation by environmental factors. PMID:24918358

Calabro, Kevin; Guigonis, Jean-Marie; Teyssié, Jean-Louis; Oberhänsli, François; Goudour, Jean-Pierre; Warnau, Michel; Dechraoui Bottein, Marie-Yasmine; Thomas, Olivier P.

2014-01-01

217

Further insights into brevetoxin metabolism by de novo radiolabeling.  

PubMed

The toxic dinoflagellate Karenia brevis, responsible for early harmful algal blooms in the Gulf of Mexico, produces many secondary metabolites, including potent neurotoxins called brevetoxins (PbTx). These compounds have been identified as toxic agents for humans, and they are also responsible for the deaths of several marine organisms. The overall biosynthesis of these highly complex metabolites has not been fully ascertained, even if there is little doubt on a polyketide origin. In addition to gaining some insights into the metabolic events involved in the biosynthesis of these compounds, feeding studies with labeled precursors helps to discriminate between the de novo biosynthesis of toxins and conversion of stored intermediates into final toxic products in the response to environmental stresses. In this context, the use of radiolabeled precursors is well suited as it allows working with the highest sensitive techniques and consequently with a minor amount of cultured dinoflagellates. We were then able to incorporate [U-¹?C]-acetate, the renowned precursor of the polyketide pathway, in several PbTx produced by K. brevis. The specific activities of PbTx-1, -2, -3, and -7, identified by High-Resolution Electrospray Ionization Mass Spectrometer (HRESIMS), were assessed by HPLC-UV and highly sensitive Radio-TLC counting. We demonstrated that working at close to natural concentrations of acetate is a requirement for biosynthetic studies, highlighting the importance of highly sensitive radiolabeling feeding experiments. Quantification of the specific activity of the four, targeted toxins led us to propose that PbTx-1 and PbTx-2 aldehydes originate from oxidation of the primary alcohols of PbTx-7 and PbTx-3, respectively. This approach will open the way for a better comprehension of the metabolic pathways leading to PbTx but also to a better understanding of their regulation by environmental factors. PMID:24918358

Calabro, Kevin; Guigonis, Jean-Marie; Teyssié, Jean-Louis; Oberhänsli, François; Goudour, Jean-Pierre; Warnau, Michel; Bottein, Marie-Yasmine Dechraoui; Thomas, Olivier P

2014-06-01

218

Investigation of new dominant-negative inhibitors of anthrax protective antigen mutants for use in therapy and vaccination.  

PubMed

The lethal toxin (LeTx) of Bacillus anthracis plays a key role in the pathogenesis of anthrax. The protective antigen (PA) is a primary part of the anthrax toxin and forms LeTx by combination with lethal factor (LF). Phenylalanine-427 (F427) is crucial for PA function. This study was designed to discover potential novel therapeutic agents and vaccines for anthrax. This was done by screening PA mutants that were mutated at the F427 residue for a dominant-negative inhibitory (DNI) phenotype which was nontoxic but inhibited the toxicity of the wild-type LeTx. For this, PA residue F427 was first mutated to each of the other 19 naturally occurring amino acids. The cytotoxicity and DNI phenotypes of the mutated PA proteins were tested in the presence of 1 microg/ml LF in RAW264.7 cells and were shown to be dependent on the individual amino acid replacements. A total of 16 nontoxic mutants with various levels of DNI activity were identified in vitro. Among them, F427D and F427N mutants had the highest DNI activities in RAW264.7 cells. Both mutants inhibited LeTx intoxication in mice in a dose-dependent way. Furthermore, they induced a Th2-predominant immune response and protected mice against a challenge with five 50% lethal doses of LeTx. The protection was correlated mainly with a low level of interleukin-1 beta (IL-1 beta) and with high levels of PA-specific immunoglobulin G1, IL-6, and tumor necrosis factor alpha. Thus, PA DNI mutants, such as F427D and F427N mutants, may serve in the development of novel therapeutic agents and vaccines to fight B. anthracis infections. PMID:19620345

Cao, Sha; Guo, Aizhen; Liu, Ziduo; Tan, Yadi; Wu, Gaobing; Zhang, Chengcai; Zhao, Yaxing; Chen, Huanchun

2009-10-01

219

Generation of mouse polyclonal and human monoclonal antibodies against Bacillus anthracis toxin.  

PubMed

High titer antisera against the protective antigen (PA) from Bacillus anthracis were generated immunizing Balb/c mice two times intraperitoneally with PA in combination with lipopeptide adjuvant P3CSK4. The sera were able to protect the mouse macrophage cell line J774A.1 from an anthrax toxin challenge. We also tested the blood of anthrax vaccine-immunized persons for PA- and lethal factor (LF)-specific antibodies. An increased titer was found after three immunizations, and the sera were also able to protect the mouse macrophage cell line from a toxin challenge. For the preparation of human monoclonal antibodies, we used peripheral blood lymphocytes. After in vitro stimulation using PA or synthetic peptides derived from PA, B lymphocytes were immortalized by PEG fusion with the human mouse heteromyeloma cell line CB-F7. We obtained several clones producing high amounts of PA-specific immunoglobulin (Ig). PMID:15929604

Huber, M; Vor Dem Esche, U; Grunow, R; Bessler, W G

2005-01-01

220

Anthrax eTool: Protecting the Worksite against Terrorism  

MedlinePLUS

... FAQs | About OSHA OSHA Newsletter RSS Feeds What's New | Offices Home Workers Regulations Enforcement Data & Statistics Training Publications Newsroom Small Business Anti-Retaliation eTools Home : Anthrax Credits What is ...

221

[Anthrax meningoencephalitis: a case report and review of Turkish literature].  

PubMed

The incidence of anthrax is decreasing in Turkey, however, it is still endemic in some regions of the country. Although central nervous system involvement is rare in cases with anthrax, high mortality rates are significant. Here, we report a 46-years old woman who was anthrax meningoencephalitis. The patient was from Yozgat located in Central Anatolia, Turkey. Her history revealed that following peeling the skin of sheeps and consuming their meat a week ago, a lesion developed in her left forearm and she had been treated with penicilin G with the diagnosis of cutaneous anthrax in a local health center. The patient was admitted to the emergency room of our hospital due to increased headache and loss of conciousness and diagnosed as anthrax meningitis. Crytallized penicilin G (24 MU/day IV) and vancomycin (2 g/day IV) were initiated. The macroscopy of cerebrospinal fluid (CSF) sample was haemorrhagic, white blood cell count was 40/mm3 (80% of neutrophil) and Gram staining of CSF yielded abundant gram-positive bacilli. The diagnosis was confirmed by the isolation of Bacillus anthracis from CSF culture. Although the isolate was susceptible to penicillin and dexamethasone was added to the treatment, the patient died. Review of the Turkish literature revealed seven cases of anthrax with central nervous system involvement between 1980-2008. One of the patients was an 11-years old boy and the others were adults aged between 19 and 64 years. The source of the infection was skin in four patients and inhalation in one patient. The most common findings in all of the patients were inhabitance in rural area, haemorrhagic CSF and loss of all patients despite appropriate antibiotic therapy. In conclusion, anthrax meningitis and meningoencephalitis should be considered in the differential diagnosis of haemorrhagic meningitis in areas where anthrax is endemic and high rate of mortality despite appropriate therapy should always be kept in mind. PMID:20084923

Metan, Gökhan; Uysal, Burcu; Co?kun, Ramazan; Perçin, Duygu; Do?anay, Mehmet

2009-10-01

222

Anthrax: A disease of biowarfare and public health importance  

PubMed Central

Bioterrorism has received a lot of attention in the first decade of this century. Biological agents are considered attractive weapons for bioterrorism as these are easy to obtain, comparatively inexpensive to produce and exhibit widespread fear and panic than the actual potential of physical damage. Bacillus anthracis (B. anthracis), the etiologic agent of anthrax is a Gram positive, spore forming, non-motile bacterium. This is supposed to be one of the most potent BW agents because its spores are extremely resistant to natural conditions and can survive for several decades in the environment. B. anthracis spores enter the body through skin lesion (cutaneous anthrax), lungs (pulmonary anthrax), or gastrointestinal route (gastrointestinal anthrax) and germinate, giving rise to the vegetative form. Anthrax is a concern of public health also in many countries where agriculture is the main source of income including India. Anthrax has been associated with human history for a very long time and regained its popularity after Sept 2001 incidence in United States. The present review article describes the history, biology, life cycle, pathogenicity, virulence, epidemiology and potential of B. anthracis as biological weapon. PMID:25610847

Goel, Ajay Kumar

2015-01-01

223

Anthrax: A disease of biowarfare and public health importance.  

PubMed

Bioterrorism has received a lot of attention in the first decade of this century. Biological agents are considered attractive weapons for bioterrorism as these are easy to obtain, comparatively inexpensive to produce and exhibit widespread fear and panic than the actual potential of physical damage. Bacillus anthracis (B. anthracis), the etiologic agent of anthrax is a Gram positive, spore forming, non-motile bacterium. This is supposed to be one of the most potent BW agents because its spores are extremely resistant to natural conditions and can survive for several decades in the environment. B. anthracis spores enter the body through skin lesion (cutaneous anthrax), lungs (pulmonary anthrax), or gastrointestinal route (gastrointestinal anthrax) and germinate, giving rise to the vegetative form. Anthrax is a concern of public health also in many countries where agriculture is the main source of income including India. Anthrax has been associated with human history for a very long time and regained its popularity after Sept 2001 incidence in United States. The present review article describes the history, biology, life cycle, pathogenicity, virulence, epidemiology and potential of B. anthracis as biological weapon. PMID:25610847

Goel, Ajay Kumar

2015-01-16

224

Recent developments in monoclonal antibody radiolabeling techniques  

SciTech Connect

Monoclonal antibodies (MAbs) have shown the potential to serve as selective carriers of radionuclides to specific in vivo antigens. Accordingly, there has been an intense surge of research activity in an effort to develop and evaluate MAb-based radiopharmaceuticals for tumor imaging (radioimmunoscintigraphy) and therapy (radioimmunotherapy), as well as for diagnosing nonmalignant diseases. A number of problems have recently been identified, related to the MAbs themselves and to radiolabeling techniques, that comprise both the selectivity and the specificity of the in vivo distribution of radiolabeled MAbs. This paper will address some of these issues and primarily discuss recent developments in the techniques for radiolabeling monoclonal antibodies that may help resolve problems related to the poor in vivo stability of the radiolabel and may thus produce improved biodistribution. Even though many issues are identical with therapeutic radionuclides, the discussion will focus mainly on radioimmunoscintigraphic labels. 78 refs., 6 tabs.

Srivastava, S.C.; Mease, R.C.

1989-01-01

225

Multiple Imputation by Ordered Monotone Blocks with Application to the Anthrax Vaccine Research Program  

E-print Network

Multiple Imputation by Ordered Monotone Blocks with Application to the Anthrax Vaccine Research with missing values. The CDC Anthrax Vaccine Research Program (AVRP) dataset created new challenges for MI due

West, Mike

226

Screen-printed fluorescent sensors for rapid and sensitive anthrax biomarker detection.  

PubMed

Since the 2001 anthrax attacks, efforts have focused on the development of an anthrax detector with rapid response and high selectivity and sensitivity. Here, we demonstrate a fluorescence sensor for detecting anthrax biomarker with high sensitivity and selectivity using a screen-printing method. A lanthanide-ethylenediamine tetraacetic acid complex was printed on a flexible polyethersulfone film. Screen-printing deposition of fluorescent detecting moieties produced fluorescent patterns that acted as a visual alarm against anthrax. PMID:23518174

Lee, Inkyu; Oh, Wan-Kyu; Jang, Jyongsik

2013-05-15

227

Clinical Presentation of Inhalational Anthrax Following Bioterrorism Exposure Report of 2 Surviving Patients  

Microsoft Academic Search

The use of anthrax as a weapon of biological terrorism has moved from theory to reality in recent weeks. Following processing of a letter containing anthrax spores that had been mailed to a US senator, 5 cases of inhalational anthrax have occurred among postal workers employed at a major postal facility in Wash- ington, DC. This report details the clinical

Thom A. Mayer; Susan Bersoff-Matcha; Cecele Murphy; James Earls; Scott Harper; Denis Pauze; Michael Nguyen; Jonathan Rosenthal; Donald Cerva; Glenn Druckenbrod; Dan Hanfling; Naaz Fatteh; Anthony Napoli; Ashna Nayyar; Elise L. Berman

228

Modeling Clinician Detection Time of a Disease Outbreak Due to Inhalational Anthrax  

E-print Network

Modeling Clinician Detection Time of a Disease Outbreak Due to Inhalational Anthrax Christina of anthrax spores, when the clinicians only have access to traditional clinical information (e diagnose a patient as having inhala- tion anthrax (IA). One way involves obtaining a chest radiograph

Wong, Weng-Keen

229

Meeting the Challenge of Interdependent Critical Networks under Threat : The Paris Initiative, "Anthrax and Beyond"  

E-print Network

, "Anthrax and Beyond" Patrick LAGADEC Erwann MICHEL-KERJAN June 2004 Cahier n° 2004-014 ECOLE POLYTECHNIQUE Initiative, "Anthrax and Beyond"1 Patrick LAGADEC2 Erwann MICHEL-KERJAN3 June 2004 Cahier n° 2004 the creation of specific partnerships. In the aftermath of 2001 Anthrax crisis we suggested launching

Paris-Sud XI, Université de

230

Multi-Reward Policies for Medical Applications: Anthrax Attacks and Smart Wheelchairs  

E-print Network

Multi-Reward Policies for Medical Applications: Anthrax Attacks and Smart Wheelchairs Harold Soh in the medical domain: anthrax re- sponse and smart-wheelchair control. For the first problem, we use a discrete or objectives to con- sider. For example, during the early stages of a possible anthrax outbreak, information

Demiris, Yiannis

231

Investigation and Control of Anthrax Outbreak at the Human–Animal Interface, Bhutan, 2010  

PubMed Central

In 2010, we investigated anthrax outbreak in Bhutan. A total of 43 domestic animals died, and cutaneous anthrax developed in 9 persons, and 1 died. All affected persons had contact with the carcasses of infected animals. Comprehensive preparedness and response guidelines are needed to increase public awareness of anthrax in Bhutan. PMID:25147965

Thapa, Nirmal K.; Wangdi, Karma; Dorji, Tshering; Dorjee, Jambay; Marston, Chung K.; Hoffmaster, Alex R.

2014-01-01

232

Laboratory Aspects of Bioterrorism-related Anthrax - from Identification to Molecular Subtyping to Microbial Forensics  

Microsoft Academic Search

During the bioterrorism-associated anthrax investigation of 2001 in the United States, 11 patients were diagnosed with inhalational anthrax and 11 more with the cutaneous forms of the disease. Over 125,000 specimens were processed at laboratories of the Laboratory Response Network including those at the Centers for Disease Control and Prevention. Although the 2001 anthrax investigation initially began as a public

Tanja Popoviæ; Mindy Glass

2003-01-01

233

Public response to an anthrax attack: reactions to mass prophylaxis in a scenario involving inhalation anthrax from an unidentified source.  

PubMed

An attack with Bacillus anthracis ("anthrax") is a known threat to the United States. When weaponized, it can cause inhalation anthrax, the deadliest form of the disease. Due to the rapid course of inhalation anthrax, delays in initiation of antibiotics may decrease survival chances. Because a rapid response would require cooperation from the public, there is a need to understand the public's response to possible mass dispensing programs. To examine the public's response to a mass prophylaxis program, this study used a nationally representative poll of 1,092 adults, supplemented by a targeted focus on 3 metropolitan areas where anthrax attacks occurred in 2001: New York City (n=517), Washington, DC (n=509), and Trenton/Mercer County, NJ (n=507). The poll was built around a "worst-case scenario" in which cases of inhalation anthrax are discovered without an identified source and the entire population of a city or town is asked to receive antibiotic prophylaxis within a 48-hour period. Findings from this poll provide important signs of public willingness to comply with public health recommendations for obtaining antibiotics from a dispensing site, although they also indicate that public health officials may face several challenges to compliance, including misinformation about the contagiousness of inhalation anthrax; fears about personal safety in crowds; distrust of government agencies to provide sufficient, safe, and effective medicine; and hesitation about ingesting antibiotic pills after receiving them. In general, people living in areas where anthrax attacks occurred in 2001 had responses similar to those of the nation as a whole. PMID:21819225

SteelFisher, Gillian; Blendon, Robert; Ross, Laura J; Collins, Blanche C; Ben-Porath, Eran N; Bekheit, Mark M; Mailhot, Johanna R

2011-09-01

234

Anthrax vaccine adsorbed: further evidence supporting continuing the vaccination series rather than restarting the series when doses are delayed.  

PubMed

Whether to restart or continue the series when anthrax vaccine doses are missed is a frequent medical management problem. We applied the noninferiority analysis model to this prospective study comparing the Bacillus anthracis protective antigen (PA) IgG antibody response and lethal toxin neutralization activity at day 28 to the anthrax vaccine adsorbed (AVA) (Biothrax®) administered on schedule or delayed. A total of 600 volunteers were enrolled: 354 in the on-schedule cohort; 246 in the delayed cohort. Differences were noted in immune responses between cohorts (p<0.0001) and among the racial categories (p<0.0001). Controlling for covariates, the delayed cohort was non-inferior to the on-schedule cohort for the rate of 4-fold rise in both anti-PA IgG concentration (p<0.0001) and TNA ED50 titers (p<0.0001); as well as the mean log10-transformed anti-PA IgG concentration (p<0.0001) and the mean log10-transformed TNA ED50 titers (p<0.0001). Providing a missed AVA dose after a delay as long as 5-7 years, elicits anti-PA IgG antibody and TNA ED50 responses that are robust and non-inferior to the responses observed when the 6-month dose is given on-schedule. These important data suggest it is not necessary to restart the series when doses of the anthrax vaccine are delayed as long as 5 or more years. PMID:24837771

Pittman, Phillip R; Cavicchia, M A; Kingsbury, J L; Johnson, N A; Barrera-Oro, J G; Schmader, T; Korman, L; Quinn, X; Ranadive, M

2014-09-01

235

Radiolabeled Nanoparticles for Multimodality Tumor Imaging  

PubMed Central

Each imaging modality has its own unique strengths. Multimodality imaging, taking advantages of strengths from two or more imaging modalities, can provide overall structural, functional, and molecular information, offering the prospect of improved diagnostic and therapeutic monitoring abilities. The devices of molecular imaging with multimodality and multifunction are of great value for cancer diagnosis and treatment, and greatly accelerate the development of radionuclide-based multimodal molecular imaging. Radiolabeled nanoparticles bearing intrinsic properties have gained great interest in multimodality tumor imaging over the past decade. Significant breakthrough has been made toward the development of various radiolabeled nanoparticles, which can be used as novel cancer diagnostic tools in multimodality imaging systems. It is expected that quantitative multimodality imaging with multifunctional radiolabeled nanoparticles will afford accurate and precise assessment of biological signatures in cancer in a real-time manner and thus, pave the path towards personalized cancer medicine. This review addresses advantages and challenges in developing multimodality imaging probes by using different types of nanoparticles, and summarizes the recent advances in the applications of radiolabeled nanoparticles for multimodal imaging of tumor. The key issues involved in the translation of radiolabeled nanoparticles to the clinic are also discussed. PMID:24505237

Xing, Yan; Zhao, Jinhua; Conti, Peter S.; Chen, Kai

2014-01-01

236

Dances with anthrax: wolves (Canis lupus) kill anthrax bacteremic plains bison (Bison bison bison) in southwestern Montana.  

PubMed

Bacillus anthracis, the cause of anthrax, was recovered from two plains bison (Bison bison bison) cows killed by wolves (Canis lupus) in Montana, USA, without associated wolf mortality in July 2010. This bison herd experienced an epizootic in summer 2008, killing ? 8% of the herd, the first documented in the region in several decades. No wolf deaths were associated with the 2008 event. Surveillance has continued since 2008, with research, ranch, and wildlife personnel diligent during summer. As part of this, we tested wolf-killed bison and elk (Cervus elaphus) for anthrax during the 2010 summer using lateral flow immunochromatographic assays (LFIA). Two bison cows were positive for protective antigen, confirming active bacteremia. The LFIA results were confirmed with traditional bacteriology recovering viable B. anthracis. No wolf fatalities were associated with the bison deaths, despite consuming the meat. Low-level anthrax occurrence in large, rough terrain landscapes remains difficult to detect, particularly if mortality in the herbivore host is not a consequence of infection. In these instances, surveillance of predators with large home ranges may provide a more sensitive indicator of anthrax emergence or reemergence in such systems. Though speculative, it is also possible that anthrax infection in the bison increased predation risk. These results also suggest B. anthracis remains a threat to wildlife and associated livestock in southwestern Montana. PMID:24484485

Blackburn, Jason K; Asher, Valpa; Stokke, Stephen; Hunter, David L; Alexander, Kathleen A

2014-04-01

237

Sverdlovsk Anthrax Outbreak: An Educational Case Study  

NASA Astrophysics Data System (ADS)

In April and May of 1979 an Anthrax epidemic broke out in the city of Sverdlovsk (now Ekaterinburg) in the former Soviet Union. Sixty-four people were reported to have died from the outbreak, although there is still debate concerning the actual number of victims. While Soviet officials initially attributed this outbreak to contaminated meat, the US Government maintained that the outbreak was due to a leakage from a biological weapons facility. We have created and implemented an undergraduate educational exercise based on the forensic analysis of this event. Students were provided case data of the victims, area satellite images and meteorological data. One goal of the exercise was for students to reconstruct the most probable scenario of events through valid inference based on the limited information and uncertainties associated with the data set. Another goal was to make students sensitive to issues of biological weapons and bioterrorism. The exercise was highly rated by students even before the events of September 11. There is a clear need to educate students, particularly in the sciences, to be aware of the signatures of terrorist activities. Evidence of terrorist activities is more likely to appear from unintended discoveries than from active intelligence gathering. We believe our national security can be enhanced by sensitizing those that monitor the natural environment to the signatures of terrorist activities through the types of educational exercises that we have developed.

Steele, S. J.; van der Vink, G.

2002-05-01

238

Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors.  

PubMed

Dendrimers are unique highly branched macromolecules with numerous groundbreaking biomedical applications under development. Here we identified poly(amido amine) (PAMAM) dendrimers as novel blockers for the pore-forming B components of the binary anthrax toxin (PA63) and Clostridium botulinum C2 toxin (C2IIa). These pores are essential for delivery of the enzymatic A components of the internalized toxins from endosomes into the cytosol of target cells. We demonstrate that at low ?M concentrations cationic PAMAM dendrimers block PA63 and C2IIa to inhibit channel-mediated transport of the A components, thereby protecting HeLa and Vero cells from intoxication. By channel reconstitution and high-resolution current recording, we show that the PAMAM dendrimers obstruct transmembrane PA63 and C2IIa pores in planar lipid bilayers at nM concentrations. These findings suggest a new potential role for the PAMAM dendrimers as effective polyvalent channel-blocking inhibitors, which can protect human target cells from intoxication with binary toxins from pathogenic bacteria. PMID:24954629

Förstner, Philip; Bayer, Fabienne; Kalu, Nnanya; Felsen, Susanne; Förtsch, Christina; Aloufi, Abrar; Ng, David Y W; Weil, Tanja; Nestorovich, Ekaterina M; Barth, Holger

2014-07-14

239

Structure-based redesign of an edema toxin inhibitor  

PubMed Central

Edema Factor toxin (EF) of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3?,5?-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-Oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an oral dosage of 15 ?g/mouse. Here, molecular docking was used to predict improvements in potency and solubility of new derivatives of compound 1 in inhibiting edema toxin-(ET) catalyzed stimulation of cyclic AMP production in murine monocyte-macrophage cells (RAW 264.7). Structure-activity relationship (SAR) analysis of the bioassay results for 22 compounds indicated positions important for activity. Several derivatives demonstrated superior pharmacological properties compared to our initial lead compound, and are promising candidates to treat anthrax infections and diarrheal diseases induced by toxin-producing bacteria. PMID:22154558

Chen, Deliang; Ma, Lili; Kanalas, John J.; Gao, Jian; Pawlik, Jennifer; Jimenez, Maria Estrella; Walter, Mary A.; Peterson, Johnny W.; Gilbertson, Scott R.; Schein, Catherine H.

2011-01-01

240

Shared binding sites in Lepidoptera for Bacillus thuringiensis Cry1Ja and Cry1A toxins.  

PubMed

Bacillus thuringiensis toxins act by binding to specific target sites in the insect midgut epithelial membrane. The best-known mechanism of resistance to B. thuringiensis toxins is reduced binding to target sites. Because alteration of a binding site shared by several toxins may cause resistance to all of them, knowledge of which toxins share binding sites is useful for predicting cross-resistance. Conversely, cross-resistance among toxins suggests that the toxins share a binding site. At least two strains of diamondback moth (Plutella xylostella) with resistance to Cry1A toxins and reduced binding of Cry1A toxins have strong cross-resistance to Cry1Ja. Thus, we hypothesized that Cry1Ja shares binding sites with Cry1A toxins. We tested this hypothesis in six moth and butterfly species, each from a different family: Cacyreus marshalli (Lycaenidae), Lobesia botrana (Tortricidae), Manduca sexta (Sphingidae), Pectinophora gossypiella (Gelechiidae), P. xylostella (Plutellidae), and Spodoptera exigua (Noctuidae). Although the extent of competition varied among species, experiments with biotinylated Cry1Ja and radiolabeled Cry1Ac showed that Cry1Ja and Cry1Ac competed for binding sites in all six species. A recent report also indicates shared binding sites for Cry1Ja and Cry1A toxins in Heliothis virescens (Noctuidae). Thus, shared binding sites for Cry1Ja and Cry1A occur in all lepidopteran species tested so far. PMID:11722929

Herrero, S; González-Cabrera, J; Tabashnik, B E; Ferré, J

2001-12-01

241

Botulinum Toxin Therapy  

MedlinePLUS

... toxin Botulinum toxin therapy Also called botulinum rejuvenation Brand names: Botox® Cosmetic, Dysport®, MYOBLOC®, and XEOMIN® When ... M N O P Q R S T U V W X Y Z Advertising, marketing and sponsorships ...

242

*CYANOBACTERIA AND THEIR TOXINS  

EPA Science Inventory

Cyanobacteria, or blue-green algae, are naturally-occurring contaminants of surface waters worldwide. These photosynthesizing prokaryotes thrive in warm, shallow, nutrient-rich waters. Many produce potent toxins as secondary metabolites. Cyanobacteria toxins have been document...

243

Transient Co-Expression of Post-Transcriptional Gene Silencing Suppressors for Increased in Planta Expression of a Recombinant Anthrax Receptor Fusion Protein  

PubMed Central

Potential epidemics of infectious diseases and the constant threat of bioterrorism demand rapid, scalable, and cost-efficient manufacturing of therapeutic proteins. Molecular farming of tobacco plants provides an alternative for the recombinant production of therapeutics. We have developed a transient production platform that uses Agrobacterium infiltration of Nicotiana benthamiana plants to express a novel anthrax receptor decoy protein (immunoadhesin), CMG2-Fc. This chimeric fusion protein, designed to protect against the deadly anthrax toxins, is composed of the von Willebrand factor A (VWA) domain of human capillary morphogenesis 2 (CMG2), an effective anthrax toxin receptor, and the Fc region of human immunoglobulin G (IgG). We evaluated, in N. benthamiana intact plants and detached leaves, the expression of CMG2-Fc under the control of the constitutive CaMV 35S promoter, and the co-expression of CMG2-Fc with nine different viral suppressors of post-transcriptional gene silencing (PTGS): p1, p10, p19, p21, p24, p25, p38, 2b, and HCPro. Overall, transient CMG2-Fc expression was higher on intact plants than detached leaves. Maximum expression was observed with p1 co-expression at 3.5 days post-infiltration (DPI), with a level of 0.56 g CMG2-Fc per kg of leaf fresh weight and 1.5% of the total soluble protein, a ten-fold increase in expression when compared to absence of suppression. Co-expression with the p25 PTGS suppressor also significantly increased the CMG2-Fc expression level after just 3.5 DPI. PMID:21954339

Arzola, Lucas; Chen, Junxing; Rattanaporn, Kittipong; Maclean, James M.; McDonald, Karen A.

2011-01-01

244

Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults.  

PubMed

The Centers for Disease Control and Prevention convened panels of anthrax experts to review and update guidelines for anthrax postexposure prophylaxis and treatment. The panels included civilian and military anthrax experts and clinicians with experience treating anthrax patients. Specialties represented included internal medicine, pediatrics, obstetrics, infectious disease, emergency medicine, critical care, pulmonology, hematology, and nephrology. Panelists discussed recent patients with systemic anthrax; reviews of published, unpublished, and proprietary data regarding antimicrobial drugs and anthrax antitoxins; and critical care measures of potential benefit to patients with anthrax. This article updates antimicrobial postexposure prophylaxis and antimicrobial and antitoxin treatment options and describes potentially beneficial critical care measures for persons with anthrax, including clinical procedures for infected nonpregnant adults. Changes from previous guidelines include an expanded discussion of critical care and clinical procedures and additional antimicrobial choices, including preferred antimicrobial drug treatment for possible anthrax meningitis. PMID:24447897

Hendricks, Katherine A; Wright, Mary E; Shadomy, Sean V; Bradley, John S; Morrow, Meredith G; Pavia, Andy T; Rubinstein, Ethan; Holty, Jon-Erik C; Messonnier, Nancy E; Smith, Theresa L; Pesik, Nicki; Treadwell, Tracee A; Bower, William A

2014-02-01

245

Centers for Disease Control and Prevention Expert Panel Meetings on Prevention and Treatment of Anthrax in Adults  

PubMed Central

The Centers for Disease Control and Prevention convened panels of anthrax experts to review and update guidelines for anthrax postexposure prophylaxis and treatment. The panels included civilian and military anthrax experts and clinicians with experience treating anthrax patients. Specialties represented included internal medicine, pediatrics, obstetrics, infectious disease, emergency medicine, critical care, pulmonology, hematology, and nephrology. Panelists discussed recent patients with systemic anthrax; reviews of published, unpublished, and proprietary data regarding antimicrobial drugs and anthrax antitoxins; and critical care measures of potential benefit to patients with anthrax. This article updates antimicrobial postexposure prophylaxis and antimicrobial and antitoxin treatment options and describes potentially beneficial critical care measures for persons with anthrax, including clinical procedures for infected nonpregnant adults. Changes from previous guidelines include an expanded discussion of critical care and clinical procedures and additional antimicrobial choices, including preferred antimicrobial drug treatment for possible anthrax meningitis. PMID:24447897

Hendricks, Katherine A.; Wright, Mary E.; Shadomy, Sean V.; Bradley, John S.; Morrow, Meredith G.; Pavia, Andy T.; Rubinstein, Ethan; Holty, Jon-Erik C.; Messonnier, Nancy E.; Smith, Theresa L.; Pesik, Nicki; Treadwell, Tracee A.

2014-01-01

246

Growth medium for the rapid isolation and identification of anthrax  

NASA Astrophysics Data System (ADS)

Anthrax has been recognized as a highly likely biological warfare or terrorist agent. The purpose of this work was to design a culture technique to rapidly isolate and identify `live' anthrax. In liquid or solid media form, 3AT medium (3-amino-L-tyrosine, the main ingredient) accelerated germination and growth of anthrax spores in 5 to 6 hours to a point expected at 18 to 24 hours with ordinary medium. During accelerated growth, standard definitive diagnostic tests such as sensitivity to lysis by penicillin or bacteriophage can be run. During this time, the bacteria synthesized a fluorescent and thermochemiluminescent polymer. Bacteria captured by specific antibody are, therefore, already labeled. Because living bacteria are required to generate the polymer, the test converts immunoassays for anthrax into viability assays. Furthermore, the polymer formation leads to the death of the vegetative form and non-viability of the spores produced in the medium. By altering the formulation of the medium, other microbes and even animal and human cells can be grown in it and labeled (including viruses grown in the animal or human cells).

Kiel, Johnathan L.; Parker, Jill E.; Grubbs, Teri R.; Alls, John L.

2000-07-01

247

Quantitative Pathology of Inhalational Anthrax I: Quantitative Microscopic Findings  

Microsoft Academic Search

Forty-one cases of documented inhalational anthrax from the Sverdlovsk epidemic of 1979 traced to release of aerosols of Bacillus anthracis at a secret biologic-agent production facility were evaluated by semiquantitative histopathologic analysis of tissue concentrations of organisms, inflammation, hemorrhage, and other lesions in the mediastinum, mediastinal lymph nodes, bronchi, lungs, heart, spleen, liver, intestines, kidneys, adrenal glands, and central nervous

Lev M. Grinberg; Faina A. Abramova; Olga V. Yampolskaya; David H. Walker; Jerome H. Smith

2001-01-01

248

Space Technology to Device that Destroys Pathogens Such As Anthrax  

NASA Technical Reports Server (NTRS)

This is a photo of a technician at KES Science and Technology Inc., in Kernesaw, Georgia, assembling the AiroCide Ti02, an anthrax-killing device about the size of a small coffee table. The anthrax-killing air scrubber, AiroCide Ti02, is a tabletop-size metal box that bolts to office ceilings or walls. Its fans draw in airborne spores and airflow forces them through a maze of tubes. Inside, hydroxyl radicals (OH-) attack and kill pathogens. Most remaining spores are destroyed by high-energy ultraviolet photons. Building miniature greenhouses for experiments on the International Space Station has led to the invention of this device that annihilates anthrax, a bacteria that can be deadly when inhaled. The research enabling the invention started at the University of Wisconsin's (Madison) Center for Space Automation and Robotics (WCSAR), one of 17 NASA Commercial Space Centers. A special coating technology used in this anthrax-killing invention is also being used inside WCSAR-built plant growth units on the International Space Station. This commercial research is managed by the Space Product Development Program at the Marshall Space Flight Center.

2002-01-01

249

Microfluidic radiolabeling of biomolecules with PET radiometals  

PubMed Central

Introduction A robust, versatile and compact microreactor has been designed, fabricated and tested for the labeling of bifunctional chelate conjugated biomolecules (BFC-BM) with PET radiometals. Methods The developed microreactor was used to radiolabel a chelate, either 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) that had been conjugated to cyclo(Arg-Gly-Asp-DPhe-Lys) peptide, with both 64Cu and 68Ga respectively. The microreactor radiolabeling conditions were optimized by varying temperature, concentration and residence time. Results Direct comparisons between the microreactor approach and conventional methods showed improved labeling yields and increased reproducibility with the microreactor under identical labeling conditions, due to enhanced mass and heat transfer at the microscale. More importantly, over 90% radiolabeling yields (incorporation of radiometal) were achieved with a 1:1 stoichiometry of bifunctional chelate biomolecule conjugate (BFC-BM) to radiometal in the microreactor, which potentially obviates extensive chromatographic purification that is typically required to remove the large excess of unlabeled biomolecule in radioligands prepared using conventional methods. Moreover, higher yields for radiolabeling of DOTA-functionalized BSA protein (Bovine Serum Albumin) were observed with 64Cu/68Ga using the microreactor, which demonstrates the ability to label both small and large molecules. Conclusions A robust, reliable, compact microreactor capable of chelating radiometals with common chelates has been developed and validated. Based on our radiolabeling results, the reported microfluidic approach overall outperforms conventional radiosynthetic methods, and is a promising technology for the radiometal labeling of commonly utilized BFC-BM in aqueous solutions. PMID:23078875

Zeng, Dexing; Desai, Amit V.; Ranganathan, David; Wheeler, Tobias D.; Kenis, Paul J. A.; Reichert, David E.

2012-01-01

250

Radiolabeled antibodies for therapy of infectious diseases  

PubMed Central

Novel approaches to treatment of infectious diseases are urgently needed. This need has resulted in renewing the interest in antibodies for therapy of infectious diseases. Radioimmunotherapy (RIT) is a cancer treatment modality, which utilizes radiolabeled monoclonal antibodies (mAbs). During the last decade we have translated RIT into the field of experimental fungal, bacterial and HIV infections. In addition, successful proof of principle experiments with radiolabeled pan-antibodies that bind to antigens shared by major pathogenic fungi were performed in vitro. The armamentarium of pan-antibodies would result in reducing the dependence on microorganism-specific antibodies and thus would speed up the development of RIT of infections. We believe that the time is ripe for deploying RIT into the clinic to combat infectious diseases. PMID:25599011

Dadachova, Ekaterina; Casadevall, Arturo

2014-01-01

251

Clinical and epidemiological investigation of a fatal anthrax case in China.  

PubMed

Anthrax is a recessive infectious disease caused by the bacterium Bacillus anthracis, and is primarily a zoonotic disease. Until recently, Bacillus anthracis infections were relatively infrequent and confined to agrarian communities in underdeveloped countries. No anthrax cases were reported in Changchun City in the past few decades until a male patient from the Inner Mongolia Autonomous Region presented the anthrax disease manifestation. This paper describes an anthrax patient's diagnosis, isolation and treatment which involved institutions in two different Chinese provinces; the foci epidemiological investigation alongside with the outbreak management process, which is of great significance to control the spread of the recessive infection is also described. PMID:25699498

Chen, Haiying; Bao, Wanguo; Wang, Yang; Zhang, Kaiyu; Wang, Feng

2015-02-01

252

Integrated MOSFET-Embedded-Cantilever-Based Biosensor Characteristic for Detection of Anthrax Simulant  

SciTech Connect

In this work, MOSFET-embedded cantilevers are configured as microbial sensors for detection of anthrax simulants, Bacillus thuringiensis. Anthrax simulants attached to the chemically treated gold-coated cantilever cause changes in the MOSFET drain current due to the bending of the cantilever which indicates the detection of anthrax simulant. Electrical properties of the anthrax simulant are also responsible for the change in the drain current. The test results suggest a detection range of 10 L of stimulant test solution (a suspension population of 1.3 107 colony-forming units/mL diluted in 40% ethanol and 60% deionized water) with a linear response of 31 A/ L.

Mostafa, Salwa [University of Tennessee, Knoxville (UTK); Lee, Ida [ORNL; Islam, Syed K [University of Tennessee, Knoxville (UTK); Eliza, Sazia A. [University of Tennessee, Knoxville (UTK); Shekhawat, Gajendra [Northwestern University, Evanston; Dravid, Vinayak [Northwestern University, Evanston; Tulip, Fahmida S [ORNL

2011-01-01

253

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model.  

PubMed

AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 10(7), 1.5 × 10(9), or 3.5 × 10(10) viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 10(10) viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. PMID:25673303

Krishnan, Vyjayanthi; Andersen, Bo H; Shoemaker, Christine; Sivko, Gloria S; Tordoff, Kevin P; Stark, Gregory V; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew; Roberts, M Scot

2015-04-01

254

Bacillus anthracis Edema Toxin Suppresses Human Macrophage Phagocytosis and Cytoskeletal Remodeling via the Protein Kinase A and Exchange Protein Activated by Cyclic AMP Pathways  

Microsoft Academic Search

Bacillus anthracis, the etiological agent of anthrax, is a gram-positive spore-forming bacterium. It produces edema toxin (EdTx), a powerful adenylate cyclase that increases cyclic AMP (cAMP) levels in host cells. Because other cAMP-increasing agents inhibit key macrophage (M) functions, such as phagocytosis, it was hypothesized that EdTx would exhibit similar suppressive activities. Our previous GeneChip data showed that EdTx downregulated

Linsey A. Yeager; Ashok K. Chopra; Johnny W. Peterson

2009-01-01

255

Radiolabeled Metaiodobenzylguanidine for the Treatment of Neuroblastoma  

PubMed Central

Introduction Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors. Methods The available English language literature was reviewed for original research investigating in vitro, in vivo, and clinical applications of radiolabeled MIBG for neuroblastoma. Results MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with 131I-MIBG showing enhanced activity in larger tumors compared to 125I-MIBG. Clinical studies of 131I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30–40% with 131I-MIBG in this population. More recent studies have focused on the use of 131I-MIBG in combination with chemotherapy or myeloablative regimens. Conclusions 131I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease. PMID:18707633

DuBois, Steven G.; Matthay, Katherine K.

2008-01-01

256

SPECT assay of radiolabeled monoclonal antibodies  

SciTech Connect

The accurate determination of the biodistribution of radiolabeled monoclonal antibodies (MoAbs) is important for calculation of dosimetry and evaluation of pharmacokinetic variables such as antibody dose and route of administration. The hypothesis of this application is that the biodistribution of radiolabeled monoclonal antibodies (MoAbs) can be quantitatively determined using single photon emission computed tomography (SPECT). The major thrusts during the third year include the continued development and evaluation of improved 3D SPECT acquisition and reconstruction approaches to improve quantitative imaging of radiolabeled monoclonal antibodies (MoAbs), and the implementation and evaluation of algorithms to register serial SPECT image data sets, or to register 3D SPECT images with 3D image data sets acquired from positron emission tomography (PEI) and magnetic resonance images (MRI). The research has involved the investigation of statistical models and iterative reconstruction algorithms that accurately account for the physical characteristics of the SPECT acquisition system. It is our belief that SPECT quantification can be improved by accurately modeling the physical processes such as attenuation, scatter, geometric collimator response, and other factors that affect the measured projection data.

Jaszczak, R.J.

1992-02-01

257

Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity  

PubMed Central

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified. PMID:24788397

Ascough, Stephanie; Ingram, Rebecca J.; Chu, Karen K.; Reynolds, Catherine J.; Musson, Julie A.; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J.; Gallagher, Theresa B.; Dyson, Hugh; Williamson, E. Diane; Robinson, John H.; Maillere, Bernard; Boyton, Rosemary J.; Altmann, Daniel M.

2014-01-01

258

Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene (ANTXR2)  

PubMed Central

Objectives ANTXR2 variants have been associated with ankylosing spondylitis (AS) in two previous genome-wide association studies (GWAS) (p?9×10?8). However, a genome-wide significant association (p<5×10?8) was not observed. We conducted a more comprehensive analysis of ANTXR2 in an independent UK sample to confirm and refine this association. Methods A replication study was carried out with 2978 cases and 8365 controls. Then, these were combined with non-overlapping samples from the two previous GWAS in a meta-analysis. Human leukocyte antigen (HLA)-B27 stratification was also performed to test for ANTXR2-HLA-B27 interaction. Results Out of nine single nucleotide polymorphisms (SNP) in the study, five SNPs were nominally associated (p<0.05) with AS in the replication dataset. In the meta-analysis, eight SNPs showed evidence of association, the strongest being with rs12504282 (OR=0.88, p=6.7×10?9). Seven of these SNPs showed evidence for association in the HLA-B27-positive subgroup, but none was associated with HLA-B27-negative AS. However, no statistically significant interaction was detected between HLA-B27 and ANTXR2 variants. Conclusions ANTXR2 variants are clearly associated with AS. The top SNPs from two previous GWAS (rs4333130 and rs4389526) and this study (rs12504282) are in strong linkage disequilibrium (r2?0.76). All are located near a putative regulatory region. Further studies are required to clarify the role played by these ANTXR2 variants in AS. PMID:25169729

Karaderi, T; Keidel, S M; Pointon, J J; Appleton, L H; Brown, M A; Evans, D M; Wordsworth, B P

2014-01-01

259

Delivery of Antibody Mimics into Mammalian Cells via Anthrax Toxin Protective Antigen  

E-print Network

Antibody mimics have significant scientific and therapeutic utility for the disruption of protein–protein interactions inside cells; however, their delivery to the cell cytosol remains a major challenge. Here we show that ...

Liao, Xiaoli

260

Comparative efficacy of Bacillus anthracis live spore vaccine and protective antigen vaccine against anthrax in the guinea pig.  

PubMed Central

Several strains of Bacillus anthracis have been reported previously to cause fatal infection in immunized guinea pigs. In this study, guinea pigs were immunized with either a protective antigen vaccine or a live Sterne strain spore vaccine, then challenged with virulent B. anthracis strains isolated from various host species from the United States and foreign sources. Confirmation of previously reported studies (which used only protective antigen vaccines) was made with the identification of 9 of the 27 challenge isolates as being vaccine resistant. However, guinea pigs immunized with the live Sterne strain spore vaccine were fully protected against these nine isolates. In experiments designed to determine the basis of vaccine resistance, guinea pigs which were immunized with individual toxin components and which demonstrated enzyme-linked immunosorbent assay antibody titers comparable to those induced by Sterne strain vaccine were not protected when challenged with a vaccine-resistant isolate. We concluded that antibodies to toxin components may not be sufficient to provide protection against all strains of B. anthracis and that other antigens may play a role in active immunity. As a practical matter, it follows that the efficacy of anthrax vaccines must be tested by using vaccine-resistant isolates if protection against all possible challenge strains is to be assured. PMID:3084385

Little, S F; Knudson, G B

1986-01-01

261

Impedance spectroscopy for the detection and identification of unknown toxins  

NASA Astrophysics Data System (ADS)

Advancements in biological and chemical warfare has allowed for the creation of novel toxins necessitating a universal, real-time sensor. We have used a function-based biosensor employing impedance spectroscopy using a low current density AC signal over a range of frequencies (62.5 Hz-64 kHz) to measure the electrical impedance of a confluent epithelial cell monolayer at 120 sec intervals. Madin Darby canine kidney (MDCK) epithelial cells were grown to confluence on thin film interdigitated gold electrodes. A stable impedance measurement of 2200 ? was found after 24 hrs of growth. After exposure to cytotoxins anthrax lethal toxin and etoposide, the impedance decreased in a linear fashion resulting in a 50% drop in impedance over 50hrs showing significant difference from the control sample (~20% decrease). Immunofluorescent imaging showed that apoptosis was induced through the addition of toxins. Similarities of the impedance signal shows that the mechanism of cellular death was the same between ALT and etoposide. A revised equivalent circuit model was employed in order to quantify morphological changes in the cell monolayer such as tight junction integrity and cell surface area coverage. This model showed a faster response to cytotoxin (2 hrs) compared to raw measurements (20 hrs). We demonstrate that herein that impedance spectroscopy of epithelial monolayers serves as a real-time non-destructive sensor for unknown pathogens.

Riggs, B. C.; Plopper, G. E.; Paluh, J. L.; Phamduy, T. B.; Corr, D. T.; Chrisey, D. B.

2012-06-01

262

[Hemolysis of Scolopendra toxins].  

PubMed

The hemolysis of toxins from alive Scolopendra subspinipes mutilans, medicinal material of Scolopendra subspimipes mutilans and S. multidens have been compared. The result shows that all the toxins have hemolytic activity. The hemolytic activity of the toxin from the medicinal materials of S. subspinipes mutilans is obviously lower than that from alive ones, and that from fresh medicinal materials are twice as high that from old ones, and that from S. multidens is higher than that from S. subspinipes multilans. PMID:12572496

Deng, F; Fang, H; Wang, K

1997-01-01

263

Identification and validation of a linear protective neutralizing epitope in the ?-pore domain of alpha toxin.  

PubMed

The plethora of virulence factors associated with Staphylococcus aureus make this bacterium an attractive candidate for a molecularly-designed epitope-focused vaccine. This approach, which necessitates the identification of neutralizing epitopes for incorporation into a vaccine construct, is being evaluated for pathogens where conventional approaches have failed to elicit protective humoral responses, like HIV-1 and malaria, but may also hold promise for pathogens like S. aureus, where the elicitation of humoral immunity against multiple virulence factors may be required for development of an effective vaccine. Among the virulence factors employed by S. aureus, animal model and epidemiological data suggest that alpha toxin, a multimeric ?-pore forming toxin like protective antigen from Bacillus anthracis, is particularly critical, yet no candidate neutralizing epitopes have been delineated in alpha toxin to date. We have previously shown that a linear determinant in the 2?2-2?3 loop of the pore forming domain of B. anthracis protective antigen is a linear neutralizing epitope. Antibody against this site is highly potent for neutralizing anthrax lethal toxin in vitro and for protection of rabbits in vivo from virulent B. anthracis. We hypothesized that sequences in the ?-pore of S. aureus alpha toxin that share structural and functional homology to ?-pore sequences in protective antigen would contain a similarly critical neutralizing epitope. Using an in vivo mapping strategy employing peptide immunogens, an optimized in vitro toxin neutralization assay, and an in vivo dermonecrosis model, we have now confirmed the presence of this epitope in alpha toxin, termed the pore neutralizing determinant. Antibody specific for this determinant neutralizes alpha toxin in vitro, and is highly effective for mitigating dermonecrosis and bacterial growth in a mouse model of S. aureus USA300 skin infection. The delineation of this linear neutralizing determinant in alpha toxin could facilitate the development of an epitope-focused vaccine against S. aureus. PMID:25635901

Oscherwitz, Jon; Cease, Kemp B

2015-01-01

264

Identification and Validation of a Linear Protective Neutralizing Epitope in the ?-Pore Domain of Alpha Toxin  

PubMed Central

The plethora of virulence factors associated with Staphylococcus aureus make this bacterium an attractive candidate for a molecularly-designed epitope-focused vaccine. This approach, which necessitates the identification of neutralizing epitopes for incorporation into a vaccine construct, is being evaluated for pathogens where conventional approaches have failed to elicit protective humoral responses, like HIV-1 and malaria, but may also hold promise for pathogens like S. aureus, where the elicitation of humoral immunity against multiple virulence factors may be required for development of an effective vaccine. Among the virulence factors employed by S. aureus, animal model and epidemiological data suggest that alpha toxin, a multimeric ?-pore forming toxin like protective antigen from Bacillus anthracis, is particularly critical, yet no candidate neutralizing epitopes have been delineated in alpha toxin to date. We have previously shown that a linear determinant in the 2?2-2?3 loop of the pore forming domain of B. anthracis protective antigen is a linear neutralizing epitope. Antibody against this site is highly potent for neutralizing anthrax lethal toxin in vitro and for protection of rabbits in vivo from virulent B. anthracis. We hypothesized that sequences in the ?-pore of S. aureus alpha toxin that share structural and functional homology to ?-pore sequences in protective antigen would contain a similarly critical neutralizing epitope. Using an in vivo mapping strategy employing peptide immunogens, an optimized in vitro toxin neutralization assay, and an in vivo dermonecrosis model, we have now confirmed the presence of this epitope in alpha toxin, termed the pore neutralizing determinant. Antibody specific for this determinant neutralizes alpha toxin in vitro, and is highly effective for mitigating dermonecrosis and bacterial growth in a mouse model of S. aureus USA300 skin infection. The delineation of this linear neutralizing determinant in alpha toxin could facilitate the development of an epitope-focused vaccine against S. aureus. PMID:25635901

Oscherwitz, Jon; Cease, Kemp B.

2015-01-01

265

Toxin–antitoxin systems  

PubMed Central

Toxin–antitoxin (TA) systems are small genetic elements composed of a toxin gene and its cognate antitoxin. The toxins of all known TA systems are proteins while the antitoxins are either proteins or non-coding RNAs. Based on the molecular nature of the antitoxin and its mode of interaction with the toxin the TA modules are currently grouped into five classes. In general, the toxin is more stable than the antitoxin but the latter is expressed to a higher level. If supply of the antitoxin stops, for instance under special growth conditions or by plasmid loss in case of plasmid encoded TA systems, the antitoxin is rapidly degraded and can no longer counteract the toxin. Consequently, the toxin becomes activated and can act on its cellular targets. Typically, TA toxins act on crucial cellular processes including translation, replication, cytoskeleton formation, membrane integrity, and cell wall biosynthesis. TA systems and their components are also versatile tools for a multitude of purposes in basic research and biotechnology. Currently, TA systems are frequently used for selection in cloning and for single protein expression in living bacterial cells. Since several TA toxins exhibit activity in yeast and mammalian cells they may be useful for applications in eukaryotic systems. TA modules are also considered as promising targets for the development of antibacterial drugs and their potential to combat viral infection may aid in controlling infectious diseases. PMID:24251069

Unterholzner, Simon J; Poppenberger, Brigitte; Rozhon, Wilfried

2013-01-01

266

Determination of benzethonium chloride in anthrax vaccine adsorbed by HPLC  

Microsoft Academic Search

A novel and sensitive HPLC method for the determination of benzethonium chloride (BZC) in anthrax vaccine was developed. Adjuvant Alhydrogel was removed by syringe filter after a simple sample pretreatment—acidification prior to injection. Chromatography was performed by isocratic reverse phase separation with methanol\\/262mM ammonium acetate (80\\/20, v\\/v) on an endcapped C18 column with diode array detector (DAD). The method showed

Hsiaoling Wang; Alfred V. Del Grosso; Joan C. May

2006-01-01

267

What I need to know about anthrax today.  

PubMed

The US Department of Defense has been concerned about the use of anthrax as a biological weapon by an enemy on US troops for a number of years. This is the reason why the military has embarked on a vaccination program for its forces deployed to regions of the world, which are considered high-risk areas. These areas have been in the Southwest Asia-Persian Gulf region as well as the Korean Peninsula. Many intelligence personnel have also been concerned about the possibility of biological agents being used by terrorists in the Continental United States. The recent anthrax incidents in Florida and elsewhere in the United States have significantly heightened concerns along these lines, especially following the terrorist attacks on the World Trade Center and the Pentagon on September 11th. The death of a Florida businessman, identification of infection in one of his co-workers, evidence of exposure and in some instances, cutaneous infection in some others, as well as evidence of contamination in their buildings, raised further concerns of the possibility of terrorist activity using biological warfare in this country. It is somewhat ironic that a disease that you probably haven't heard about since medical school has become the focus of national attention. Our goal in this communication is to refresh your understanding of what anthrax is and what you need to know about it today since anthrax is counted among the weapons of mass destruction. As a member of the medical profession, you will need to know what to look for in patients and how to treat them if they are contaminated with this biological agent. You will also have to serve as the "front line" of the public health system and alert the police and public health agencies. PMID:11787310

Harris, R D; Grabenstein, J D

2001-12-01

268

Economic Impacts of a Wide Area Release of Anthrax  

SciTech Connect

This analysis explores economic impacts that might result from a wide-area release of anthrax. The intent is not to provide a quantitative analysis of such a disaster, but to: 1. Define the general categories of economic impacts that the region should be concerned about; and, 2. Explore what types of private sector businesses or industries, if any, may have the greatest impact on speeding the economic recovery of the region.

Judd, Kathleen S.; Olson, Jarrod; Stein, Steven L.; Lesperance, Ann M.

2009-05-29

269

Space Technology to Device That Destroys Pathogens Such as Anthrax  

NASA Technical Reports Server (NTRS)

AiroCide Ti02, an anthrax-killing air scrubber manufactured by KES Science and Technology Inc., in Kernesaw, Georgia, looks like a square metal box when it is installed on an office wall. Its fans draw in airborne spores and airflow forces them through a maze of tubes. Inside, hydroxyl radicals (OH-) attack and kill pathogens. Most remaining spores are destroyed by high-energy ultraviolet photons. Building miniature greenhouses for experiments on the International Space Station (ISS) has led to the invention of this device that annihilates anthrax-a bacteria that can be deadly when inhaled. The research enabling the invention started at the University of Wisconsin (Madison) Center for Space Automation and Robotics (WCSAR), one of 17 NASA Commercial Space Centers. A special coating technology used in the anthrax-killing invention is also being used inside WCSAR-built plant growth units on the ISS. This commercial research is managed by the Space Product Development Program at the Marshall Space Flight Center.

2002-01-01

270

Interactions between Bacillus anthracis and Plants May Promote Anthrax Transmission  

PubMed Central

Environmental reservoirs are essential in the maintenance and transmission of anthrax but are poorly characterized. The anthrax agent, Bacillus anthracis was long considered an obligate pathogen that is dormant and passively transmitted in the environment. However, a growing number of laboratory studies indicate that, like some of its close relatives, B. anthracis has some activity outside of its vertebrate hosts. Here we show in the field that B. anthracis has significant interactions with a grass that could promote anthrax spore transmission to grazing hosts. Using a local, virulent strain of B. anthracis, we performed a field experiment in an enclosure within a grassland savanna. We found that B. anthracis increased the rate of establishment of a native grass (Enneapogon desvauxii) by 50% and that grass seeds exposed to blood reached heights that were 45% taller than controls. Further we detected significant effects of E. desvauxii, B. anthracis, and their interaction on soil bacterial taxa richness and community composition. We did not find any evidence for multiplication or increased longevity of B. anthracis in bulk soil associated with grass compared to controls. Instead interactions between B. anthracis and plants may result in increased host grazing and subsequently increased transmission to hosts. PMID:24901846

Ganz, Holly H.; Turner, Wendy C.; Brodie, Eoin L.; Kusters, Martina; Shi, Ying; Sibanda, Heniritha; Torok, Tamas; Getz, Wayne M.

2014-01-01

271

Injectional anthrax at a Scottish district general hospital.  

PubMed

This retrospective, descriptive case-series reviews the clinical presentations and significant laboratory findings of patients diagnosed with and treated for injectional anthrax (IA) since December 2009 at Monklands Hospital in Central Scotland and represents the largest series of IA cases to be described from a single location. Twenty-one patients who fulfilled National Anthrax Control Team standardized case definitions of confirmed, probable or possible IA are reported. All cases survived and none required limb amputation in contrast to an overall mortality of 28% being experienced for this condition in Scotland. We document the spectrum of presentations of soft tissue infection ranging from mild cases which were managed predominantly with oral antibiotics to severe cases with significant oedema, organ failure and coagulopathy. We describe the surgical management, intensive care management and antibiotic management including the first description of daptomycin being used to treat human anthrax. It is noted that some people who had injected heroin infected with Bacillus anthracis did not develop evidence of IA. Also highlighted are biochemical and haematological parameters which proved useful in identifying deteriorating patients who required greater levels of support and surgical debridement. PMID:25078285

Inverarity, D J; Forrester, V M; Cumming, J G R; Paterson, P J; Campbell, R J; Brooks, T J G; Carson, G L; Ruddy, J P

2015-04-01

272

A Three-Dose Intramuscular Injection Schedule of Anthrax Vaccine Adsorbed Generates Sustained Humoral and Cellular Immune Responses to Protective Antigen and Provides Long-Term Protection against Inhalation Anthrax in Rhesus Macaques  

PubMed Central

A 3-dose (0, 1, and 6 months) intramuscular (3-IM) priming series of a human dose (HuAVA) and dilutions of up to 1:10 of anthrax vaccine adsorbed (AVA) provided statistically significant levels of protection (60 to 100%) against inhalation anthrax for up to 4 years in rhesus macaques. Serum anti-protective antigen (anti-PA) IgG and lethal toxin neutralization activity (TNA) were detectable following a single injection of HuAVA or 1:5 AVA or following two injections of diluted vaccine (1:10, 1:20, or 1:40 AVA). Anti-PA and TNA were highly correlated (overall r2 = 0.89 for log10-transformed data). Peak responses were seen at 6.5 months. In general, with the exception of animals receiving 1:40 AVA, serum anti-PA and TNA responses remained significantly above control levels at 28.5 months (the last time point measured for 1:20 AVA), and through 50.5 months for the HuAVA and 1:5 and 1:10 AVA groups (P < 0.05). PA-specific gamma interferon (IFN-?) and interleukin-4 (IL-4) CD4+ cell frequencies and T cell stimulation indices were sustained through 50.5 months (the last time point measured). PA-specific memory B cell frequencies were highly variable but, in general, were detectable in peripheral blood mononuclear cells (PBMC) by 2 months, were significantly above control levels by 7 months, and remained detectable in the HuAVA and 1:5 and 1:20 AVA groups through 42 months (the last time point measured). HuAVA and diluted AVA elicited a combined Th1/Th2 response and robust immunological priming, with sustained production of high-avidity PA-specific functional antibody, long-term immune cell competence, and immunological memory (30 months for 1:20 AVA and 52 months for 1:10 AVA). Vaccinated animals surviving inhalation anthrax developed high-magnitude anamnestic anti-PA IgG and TNA responses. PMID:22933399

Sabourin, Carol L.; Niemuth, Nancy A.; Li, Han; Semenova, Vera A.; Rudge, Thomas L.; Mayfield, Heather J.; Schiffer, Jarad; Mittler, Robert S.; Ibegbu, Chris C.; Wrammert, Jens; Ahmed, Rafi; Brys, April M.; Hunt, Robert E.; Levesque, Denyse; Estep, James E.; Barnewall, Roy E.; Robinson, David M.; Plikaytis, Brian D.; Marano, Nina

2012-01-01

273

Anthrax pathogen evades the mammalian immune system through stealth siderophore Strong, B. Rowe Byers, and Kenneth N. Raymond  

E-print Network

production Anthrax pathogen evades the mammalian immune system through stealth siderophore Strong, see: Reprints www.pnas.org/misc/reprints.shtml To order reprints, see: Notes: #12;Anthrax pathogen anthrax, caused by inhalation or ingestion of Bacillus anthracis spores, is characterized by rapid

Strong, Roland K.

274

9 CFR 309.7 - Livestock affected with anthrax; cleaning and disinfection of infected livestock pens and driveways.  

Code of Federal Regulations, 2010 CFR

...2010-01-01 false Livestock affected with anthrax; cleaning and disinfection of infected... § 309.7 Livestock affected with anthrax; cleaning and disinfection of infected...ante-mortem inspection to be affected with anthrax shall be identified as U.S....

2010-01-01

275

Two-Photon Intravital Imaging of Lungs during Anthrax Infection Reveals Long-Lasting Macrophage-Dendritic Cell Contacts  

E-print Network

Two-Photon Intravital Imaging of Lungs during Anthrax Infection Reveals Long-Lasting Macrophage, the agent of anthrax. We show that after alveolar macrophages capture spores, CD11b-positive dendritic cells to the draining lymph nodes and elicit the immune response in pulmonary anthrax. The intimate and long-last- ing

Paris-Sud XI, Université de

276

9 CFR 309.7 - Livestock affected with anthrax; cleaning and disinfection of infected livestock pens and driveways.  

Code of Federal Regulations, 2012 CFR

...2012-01-01 false Livestock affected with anthrax; cleaning and disinfection of infected... § 309.7 Livestock affected with anthrax; cleaning and disinfection of infected...ante-mortem inspection to be affected with anthrax shall be identified as U.S....

2012-01-01

277

9 CFR 309.7 - Livestock affected with anthrax; cleaning and disinfection of infected livestock pens and driveways.  

Code of Federal Regulations, 2011 CFR

...2011-01-01 false Livestock affected with anthrax; cleaning and disinfection of infected... § 309.7 Livestock affected with anthrax; cleaning and disinfection of infected...ante-mortem inspection to be affected with anthrax shall be identified as U.S....

2011-01-01

278

9 CFR 309.7 - Livestock affected with anthrax; cleaning and disinfection of infected livestock pens and driveways.  

Code of Federal Regulations, 2014 CFR

...2014-01-01 false Livestock affected with anthrax; cleaning and disinfection of infected... § 309.7 Livestock affected with anthrax; cleaning and disinfection of infected...ante-mortem inspection to be affected with anthrax shall be identified as U.S....

2014-01-01

279

9 CFR 309.7 - Livestock affected with anthrax; cleaning and disinfection of infected livestock pens and driveways.  

Code of Federal Regulations, 2013 CFR

...2013-01-01 false Livestock affected with anthrax; cleaning and disinfection of infected... § 309.7 Livestock affected with anthrax; cleaning and disinfection of infected...ante-mortem inspection to be affected with anthrax shall be identified as U.S....

2013-01-01

280

Toxins from Bacteria  

PubMed Central

Bacterial toxins damage the host at the site of bacterial infection or distanced from the site of infections. Bacterial toxins can be single proteins or organized as oligomeric protein complexes and are organized with distinct AB structure-function properties. The A domain encodes a catalytic activity; ADP-ribosylation of host proteins is the earliest post-translational modification determine to be performed by bacterial toxin, and now include glucosylation and proteolysis among other s. Bacterial toxins also catalyze the non-covalent modification of host protein function or can modify host cell properties through direct protein-protein interactions. The B domain includes two functional domains: a receptor-binding domain, which defines the tropism of a toxin for a cell and a translocation domain that delivers A domain across a lipid bilayer, either on the plasma membrane or the endosome. Bacterial toxins are often characterized based upon the section mechanism that delivers the toxin out of the bacterium, termed type I–VII. This review will overview the major families of bacterial toxins and will also describe the specific structure-function properties of the botulinum neurotoxins. PMID:20358680

Henkel, James S.; Baldwin, Michael R.; Barbieri, Joseph T.

2010-01-01

281

Molecular Characterization of Bacillus Strains Involved in Outbreaks of Anthrax in France in 1997  

Microsoft Academic Search

Outbreaks of anthrax zoonose occurred in two regions of France in 1997. Ninety-four animals died, and there were three nonfatal cases in humans. The diagnosis of anthrax was rapidly confirmed by bacteriological and molecular biological methods. The strains of Bacillus anthracis in animal and soil samples were identified by a multiplex PCR assay. They all belonged to the variable-number tandem

GUY PATRA; JOSEE VAISSAIRE; MARTINE WEBER-LEVY; CLAUDINE LE DOUJET; MICHELE MOCK

282

Development of an in vitro-based potency assay for anthrax vaccine  

Microsoft Academic Search

The potency assay currently used to evaluate consistency of manufacture for the anthrax vaccine is contingent upon meeting specified parameters after statistical analysis of the percent survival and time to death of vaccinated guinea pigs after challenge with spores of a virulent strain of Bacillus anthracis. During the development of a new anthrax vaccine based upon recombinant protective antigen (rPA)

S. F. Little; W. M. Webster; B. E. Ivins; P. F. Fellows; S. L. Norris; G. P. Andrews

2004-01-01

283

News Note: A new dual vaccine for protection against both smallpox and anthrax  

Cancer.gov

Scientists have developed and tested a new protective vaccine against smallpox and anthrax, two agents of bioterrorism, in animal models. Liyanage P. Perera, Ph.D., NCI, and colleagues made the enhanced dual vaccine by inserting the genes for protective parts of anthrax and the immune-boosting chemical, interleukin-15, into the backbone of the licensed smallpox vaccine, ACAM2000.

284

mu-conotoxin GIIIA, a peptide ligand for muscle sodium channels: Chemical synthesis, radiolabeling, and receptor characterization  

SciTech Connect

The peptide conotoxin GIIIA from Conus geographus L. venom, which specifically blocks sodium channels in muscle, has been synthesized by a solid-phase method. The three disulfide bridges were formed by air oxidation. After HPLC purification, the synthetic product was shown to be identical with the native conotoxin GIIIA from Conus geographus. A high specific activity, /sup 125/I derivative of mu-conotoxin was prepared and used for binding assays to the Na channel from Electrophorus electric organ. Specific binding could be abolished by competition with tetrodotoxin. The radiolabeled toxin was specifically cross-linked to the Na channel. These studies demonstrate that mu-conotoxin GIIIA can be used to define the guanidinium toxin binding site and will be a useful ligand for understanding functionally important differences between Na channel subtypes.

Cruz, L.J.; Kupryszewski, G.; LeCheminant, G.W.; Gray, W.R.; Olivera, B.M.; Rivier, J.

1989-04-18

285

Bacillus anthracis genomic DNA enhances lethal toxin¿induced cytotoxicity through TNF-¿ production.  

PubMed

Background Bacillus anthracis is the etiological agent of anthrax. Lethal toxin (LT) produced by B. anthracis is a well-known key virulence factor for anthrax because of its strong cytotoxic activity. However, little is known about the role of B. anthracis genomic DNA (BAG) in anthrax pathogenesis.ResultsWe examined the effect of BAG on TNF-¿ production and LT-mediated cytotoxicity during B. anthracis spore infection in mouse macrophage cell lines (RAW264.7 cells and J774A.1) and BALB/c mice. Infection of RAW264.7 cells with B. anthracis spores induced TNF-¿ expression in a multiplicity of infection (MOI)-dependent manner, and this enhancement was attenuated by the toll-like receptor (TLR) 9 inhibitor oligodeoxynucleotide (ODN)2088. BAG led to TNF-¿ expression in a dose- and time-dependent manner when applied to RAW264.7 cells. TNF-¿ expression induced by BAG was reduced by either pretreatment with TLR9 inhibitors (ODN2088 and chloroquine (CQ)) or transfection with TLR9 siRNA. Furthermore, BAG-induced TNF-¿ production in TLR9+/+ macrophages was completely abrogated in TLR9¿/¿ macrophages. BAG enhanced the phosphorylation of mitogen-activated protein kinases (MAPK), and BAG-induced TNF-¿ expression was attenuated by pretreatment with MAPK inhibitors. A reporter gene assay and confocal microscopy demonstrated that BAG increased NF-¿B activation, which is responsible for TNF-¿ expression. Treatment with BAG alone showed no cytotoxic activity on the macrophage cell line J774A.1, whereas LT-mediated cytotoxicity was enhanced by treatment with BAG or TNF-¿. Enhanced LT-induced lethality was also confirmed by BAG administration in mice. Furthermore, LT plus BAG-mediated lethality was significantly recovered by administration of Infliximab, an anti-TNF-¿ monoclonal antibody.ConclusionsOur results suggest that B. anthracis DNA may contribute to anthrax pathogenesis by enhancing LT activity via TLR9-mediated TNF-¿ production. PMID:25472474

Jeon, Jun; Kim, Yeon; Choi, Min; Kim, Kyung; Lee, Hae-Ri; Jang, Jeyoun; Kim, Yu-Ri; Chun, Jeong-Hoon; Eo, Seong; Kim, Tae; Rhie, Gi-Eun

2014-12-01

286

A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol  

PubMed Central

A 10-aa motif in transmembrane helix 1 of diphtheria toxin that is conserved in anthrax edema factor, anthrax lethal factor, and botulinum neurotoxin serotypes A, C, and D was identified by blast, clustal w, and meme computational analysis. Using the diphtheria toxin-related fusion protein toxin DAB389IL-2, we demonstrate that introduction of the L221E mutation into a highly conserved residue within this motif results in a nontoxic catalytic domain translocation deficient phenotype. To further probe the function of this motif in the process by which the catalytic domain is delivered from the lumen of early endosomes to the cytosol, we constructed a gene encoding a portion of diphtheria toxin transmembrane helix 1, T1, which carries the motif and is expressed from a CMV promoter. We then isolated stable transfectants of Hut102/6TG cells that express the T1 peptide, Hut102/6TG-T1. In contrast to the parental cell line, Hut102/6TG-T1 cells are ca. 104-fold more resistant to the fusion protein toxin. This resistance is completely reversed by coexpression of small interfering RNA directed against the gene encoding the T1 peptide in Hut102/6TG-T1 cells. We further demonstrate by GST-DT140-271 pull-down experiments in the presence and absence of synthetic T1 peptides the specific binding of coatomer protein complex subunit ? to this region of the diphtheria toxin transmembrane domain. PMID:16230620

Ratts, Ryan; Trujillo, Carolina; Bharti, Ajit; vanderSpek, Johanna; Harrison, Robert; Murphy, John R.

2005-01-01

287

Enzymatic Detoxification of HC-toxin, the Host-Selective Cyclic Peptide from Cochliobolus carbonum 1  

PubMed Central

Resistance to the fungal plant pathogen Cochliobolus carbonum race 1 and to its host-selective toxin, HC-toxin, is determined by Hm, a single dominant gene in the host plant maize, (Zea mays L). Radiolabeled HC-toxin of specific activity 70 milliCuries per millimole, prepared by feeding tritiated d,l-alanine to the fungus, was used to study its fate in maize leaf tissues. HC-toxin was converted by resistant leaf segments to a single compound, identified by mass spectrometry and nuclear magnetic resonance as the 8-hydroxy derivative of HC-toxin formed by reduction of the 8-keto group of 2-amino-9, 10-epoxy-8-oxo-decanoic acid, one of the amino acids in HC-toxin. Reduction of HC-toxin occurred in cell-free preparations from etiolated (Hm/hm) maize shoots, and the activity was sensitive to heat and proteolytic digestion, dependent on NADPH, and inhibited by p-hydroxymercuribenzoate and disulfiram. The enzyme (from the Hm/hm genotype) was partially purified by ammonium sulfate precipitation and diethylaminoethyl-ion exchange chromatography. By gel filtration chromatography, the enzyme had a molecular weight of 42,000. NADH was approximately 30% as effective as NADPH as a hydride donor, and flavin-containing cofactors had no effect on activity. When HC-toxin was introduced to maize leaf segments through the transpiration stream, leaf segments from both resistant and susceptible maize inactivated toxin equally well over a time-course of 9 hours. Although these data suggest no relationship between toxin metabolism and host selectivity, we discuss findings in apparent conflict with the current data and describe why the relationship between enzymatic reduction of HC-toxin and Hm remains unresolved. ImagesFigure 2Figure 4 PMID:16668492

Meeley, Robert B.; Walton, Jonathan D.

1991-01-01

288

Metastatic insulinoma managed with radiolabeled somatostatin analog.  

PubMed

Insulinoma is a rare pancreatic neuroendocrine tumor. Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium ((177)LU). PMID:24455330

Costa, Ricardo; Costa, Rubens; Bacchi, Carlos E; Almeida Filho, Paulo

2013-01-01

289

Metastatic Insulinoma Managed with Radiolabeled Somatostatin Analog  

PubMed Central

Insulinoma is a rare pancreatic neuroendocrine tumor. Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium (177LU). PMID:24455330

Costa, Ricardo; Bacchi, Carlos E.; Almeida Filho, Paulo

2013-01-01

290

Bacterial toxins: friends or foes?  

PubMed Central

Many emerging and reemerging bacterial pathogens synthesize toxins that serve as primary virulence factors. We highlight seven bacterial toxins produced by well-established or newly emergent pathogenic microbes. These toxins, which affect eukaryotic cells by a variety of means, include Staphylococcus aureus alpha-toxin, Shiga toxin, cytotoxic necrotizing factor type 1, Escherichia coli heat-stable toxin, botulinum and tetanus neurotoxins, and S. aureus toxic-shock syndrome toxin. For each, we discuss the information available on its synthesis and structure, mode of action, and contribution to virulence. We also review the role certain toxins have played in unraveling signal pathways in eukaryotic cells and summarize the beneficial uses of toxins and toxoids. Our intent is to illustrate the importance of the analysis of bacterial toxins to both basic and applied sciences. PMID:10221874

Schmitt, C. K.; Meysick, K. C.; O'Brien, A. D.

1999-01-01

291

Radiolabeled dimethyl branched long chain fatty acid for heart imaging  

DOEpatents

A radiolabeled long chain fatty acid for heart imaging that has dimethyl branching at one of the carbons of the chain which inhibits the extent to which oxidation can occur. The closer to the carboxyl the branching is positioned, the more limited the oxidation, thereby resulting in prolonged retention of the radiolabeled compound in the heart.

Knapp, Jr., Furn F. (Oak Ridge, TN); Goodman, Mark M. (Knoxville, TN); Kirsch, Gilbert (Woippy, FR)

1988-08-16

292

Swab protocol for rapid laboratory diagnosis of cutaneous anthrax.  

PubMed

The clinical laboratory diagnosis of cutaneous anthrax is generally established by conventional microbiological methods, such as culture and directly straining smears of clinical specimens. However, these methods rely on recovery of viable Bacillus anthracis cells from swabs of cutaneous lesions and often yield negative results. This study developed a rapid protocol for detection of B. anthracis on clinical swabs. Three types of swabs, flocked-nylon, rayon, and polyester, were evaluated by 3 extraction methods, the swab extraction tube system (SETS), sonication, and vortex. Swabs were spiked with virulent B. anthracis cells, and the methods were compared for their efficiency over time by culture and real-time PCR. Viability testing indicated that the SETS yielded greater recovery of B. anthracis from 1-day-old swabs; however, reduced viability was consistent for the 3 extraction methods after 7 days and nonviability was consistent by 28 days. Real-time PCR analysis showed that the PCR amplification was not impacted by time for any swab extraction method and that the SETS method provided the lowest limit of detection. When evaluated using lesion swabs from cutaneous anthrax outbreaks, the SETS yielded culture-negative, PCR-positive results. This study demonstrated that swab extraction methods differ in their efficiency of recovery of viable B. anthracis cells. Furthermore, the results indicated that culture is not reliable for isolation of B. anthracis from swabs at ? 7 days. Thus, we recommend the use of the SETS method with subsequent testing by culture and real-time PCR for diagnosis of cutaneous anthrax from clinical swabs of cutaneous lesions. PMID:23035192

Dauphin, Leslie A; Marston, Chung K; Bhullar, Vinod; Baker, Daniel; Rahman, Mahmudur; Hossain, M Jahangir; Chakraborty, Apurba; Khan, Salah Uddin; Hoffmaster, Alex R

2012-12-01

293

Keeping the Air Clean and Safe: An Anthrax Smoke Detector  

NASA Technical Reports Server (NTRS)

Scientists at work in the Planetary Protection division at NASA s Jet Propulsion Laboratory (JPL) sterilize everything before blasting it to the Red Planet. They take great pains to ensure that all spacecraft are void of bacterial life, especially the microscopic bacteria that can live hundreds of years in their spore states. No one is quite sure what Earthly germs would do on Mars, but scientists agree that it is safest to keep the Martian terrain as undisturbed as possible. Errant Earth germs would also render useless the instruments placed on exploration rovers to look for signs of life, as the life that they registered would be life that came with them from Earth. A team at JPL, headed by Dr. Adrian Ponce, developed a bacterial spore-detection system that uses a simple and robust chemical reaction that visually alerts Planetary Protection crews. It is a simple air filter that traps micron-sized bacterial spores and then submits them to the chemical reaction. When the solution is then viewed under an ultraviolet light, the mixture will glow green if it is contaminated by bacteria. Scientists can then return to the scrubbing and cleaning stages of the sterilization process to remove these harmful bacteria. The detection system is the space-bound equivalent of having your hands checked for cleanliness before being allowed to the table; and although intended to keep terrestrial germs from space, this technology has awesome applications here on Mother Earth. The bacterial spore-detection unit can recognize anthrax and other harmful, spore-forming bacteria and alert people of the impending danger. As evidenced in the anthrax mailings of fall 2001 in the United States, the first sign of anthrax exposure was when people experienced flu-like symptoms, which unfortunately, can take as much as a week to develop after contamination. Anthrax cost 5 people their lives and infected 19 others; and the threat of bioterrorism became a routine concern, with new threats popping up nearly everyday. The attacks threatened the safety that so many Americans took for granted, as the very air that people breathed became suspect. Any building with a circulation system, where large groups congregate, was now a potential target.

2005-01-01

294

Decontamination of Anthrax spores in critical infrastructure and critical assets.  

SciTech Connect

Decontamination of anthrax spores in critical infrastructure (e.g., subway systems, major airports) and critical assets (e.g., the interior of aircraft) can be challenging because effective decontaminants can damage materials. Current decontamination methods require the use of highly toxic and/or highly corrosive chemical solutions because bacterial spores are very difficult to kill. Bacterial spores such as Bacillus anthracis, the infectious agent of anthrax, are one of the most resistant forms of life and are several orders of magnitude more difficult to kill than their associated vegetative cells. Remediation of facilities and other spaces (e.g., subways, airports, and the interior of aircraft) contaminated with anthrax spores currently requires highly toxic and corrosive chemicals such as chlorine dioxide gas, vapor- phase hydrogen peroxide, or high-strength bleach, typically requiring complex deployment methods. We have developed a non-toxic, non-corrosive decontamination method to kill highly resistant bacterial spores in critical infrastructure and critical assets. A chemical solution that triggers the germination process in bacterial spores and causes those spores to rapidly and completely change to much less-resistant vegetative cells that can be easily killed. Vegetative cells are then exposed to mild chemicals (e.g., low concentrations of hydrogen peroxide, quaternary ammonium compounds, alcohols, aldehydes, etc.) or natural elements (e.g., heat, humidity, ultraviolet light, etc.) for complete and rapid kill. Our process employs a novel germination solution consisting of low-cost, non-toxic and non-corrosive chemicals. We are testing both direct surface application and aerosol delivery of the solutions. A key Homeland Security need is to develop the capability to rapidly recover from an attack utilizing biological warfare agents. This project will provide the capability to rapidly and safely decontaminate critical facilities and assets to return them to normal operations as quickly as possible, sparing significant economic damage by re-opening critical facilities more rapidly and safely. Facilities and assets contaminated with Bacillus anthracis (i.e., anthrax) spores can be decontaminated with mild chemicals as compared to the harsh chemicals currently needed. Both the 'germination' solution and the 'kill' solution are constructed of 'off-the-shelf,' inexpensive chemicals. The method can be utilized by directly spraying the solutions onto exposed surfaces or by application of the solutions as aerosols (i.e., small droplets), which can also reach hidden surfaces.

Boucher, Raymond M.; Crown, Kevin K.; Tucker, Mark David; Hankins, Matthew Granholm

2010-05-01

295

Topical Botulinum Toxin  

PubMed Central

Nanotechnology is a rapidly growing discipline that capitalizes on the unique properties of matter engineered on the nanoscale. Vehicles incorporating nanotechnology have led to great strides in drug delivery, allowing for increased active ingredient stability, bioavailability, and site-specific targeting. Botulinum toxin has historically been used for the correction of neurological and neuromuscular disorders, such as torticollis, blepharospasm, and strabismus. Recent dermatological indications have been for the management of axillary hyperhydrosis and facial rhytides. Traditional methods of botulinum toxin delivery have been needle-based. These have been associated with increased pain and cost. Newer methods of botulinum toxin formulation have yielded topical preparations that are bioactive in small pilot clinical studies. While there are some risks associated with topical delivery, the refinement and standardization of delivery systems and techniques for the topical administration of botulinum toxin using nanotechnology is anticipated in the near future. PMID:20725542

Collins, Ashley

2010-01-01

296

The effect of seasonal variation on anthrax epidemiology in the upper Zambezi floodplain of western Zambia  

PubMed Central

Anthrax has become endemic throughout the upper Zambezi floodplain located in the Western Province of Zambia over the recent years. To date, no comprehensive study has been carried out to determine whether recurrence of anthrax outbreaks may be linked to differences in precipitation and human activities. Retrospective data for the period 1999 to 2007 showed that a total of 1,216 bovine cases of anthrax were reported. During the same period, 1,790 human anthrax cases and a corresponding case fatality rate of 4.63% (83/1,790) was documented in the upper Zambezi floodplain. Occurrence of human cases was highly correlated with cattle outbreaks (r = 0.94, p < 0.001). Differences in precipitation were significantly associated with the occurrence of anthrax outbreaks (?2 = 4.75, p < 0.03), indicating that the likelihood of outbreaks occurring was higher during the dry months when human occupancy of the floodplain was greater compared to the flooding months when people and livestock moved out of this region. Human dependency on the floodplain was shown to significantly influence the epidemiology of anthrax in the upper Zambezi floodplain of western Zambia. Methods for mitigating anthrax outbreaks by disrupting the cycle of transmission are herein highlighted. PMID:23000586

Banda, Fredrick; Siamudaala, Victor Mukulule; Munyeme, Musso; Kasanga, Christopher Jacob; Hamududu, Byman

2012-01-01

297

Surveillance and control of anthrax and rabies in wild herbivores and carnivores in Namibia.  

PubMed

Anthrax has been studied intensively in Etosha National Park, Namibia since 1966; in addition, since 1975, mortality due to rabies and all other causes has been recorded, totalling 6,190 deaths. Standard diagnostic procedures demonstrated that at least 811 deaths (13%) were due to anthrax and 115 deaths (2%) were caused by rabies. Of the total number of deaths due to anthrax, 97% occurred in zebra (Equus burchelli), elephant (Loxodonta africana), wildebeest (Connochaetes taurinus) and springbok (Antidorcas marsupialis) while 96% of rabies deaths occurred in kudu (Tragelaphus strepsiceros), jackal (Canis mesomelas), bat-eared fox (Otocyon megalotis) and lion (Panthera leo). Anthrax deaths were highest in the rainy season for zebra, wildebeest and springbok, while elephant mortality peaked during dry seasons. No statistical relationship existed between seasonal rainfall and overall incidence of either anthrax or rabies. Control of anthrax is limited to prophylactic inoculation when rare or endangered species are threatened. Incineration of anthrax carcasses and chemical disinfection of drinking water are not feasible at Etosha. Rabies control consists of the destruction of rabid animals and incineration of their carcasses when possible. PMID:8518440

Berry, H H

1993-03-01

298

Radiolabeled antagonistic bombesin peptidomimetics for tumor targeting.  

PubMed

The replacement of amide bonds in the backbone of peptides by proteolytically stable?1,2,3-triazole isosteres can provide novel peptidomimetics with promising properties for the development of tumor-targeting radiopeptides. On the basis of our previous work with radiolabeled agonistic bombesin (BBN) derivatives of the sequence [Nle(14) ]BBN(7-14), we substituted selected amide bonds of the structurally closely related antagonistic peptide analog JMV594. With the exception of the C-terminal modification, amide-to-triazole substitutions tolerated by [Nle(14) ]BBN(7-14) without loss of biological function led to abolished receptor affinity in the case of JMV594. These findings provide an additional piece of evidence for the currently disputed differences in the modes of action of agonistic and antagonistic gastrin-releasing peptide receptor (GRPR)-targeting radiopeptides. PMID:24327435

Valverde, Ibai E; Huxol, Elena; Mindt, Thomas L

2014-04-01

299

Risk practices for animal and human anthrax in Bangladesh: an exploratory study  

PubMed Central

Introduction From August 2009 to October 2010, International Centre for Diarrheal Disease Research, Bangladesh and the Institute of Epidemiology, Disease Control and Research together investigated 14 outbreaks of anthrax which included 140 animal and 273 human cases in 14 anthrax-affected villages. Our investigation objectives were to explore the context in which these outbreaks occurred, including livestock rearing practices, human handling of sick and dead animals, and the anthrax vaccination program. Methods Field anthropologists used qualitative data-collection tools, including 15 hours of unstructured observations, 11 key informant interviews, 32 open-ended interviews, and 6 group discussions in 5 anthrax-affected villages. Results Each cattle owner in the affected communities raised a median of six ruminants on their household premises. The ruminants were often grazed in pastures and fed supplementary rice straw, green grass, water hyacinth, rice husk, wheat bran, and oil cake; lactating cows were given dicalcium phosphate. Cattle represented a major financial investment. Since Islamic law forbids eating animals that die from natural causes, when anthrax-infected cattle were moribund, farmers often slaughtered them on the household premises while they were still alive so that the meat could be eaten. Farmers ate the meat and sold it to neighbors. Skinners removed and sold the hides from discarded carcasses. Farmers discarded the carcasses and slaughtering waste into ditches, bodies of water, or open fields. Cattle in the affected communities did not receive routine anthrax vaccine due to low production, poor distribution, and limited staffing for vaccination. Conclusion Slaughtering anthrax-infected animals and disposing of butchering waste and carcasses in environments where ruminants live and graze, combined with limited vaccination, provided a context that permitted repeated anthrax outbreaks in animals and humans. Because of strong financial incentives, slaughtering moribund animals and discarding carcasses and waste products will likely continue. Long-term vaccination coverage for at-risk animal populations may reduce anthrax infection. PMID:24298326

Islam, Md. Saiful; Hossain, M. Jahangir; Mikolon, Andrea; Parveen, Shahana; Khan, M. Salah Uddin; Haider, Najmul; Chakraborty, Apurba; Titu, Abu Mohammad Naser; Rahman, M. Waliur; Sazzad, Hossain M. S.; Rahman, Mahmudur; Gurley, Emily S.; Luby, Stephen P.

2013-01-01

300

Mechanism of Lethal Toxin Neutralization by a Human Monoclonal Antibody Specific for the PA20 Region of Bacillus anthracis Protective Antigen  

PubMed Central

The primary immunogenic component of the currently approved anthrax vaccine is the protective antigen (PA) unit of the binary toxin system. PA-specific antibodies neutralize anthrax toxins and protect against infection. Recent research has determined that in humans, only antibodies specific for particular determinants are capable of effecting toxin neutralization, and that the neutralizing epitopes recognized by these antibodies are distributed throughout the PA monomer. The mechanisms by which the majority of these epitopes effect neutralization remain unknown. In this report we investigate the process by which a human monoclonal antibody specific for the amino-terminal domain of PA neutralizes lethal toxin in an in vitro assay of cytotoxicity, and find that it neutralizes LT by blocking the requisite cleavage of the amino-terminal 20 kD portion of the molecule (PA20) from the remainder of the PA monomer. We also demonstrate that the epitope recognized by this human monoclonal does not encompass the 166RKKR169 furin recognition sequence in domain 1 of PA. PMID:22069752

Reason, Donald; Liberato, Justine; Sun, Jinying; Camacho, Jessica; Zhou, Jianhui

2011-01-01

301

Rabies virus glycoprotein as a carrier for anthrax protective antigen  

SciTech Connect

Live viral vectors expressing foreign antigens have shown great promise as vaccines against viral diseases. However, safety concerns remain a major problem regarding the use of even highly attenuated viral vectors. Using the rabies virus (RV) envelope protein as a carrier molecule, we show here that inactivated RV particles can be utilized to present Bacillus anthracis protective antigen (PA) domain-4 in the viral membrane. In addition to the RV glycoprotein (G) transmembrane and cytoplasmic domains, a portion of the RV G ectodomain was required to express the chimeric RV G anthrax PA on the cell surface. The novel antigen was also efficiently incorporated into RV virions. Mice immunized with the inactivated recombinant RV virions exhibited seroconversion against both RV G and anthrax PA, and a second inoculation greatly increased these responses. These data demonstrate that a viral envelope protein can carry a bacterial protein and that a viral carrier can display whole polypeptides compared to the limited epitope presentation of previous viral systems.

Smith, Mary Ellen [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Koser, Martin [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Xiao Sa [Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029 (United States); Siler, Catherine [Departments of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); McGettigan, James P. [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Calkins, Catherine [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Pomerantz, Roger J. [Departments of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Institute of Human Virology and Biodefense, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Dietzschold, Bernhard [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Schnell, Matthias J. [Departments of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 (United States) and Departments of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States)]. E-mail: matthias.schnell@jefferson.edu

2006-09-30

302

Deterministic Models of Inhalational Anthrax in New Zealand White Rabbits  

PubMed Central

Computational models describing bacterial kinetics were developed for inhalational anthrax in New Zealand white (NZW) rabbits following inhalation of Ames strain B. anthracis. The data used to parameterize the models included bacterial numbers in the airways, lung tissue, draining lymph nodes, and blood. Initial bacterial numbers were deposited spore dose. The first model was a single exponential ordinary differential equation (ODE) with 3 rate parameters that described mucociliated (physical) clearance, immune clearance (bacterial killing), and bacterial growth. At 36 hours postexposure, the ODE model predicted 1.7×107 bacteria in the rabbit, which agreed well with data from actual experiments (4.0×107 bacteria at 36 hours). Next, building on the single ODE model, a physiological-based biokinetic (PBBK) compartmentalized model was developed in which 1 physiological compartment was the lumen of the airways and the other was the rabbit body (lung tissue, lymph nodes, blood). The 2 compartments were connected with a parameter describing transport of bacteria from the airways into the body. The PBBK model predicted 4.9×107 bacteria in the body at 36 hours, and by 45 hours the model showed all clearance mechanisms were saturated, suggesting the rabbit would quickly succumb to the infection. As with the ODE model, the PBBK model results agreed well with laboratory observations. These data are discussed along with the need for and potential application of the models in risk assessment, drug development, and as a general aid to the experimentalist studying inhalational anthrax. PMID:24527843

2014-01-01

303

Private and public economic incentives for the control of animal diseases: the case of anthrax in livestock.  

PubMed

This study examined the roles of the public and private sectors as economic components of anthrax control with direct reference to the 2005 anthrax outbreak in livestock in North Dakota. Anthrax is an endemic disease in North Dakota, which often causes disease outbreaks in livestock, leading to economic losses to the livestock industry. The economic incentives and interests behind public and private control of an anthrax outbreak are investigated. Anthrax management is most effective with the participation of public and private firms. As anthrax is an infectious disease, its control also brings positive economic externalities, which are not accounted for in a producer's decision to protect animals. Therefore, public programs designed to control the disease must be implemented. The government can change producer response to anthrax by setting up policies and incentives that encourage their participation. However, these interventions must encourage compliance and not discourage producers from actively taking part in anthrax management. Producers have economy-based interests and personal reasons for controlling anthrax in their farms. The main reason behind government intervention is to provide assurance to the public who consume livestock products. Another reason is to assist producers and veterinarians, and to achieve biosecurity and biosafety objectives. The contribution of each animal healthcare partner in making anthrax management a success in North Dakota is discussed. PMID:18786071

Ndiva Mongoh, M; Hearne, R; Khaitsa, M L

2008-10-01

304

Preparation and biodistribution of radiolabeled fullerene C60 nanocrystals  

NASA Astrophysics Data System (ADS)

The present study describes for the first time a procedure for the radiolabeling of fullerene (C60) nanocrystals (nanoC60) with Na 125I, as well as the biodistribution of radiolabeled nanoC60 (125I-nanoC60). The solvent exchange method with tetrahydrofuran was used to make colloidal water suspensions of radiolabeled nanoC60 particles. The radiolabeling procedure with the addition of Na 125I to tetrahydrofuran during dissolution of C60 gave a higher radiochemical yield of radiolabeled nanoC60 particles in comparison to the second option, in which Na 125I was added after C60 was dissolved. Using photon correlation spectroscopy and transmission electron microscopy, 125I-nanoC60 particles were found to have a crystalline structure and a mean diameter of 200-250 nm. The 125I-nanoC60 had a particularly high affinity for human serum albumin, displaying 95% binding efficiency after 1 h. Biodistribution studies of 125I-nanoC60 in rats indicated significant differences in tissue accumulation of 125I-nanoC60 and the radioactive tracer Na 125I. The higher accumulation of radiolabeled nanoC60 was observed in liver and spleen, while accumulation in thyroid, stomach, lungs and intestines was significantly lower in comparison to Na 125I. In addition to being useful for testing the biological distribution of nanoC60, the described radiolabeling procedure might have possible applications in cancer radiotherapy.

Nikoli?, Nadežda; Vranješ-Ðuri?, Sanja; Jankovi?, Drina; Ðoki?, Divna; Mirkovi?, Marija; Bibi?, Nataša; Trajkovi?, Vladimir

2009-09-01

305

Preparation and biodistribution of radiolabeled fullerene C60 nanocrystals.  

PubMed

The present study describes for the first time a procedure for the radiolabeling of fullerene (C(60)) nanocrystals (nanoC(60)) with Na (125)I, as well as the biodistribution of radiolabeled nanoC(60) ((125)I-nanoC(60)). The solvent exchange method with tetrahydrofuran was used to make colloidal water suspensions of radiolabeled nanoC(60) particles. The radiolabeling procedure with the addition of Na (125)I to tetrahydrofuran during dissolution of C(60) gave a higher radiochemical yield of radiolabeled nanoC(60) particles in comparison to the second option, in which Na (125)I was added after C(60) was dissolved. Using photon correlation spectroscopy and transmission electron microscopy, (125)I-nanoC(60) particles were found to have a crystalline structure and a mean diameter of 200-250 nm. The (125)I-nanoC(60) had a particularly high affinity for human serum albumin, displaying 95% binding efficiency after 1 h. Biodistribution studies of (125)I-nanoC(60) in rats indicated significant differences in tissue accumulation of (125)I-nanoC(60) and the radioactive tracer Na (125)I. The higher accumulation of radiolabeled nanoC(60) was observed in liver and spleen, while accumulation in thyroid, stomach, lungs and intestines was significantly lower in comparison to Na (125)I. In addition to being useful for testing the biological distribution of nanoC(60), the described radiolabeling procedure might have possible applications in cancer radiotherapy. PMID:19713574

Nikoli?, Nadezda; Vranjes-Ethuri?, Sanja; Jankovi?, Drina; Ethoki?, Divna; Mirkovi?, Marija; Bibi?, Natasa; Trajkovi?, Vladimir

2009-09-23

306

9 CFR 113.66 - Anthrax Spore Vaccine-Nonencapsulated.  

Code of Federal Regulations, 2012 CFR

... Animals and Animal Products 1 2012-01-01... Animals and Animal Products ANIMAL AND PLANT...SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS...established as pure, safe, and...

2012-01-01

307

9 CFR 113.66 - Anthrax Spore Vaccine-Nonencapsulated.  

Code of Federal Regulations, 2011 CFR

... Animals and Animal Products 1 2011-01-01... Animals and Animal Products ANIMAL AND PLANT...SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS...established as pure, safe, and...

2011-01-01

308

9 CFR 113.66 - Anthrax Spore Vaccine-Nonencapsulated.  

Code of Federal Regulations, 2014 CFR

... Animals and Animal Products 1 2014-01-01... Animals and Animal Products ANIMAL AND PLANT...SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS...established as pure, safe, and...

2014-01-01

309

9 CFR 113.66 - Anthrax Spore Vaccine-Nonencapsulated.  

Code of Federal Regulations, 2013 CFR

... Animals and Animal Products 1 2013-01-01... Animals and Animal Products ANIMAL AND PLANT...SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS...established as pure, safe, and...

2013-01-01

310

Protective antigen-specific memory B cells persist years after anthrax vaccination and correlate with humoral immunity.  

PubMed

Anthrax Vaccine Adsorbed (AVA) generates short-lived protective antigen (PA) specific IgG that correlates with in vitro toxin neutralization and protection from Bacillus anthracis challenge. Animal studies suggest that when PA-specific IgG has waned, survival after spore challenge correlates with an activation of PA-specific memory B cells. Here, we characterize the quantity and the longevity of AVA-induced memory B cell responses in humans. Peripheral blood mononuclear cells (PBMCs) from individuals vaccinated ?3 times with AVA (n = 50) were collected early (3-6 months, n = 27) or late after their last vaccination (2-5 years, n = 23), pan-stimulated, and assayed by ELISPOT for total and PA-specific memory B cells differentiated into antibody secreting cells (ASCs). PA-specific ASC percentages ranged from 0.02% to 6.25% (median: 1.57%) and did not differ between early and late post-vaccination individuals. PA-specific ASC percentages correlated with plasma PA-specific IgG (r = 0.42, p = 0.03) and toxin neutralization (r = 0.52, p = 0.003) early post vaccination. PA-specific ASC percentages correlated with supernatant anti-PA both early (r = 0.60, p = 0.001) and late post vaccination (r = 0.71, p < 0.0001). These data suggest PA-specific memory B cell responses are long-lived and can be estimated after recent vaccination by the magnitude and neutralization capacity of the humoral response. PMID:25123559

Garman, Lori; Smith, Kenneth; Farris, A Darise; Nelson, Michael R; Engler, Renata J M; James, Judith A

2014-08-01

311

Protective Antigen-Specific Memory B Cells Persist Years after Anthrax Vaccination and Correlate with Humoral Immunity  

PubMed Central

Anthrax Vaccine Adsorbed (AVA) generates short-lived protective antigen (PA) specific IgG that correlates with in vitro toxin neutralization and protection from Bacillus anthracis challenge. Animal studies suggest that when PA-specific IgG has waned, survival after spore challenge correlates with an activation of PA-specific memory B cells. Here, we characterize the quantity and the longevity of AVA-induced memory B cell responses in humans. Peripheral blood mononuclear cells (PBMCs) from individuals vaccinated ?3 times with AVA (n = 50) were collected early (3–6 months, n = 27) or late after their last vaccination (2–5 years, n = 23), pan-stimulated, and assayed by ELISPOT for total and PA-specific memory B cells differentiated into antibody secreting cells (ASCs). PA-specific ASC percentages ranged from 0.02% to 6.25% (median: 1.57%) and did not differ between early and late post-vaccination individuals. PA-specific ASC percentages correlated with plasma PA-specific IgG (r = 0.42, p = 0.03) and toxin neutralization (r = 0.52, p = 0.003) early post vaccination. PA-specific ASC percentages correlated with supernatant anti-PA both early (r = 0.60, p = 0.001) and late post vaccination (r = 0.71, p < 0.0001). These data suggest PA-specific memory B cell responses are long-lived and can be estimated after recent vaccination by the magnitude and neutralization capacity of the humoral response. PMID:25123559

Garman, Lori; Smith, Kenneth; Farris, A. Darise; Nelson, Michael R.; Engler, Renata J. M.; James, Judith A.

2014-01-01

312

Naturally Occurring Food Toxins  

PubMed Central

Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States. PMID:22069686

Dolan, Laurie C.; Matulka, Ray A.; Burdock, George A.

2010-01-01

313

Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses.  

PubMed

Pathogenic microorganisms and toxins have evolved a variety of mechanisms to gain access to the host-cell cytosol and thereby exert virulent effects upon the host. One common mechanism of cellular entry requires trafficking to an acidified endosome, which promotes translocation across the host membrane. To identify small-molecule inhibitors that block this process, a library of 30,000 small molecules was screened for inhibitors of anthrax lethal toxin. Here we report that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone, the most active compound identified in the screen, inhibits intoxication by lethal toxin and blocks the entry of multiple other acid-dependent bacterial toxins and viruses into mammalian cells. This compound, which we named EGA, also delays lysosomal targeting and degradation of the EGF receptor, indicating that it targets host-membrane trafficking. In contrast, EGA does not block endosomal recycling of transferrin, retrograde trafficking of ricin, phagolysosomal trafficking, or phagosome permeabilization by Franciscella tularensis. Furthermore, EGA does not neutralize acidic organelles, demonstrating that its mechanism of action is distinct from pH-raising agents such as ammonium chloride and bafilomycin A1. EGA is a powerful tool for the study of membrane trafficking and represents a class of host-targeted compounds for therapeutic development to treat infectious disease. PMID:24191014

Gillespie, Eugene J; Ho, Chi-Lee C; Balaji, Kavitha; Clemens, Daniel L; Deng, Gang; Wang, Yao E; Elsaesser, Heidi J; Tamilselvam, Batcha; Gargi, Amandeep; Dixon, Shandee D; France, Bryan; Chamberlain, Brian T; Blanke, Steven R; Cheng, Genhong; de la Torre, Juan Carlos; Brooks, David G; Jung, Michael E; Colicelli, John; Damoiseaux, Robert; Bradley, Kenneth A

2013-12-10

314

Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses  

PubMed Central

Pathogenic microorganisms and toxins have evolved a variety of mechanisms to gain access to the host-cell cytosol and thereby exert virulent effects upon the host. One common mechanism of cellular entry requires trafficking to an acidified endosome, which promotes translocation across the host membrane. To identify small-molecule inhibitors that block this process, a library of 30,000 small molecules was screened for inhibitors of anthrax lethal toxin. Here we report that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone, the most active compound identified in the screen, inhibits intoxication by lethal toxin and blocks the entry of multiple other acid-dependent bacterial toxins and viruses into mammalian cells. This compound, which we named EGA, also delays lysosomal targeting and degradation of the EGF receptor, indicating that it targets host-membrane trafficking. In contrast, EGA does not block endosomal recycling of transferrin, retrograde trafficking of ricin, phagolysosomal trafficking, or phagosome permeabilization by Franciscella tularensis. Furthermore, EGA does not neutralize acidic organelles, demonstrating that its mechanism of action is distinct from pH-raising agents such as ammonium chloride and bafilomycin A1. EGA is a powerful tool for the study of membrane trafficking and represents a class of host-targeted compounds for therapeutic development to treat infectious disease. PMID:24191014

Gillespie, Eugene J.; Ho, Chi-Lee C.; Balaji, Kavitha; Clemens, Daniel L.; Deng, Gang; Wang, Yao E.; Elsaesser, Heidi J.; Tamilselvam, Batcha; Gargi, Amandeep; Dixon, Shandee D.; France, Bryan; Chamberlain, Brian T.; Blanke, Steven R.; Cheng, Genhong; de la Torre, Juan Carlos; Brooks, David G.; Jung, Michael E.; Colicelli, John; Damoiseaux, Robert; Bradley, Kenneth A.

2013-01-01

315

Characterizing a “New” Disease: Epizootic and Epidemic Anthrax, 1769–1780  

PubMed Central

In 1876, Robert Koch established anthrax as the first disease linked to a microbial agent. But Koch’s efforts had followed more than 150 years of scientific progress in characterizing anthrax as a specific human and veterinary disease. Focusing on France and the period between 1769 and 1780, this brief review examines noteworthy early events in the characterization of anthrax. It suggests that some “new” diseases like anthrax might be “discovered” not only by luck, brilliance, or new technologies, but by clinical/epidemiological “puzzle-fitting,” which can assemble a cohesive picture of a seemingly specific disease entity. If such processes have operated over 2 or more centuries, studying them may yield clues about desirable interactions between epidemiology/public health and experimental science in the characterization of new diseases. PMID:12773345

Morens, David M.

2003-01-01

316

Ciguatera Toxin Information Website  

NSDL National Science Digital Library

This website provides information about the marine toxin disease Ciguatera, which is caused by the consumption of fish that have accumulated ciguatoxin in their tissues. The toxin is produced by a microscopic dinoflagellate (Gambierdiscus toxicus) that lives on the surfaces of macroalgae in coral reef ecosystems. The dinoflagellates are inadvertently consumed by herbivorous fish during grazing and the toxins bioaccumulate in the food chain, attaining highest levels in carnivores. The site includes an introduction to ciguatera, information about the symptoms with links to reported cases and medical treatments, non-medical solutions, an education section, list of retailers, news releases, related links, and more. The site is published by ToxiTech, suppliers of Cigua-CheckÂ, which is a commercially available test kit for screening fish for ciguatoxin prior to consumption.

ToxiTech

317

Evaluation of the compatibility of a second generation recombinant anthrax vaccine with aluminum-containing adjuvants  

Microsoft Academic Search

Recombinant protective antigen (rPA) is the active pharmaceutical ingredient in a second generation anthrax vaccine undergoing pre-clinical evaluation. This rPA vaccine differs from the currently licensed vaccine, anthrax vaccine adsorbed (AVA), in that the sole component is a recombinant form of protective antigen (PA). Unlike AVA the rPA vaccine contains no lethal factor (LF) or edema factor (EF), components of

Scott Jendrek; Stephen F. Little; Stanley Hem; Gautam Mitra; Steven Giardina

2003-01-01

318

In vitro correlate of immunity in a rabbit model of inhalational anthrax  

Microsoft Academic Search

A serological correlate of vaccine-induced immunity was identified in the rabbit model of inhalational anthrax. Animals were inoculated intramuscularly at 0 and 4 weeks with varying doses of Anthrax Vaccine Adsorbed (AVA) ranging from a human dose to a 1:256 dilution in phosphate-buffered saline (PBS). At 6 and 10 weeks, both the quantitative anti-protective antigen (PA) IgG ELISA and the

M. L. M Pitt; S. F Little; B. E Ivins; P Fellows; J Barth; J Hewetson; P Gibbs; M Dertzbaugh; A. M Friedlander

2001-01-01

319

PemK Toxin of Bacillus anthracis Is a Ribonuclease  

PubMed Central

Bacillus anthracis genome harbors a toxin-antitoxin (TA) module encoding pemI (antitoxin) and pemK (toxin). This study describes the rPemK as a potent ribonuclease with a preference for pyrimidines (C/U), which is consistent with our previous study that demonstrated it as a translational attenuator. The in silico structural modeling of the PemK in conjunction with the site-directed mutagenesis confirmed the role of His-59 and Glu-78 as an acid-base couple in mediating the ribonuclease activity. The rPemK is shown to form a complex with the rPemI, which is in line with its function as a TA module. This rPemI-rPemK complex becomes catalytically inactive when both the proteins interact in a molar stoichiometry of 1. The rPemI displays vulnerability to proteolysis but attains conformational stability only upon rPemK interaction. The pemI-pemK transcript is shown to be up-regulated upon stress induction with a concomitant increase in the amount of PemK and a decline in the PemI levels, establishing the role of these modules in stress. The artificial perturbation of TA interaction could unleash the toxin, executing bacterial cell death. Toward this end, synthetic peptides are designed to disrupt the TA interaction. The peptides are shown to be effective in abrogating TA interaction in micromolar range in vitro. This approach can be harnessed as a potential antibacterial strategy against anthrax in the future. PMID:20022964

Agarwal, Shivangi; Mishra, Neeraj Kumar; Bhatnagar, Sonika; Bhatnagar, Rakesh

2010-01-01

320

Microfluidic radiolabeling of biomolecules with PET radiometals Dexing Zeng a  

E-print Network

,4,7,10-Tetraazacyclodode- cane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA in radioligands prepared using conventional methods. Moreover, higher yields for radiolabeling of DOTA

Kenis, Paul J. A.

321

Periocular cutaneous anthrax in Jimma Zone, Southwest Ethiopia: a case series  

PubMed Central

Background Anthrax is a zoonotic disease caused by Bacillus anthracis. Naturally occurring human infection is rare and is generally the result of contact with anthrax-infected animals or animal products. Case presentation We examined three patients who had contact with presumed anthrax-infected animal and/or its product and presented with preseptal cellulitis with a localized itchy erythematous papule of the eyelid and non-pitting periorbital edema, followed by ulceration and dark eschar formation. All the three patients responded to intravenous antibiotics, and the lesion resolved leaving scars which caused cicatricial ectropion in all cases. Conclusion Anthrax is a rare disease but should be considered in the differential diagnosis of ulcerative (and eschar forming) preseptal cellulitis with a history of contact with anthrax-infected animals or animal products. Furthermore, cicatrization of the eyelids, one of the sequelae of periocular cutaneous anthrax, should be addressed. Urgent case report to the local zoonotic disease and infection control body and other responsible authorities is recommended. PMID:23924443

2013-01-01

322

The Physiologic Responses of Dutch Belted Rabbits Infected with Inhalational Anthrax  

PubMed Central

Bacillus anthracis, the causative agent of anthrax, is a category A priority pathogen that causes extensive damage in humans. For this reason, B. anthracis has been the focus of numerous studies using various animal models. In this study, we explored physiologic parameters in Dutch belted rabbits with inhalation anthrax to characterize the disease progression in this model. To this end, we infected Dutch belted rabbits with 100 LD50 B. anthracis Ames spores by nasal instillation and continuously recorded various physiologic parameters by using telemetry. In addition, samples were collected at selected times for serum chemistry, hematology, and blood gas analysis. The animals exhibited hemodynamic and respiratory changes that coincided with those reported in human cases of inhalational anthrax infection, including hypotension, altered heart rate, and respiratory distress. Likewise, hematology, serum chemistry, and blood gas analysis revealed trends comparable to human anthrax-related pathophysiology. The Dutch belted rabbit model of inhalational anthrax exhibited most of the physiologic, hematologic, and biochemical sequelae noted in human cases. Therefore, this rabbit model fulfills several of the criteria of a useful animal model for studying disease pathogenesis and evaluating therapeutics during inhalational anthrax. PMID:19619416

Lawrence, William S; Hardcastle, Jason M; Brining, Douglas L; Weaver, Lori E; Ponce, Cindy; Whorton, Elbert B; Peterson, Johnny W

2009-01-01

323

Toxin Plasmids of Clostridium perfringens  

PubMed Central

SUMMARY In both humans and animals, Clostridium perfringens is an important cause of histotoxic infections and diseases originating in the intestines, such as enteritis and enterotoxemia. The virulence of this Gram-positive, anaerobic bacterium is heavily dependent upon its prolific toxin-producing ability. Many of the ?16 toxins produced by C. perfringens are encoded by large plasmids that range in size from ?45 kb to ?140 kb. These plasmid-encoded toxins are often closely associated with mobile elements. A C. perfringens strain can carry up to three different toxin plasmids, with a single plasmid carrying up to three distinct toxin genes. Molecular Koch's postulate analyses have established the importance of several plasmid-encoded toxins when C. perfringens disease strains cause enteritis or enterotoxemias. Many toxin plasmids are closely related, suggesting a common evolutionary origin. In particular, most toxin plasmids and some antibiotic resistance plasmids of C. perfringens share an ?35-kb region containing a Tn916-related conjugation locus named tcp (transfer of clostridial plasmids). This tcp locus can mediate highly efficient conjugative transfer of these toxin or resistance plasmids. For example, conjugative transfer of a toxin plasmid from an infecting strain to C. perfringens normal intestinal flora strains may help to amplify and prolong an infection. Therefore, the presence of toxin genes on conjugative plasmids, particularly in association with insertion sequences that may mobilize these toxin genes, likely provides C. perfringens with considerable virulence plasticity and adaptability when it causes diseases originating in the gastrointestinal tract. PMID:23699255

Li, Jihong; Adams, Vicki; Bannam, Trudi L.; Miyamoto, Kazuaki; Garcia, Jorge P.; Uzal, Francisco A.; Rood, Julian I.

2013-01-01

324

Antimicrobial Peptides as Infection Imaging Agents: Better Than Radiolabeled Antibiotics  

PubMed Central

Nuclear medicine imaging techniques offer whole body imaging for localization of number and site of infective foci inspite of limitation of spatial resolution. The innate human immune system contains a large member of important elements including antimicrobial peptides to combat any form of infection. However, development of antibiotics against bacteria progressed rapidly and gained popularity over antimicrobial peptides but even powerful antimicrobials failed to reduce morbidity and mortality due to emergence of mutant strains of bacteria resulting in antimicrobial resistance. Differentiation between infection and inflammation using radiolabeled compounds with nuclear medicine techniques has always been a dilemma which is still to be resolved. Starting from nonspecific tracers to specific radiolabeled tracers, the question is still unanswered. Specific radiolabeled tracers included antibiotics and antimicrobial peptides which bind directly to the bacteria for efficient localization with advanced nuclear medicine equipments. However, there are merits and demerits attributed to each. In the current paper, radiolabeled antibiotics and radiolabeled peptides for infection localization have been discussed starting with the background of primitive nonspecific tracers. Radiolabeled antimicrobial peptides have certain merits compared with labeled antibiotics which make them superior agents for localization of infective focus. PMID:22675369

Akhtar, Muammad Saeed; Imran, Muhammad Babar; Nadeem, Muhammad Afzal; Shahid, Abubaker

2012-01-01

325

In silico design of smart binders to anthrax PA  

NASA Astrophysics Data System (ADS)

The development of smart peptide binders requires an understanding of the fundamental mechanisms of recognition which has remained an elusive grail of the research community for decades. Recent advances in automated discovery and synthetic library science provide a wealth of information to probe fundamental details of binding and facilitate the development of improved models for a priori prediction of affinity and specificity. Here we present the modeling portion of an iterative experimental/computational study to produce high affinity peptide binders to the Protective Antigen (PA) of Bacillus anthracis. The result is a general usage, HPC-oriented, python-based toolkit based upon powerful third-party freeware, which is designed to provide a better understanding of peptide-protein interactions and ultimately predict and measure new smart peptide binder candidates. We present an improved simulation protocol with flexible peptide docking to the Anthrax Protective Antigen, reported within the context of experimental data presented in a companion work.

Sellers, Michael; Hurley, Margaret M.

2012-06-01

326

Identifying bacterial spores and anthrax hoax materials by Raman spectroscopy  

NASA Astrophysics Data System (ADS)

The distribution of Bacillus anthracis spores through the US postal system in the autumn of 2001, initiated a secondary form of terror, the mailing of hoax materials. In the past three years nearly 20,000 letters containing harmless powders have been mailed, creating additional anxiety. Thus, there is a need for analyzers that can not only identify anthrax-causing spores to save lives, but also identify hoax materials to eliminate time-consuming and costly shutdowns. Recently, we established that Raman spectroscopy has the ability to identify both Bacilli endospores and hoax materials. Here we present Raman spectra of several Bacilli spores along with the dipicolinate salts, to further define the abilities of this technology to not only identify hoax materials, but also identify spores at the genus and species level.

Farquharson, Stuart; Brouillette, Carl R.; Smith, Wayne

2004-12-01

327

The Pitfalls of Bioterrorism Preparedness: the Anthrax and Smallpox Experiences  

PubMed Central

Bioterrorism preparedness programs have contributed to death, illness, and waste of public health resources without evidence of benefit. Several deaths and many serious illnesses have resulted from the smallpox vaccination program; yet there is no clear evidence that a threat of smallpox exposure ever existed. The anthrax spores released in 2001 have been linked to secret US military laboratories—the resultant illnesses and deaths might not have occurred if those laboratories were not in operation. The present expansion of bioterrorism preparedness programs will continue to squander health resources, increase the dangers of accidental or purposeful release of dangerous pathogens, and further undermine efforts to enforce international treaties to ban biological and chemical weapons. The public health community should acknowledge the substantial harm that bioterrorism preparedness has already caused and develop mechanisms to increase our public health resources and to allocate them to address the world’s real health needs. PMID:15451727

Cohen, Hillel W.; Gould, Robert M.; Sidel, Victor W.

2004-01-01

328

Preparation and characterization of cobalt-substituted anthrax lethal factor  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Cobalt-substituted anthrax lethal factor (CoLF) is highly active. Black-Right-Pointing-Pointer CoLF can be prepared by bio-assimilation and direct exchange. Black-Right-Pointing-Pointer Lethal factor binds cobalt tightly. Black-Right-Pointing-Pointer The electronic spectrum of CoLF reveals penta-coordination. Black-Right-Pointing-Pointer Interaction of CoLF with thioglycolic acid follows a 2-step mechanism. -- Abstract: Anthrax lethal factor (LF) is a zinc-dependent endopeptidase involved in the cleavage of mitogen-activated protein kinase kinases near their N-termini. The current report concerns the preparation of cobalt-substituted LF (CoLF) and its characterization by electronic spectroscopy. Two strategies to produce CoLF were explored, including (i) a bio-assimilation approach involving the cultivation of LF-expressing Bacillus megaterium cells in the presence of CoCl{sub 2}, and (ii) direct exchange by treatment of zinc-LF with CoCl{sub 2}. Independent of the method employed, the protein was found to contain one Co{sup 2+} per LF molecule, and was shown to be twice as active as its native zinc counterpart. The electronic spectrum of CoLF suggests the Co{sup 2+} ion to be five-coordinate, an observation similar to that reported for other Co{sup 2+}-substituted gluzincins, but distinct from that documented for the crystal structure of native LF. Furthermore, spectroscopic studies following the exposure of CoLF to thioglycolic acid (TGA) revealed a sequential mechanism of metal removal from LF, which likely involves the formation of an enzyme: Co{sup 2+}:TGA ternary complex prior to demetallation of the active site. CoLF reported herein constitutes the first spectroscopic probe of LF's active site, which may be utilized in future studies to gain further insight into the enzyme's mechanism and inhibitor interactions.

Saebel, Crystal E.; Carbone, Ryan; Dabous, John R.; Lo, Suet Y. [Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, Ontario, Canada P3E 2C6 (Canada)] [Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, Ontario, Canada P3E 2C6 (Canada); Siemann, Stefan, E-mail: ssiemann@laurentian.ca [Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, Ontario, Canada P3E 2C6 (Canada)] [Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd., Sudbury, Ontario, Canada P3E 2C6 (Canada)

2011-12-09

329

Toxin-induced respiratory distress.  

PubMed

This article describes the impact of various toxic substances on the airway and pulmonary system. Pulmonary anatomy and physiology provide the basis for understanding the response to toxin-induced injury. Simple asphyxiants displace oxygen from the inspired air. Respiratory irritants include water-soluble and water-insoluble compounds. Several inhaled agents produce direct airway injury, which may be mediated by caustic, thermal, and hydrocarbon exposures. Unique pulmonary toxins and toxicants are discussed, as well as inhaled toxin mixtures. Several inhaled toxins may also impair oxygen transport. The pulmonary system may also provide a mechanism for systemic toxin delivery on respiratory exposure. PMID:24275172

McKay, Charles A

2014-02-01

330

CYANOBACTERIA AND THEIR TOXINS  

EPA Science Inventory

Science Questions Harmful algal blooms (HAB) of cyanobacteria, also known as blue-green algae, have recently become more spatially and temporally prevalent in the US and worldwide. Cyanobacteria and their highly potent toxins are a significant hazard for human health and ...

331

CYANOBACTERIA AND THEIR TOXINS.  

EPA Science Inventory

Science Questions Harmful algal blooms (HAB) of cyanobacteria, also known as blue-green algae, have recently become more spatially and temporally prevalent in the US and worldwide. Cyanobacteria and their highly potent toxins are a significant hazard for human health and ...

332

Botulinum Toxin in Ophthalmology  

Microsoft Academic Search

Since its introduction into clinical medicine in 1980, botulinum toxin has become a major therapeutic drug with applications valuable to many medical sub-specialties. Its use was spearheaded in ophthalmology where its potential applications have expanded to cover a broad range of visually related disorders. These include dystonic movement disorders, strabismus, nystagmus, headache syndromes such as migraine, lacrimal hypersecretion syndromes, eyelid

Jonathan J. Dutton; Amy M. Fowler

2007-01-01

333

Monitoring Method of Cow Anthrax Based on Gis and Spatial Statistical Analysis  

NASA Astrophysics Data System (ADS)

Geographic information system (GIS) is a computer application system, which possesses the ability of manipulating spatial information and has been used in many fields related with the spatial information management. Many methods and models have been established for analyzing animal diseases distribution models and temporal-spatial transmission models. Great benefits have been gained from the application of GIS in animal disease epidemiology. GIS is now a very important tool in animal disease epidemiological research. Spatial analysis function of GIS can be widened and strengthened by using spatial statistical analysis, allowing for the deeper exploration, analysis, manipulation and interpretation of spatial pattern and spatial correlation of the animal disease. In this paper, we analyzed the cow anthrax spatial distribution characteristics in the target district A (due to the secret of epidemic data we call it district A) based on the established GIS of the cow anthrax in this district in combination of spatial statistical analysis and GIS. The Cow anthrax is biogeochemical disease, and its geographical distribution is related closely to the environmental factors of habitats and has some spatial characteristics, and therefore the correct analysis of the spatial distribution of anthrax cow for monitoring and the prevention and control of anthrax has a very important role. However, the application of classic statistical methods in some areas is very difficult because of the pastoral nomadic context. The high mobility of livestock and the lack of enough suitable sampling for the some of the difficulties in monitoring currently make it nearly impossible to apply rigorous random sampling methods. It is thus necessary to develop an alternative sampling method, which could overcome the lack of sampling and meet the requirements for randomness. The GIS computer application software ArcGIS9.1 was used to overcome the lack of data of sampling sites.Using ArcGIS 9.1 and GEODA to analyze the cow anthrax spatial distribution of district A. we gained some conclusions about cow anthrax' density: (1) there is a spatial clustering model. (2) there is an intensely spatial autocorrelation. We established a prediction model to estimate the anthrax distribution based on the spatial characteristic of the density of cow anthrax. Comparing with the true distribution, the prediction model has a well coincidence and is feasible to the application. The method using a GIS tool facilitates can be implemented significantly in the cow anthrax monitoring and investigation, and the space statistics - related prediction model provides a fundamental use for other study on space-related animal diseases.

Li, Lin; Yang, Yong; Wang, Hongbin; Dong, Jing; Zhao, Yujun; He, Jianbin; Fan, Honggang

334

Monte Carlo N-particle simulation of neutron-based sterilisation of anthrax contamination  

PubMed Central

Objective To simulate the neutron-based sterilisation of anthrax contamination by Monte Carlo N-particle (MCNP) 4C code. Methods Neutrons are elementary particles that have no charge. They are 20 times more effective than electrons or ?-rays in killing anthrax spores on surfaces and inside closed containers. Neutrons emitted from a 252Cf neutron source are in the 100 keV to 2 MeV energy range. A 2.5 MeV D–D neutron generator can create neutrons at up to 1013 n s?1 with current technology. All these enable an effective and low-cost method of killing anthrax spores. Results There is no effect on neutron energy deposition on the anthrax sample when using a reflector that is thicker than its saturation thickness. Among all three reflecting materials tested in the MCNP simulation, paraffin is the best because it has the thinnest saturation thickness and is easy to machine. The MCNP radiation dose and fluence simulation calculation also showed that the MCNP-simulated neutron fluence that is needed to kill the anthrax spores agrees with previous analytical estimations very well. Conclusion The MCNP simulation indicates that a 10 min neutron irradiation from a 0.5 g 252Cf neutron source or a 1 min neutron irradiation from a 2.5 MeV D–D neutron generator may kill all anthrax spores in a sample. This is a promising result because a 2.5 MeV D–D neutron generator output >1013 n s?1 should be attainable in the near future. This indicates that we could use a D–D neutron generator to sterilise anthrax contamination within several seconds. PMID:22573293

Liu, B; Xu, J; Liu, T; Ouyang, X

2012-01-01

335

A One Health, participatory epidemiology assessment of anthrax (Bacillus anthracis) management in Western Uganda.  

PubMed

Sporadic anthrax outbreaks have occurred in and around Uganda's Queen Elizabeth National Park (QENP) for years, affecting wildlife, domestic animals, and humans. Reported outbreaks (2004-2005 and 2010) in QENP collectively killed over 500 wild animals and over 400 domestic animals. A 2011 outbreak in Sheema district temporarily froze local markets while killing two humans and seven bovines. One Health is multidisciplinary at its core, yet studies sometimes focus on the effects of animals on human health to the detriment of investigating the surrounding ecological and cultural contexts. Participatory methods connect problems - such as disease - to their context. A multidisciplinary team used participatory epidemiology and conventional structured questionnaires to investigate the impacts of anthrax on human livelihoods and the related perceptions of conservation, public health, and veterinary health efforts in the QENP area. Proximities to previous anthrax outbreaks and to QENP were treated as risk factors in the collection and evaluation of data. Participants' feedback indicates that anthrax prevalence may be greater than officially reported. Community member perceptions about anthrax and other diseases appear to be more closely related to their proximity to QENP than their proximity to anthrax outbreaks. Neither risk factor had a strong effect on knowledge of disease, nor any effect on behaviors associated with disease response or control. Instead, participants reported that social pressures, the economics of poverty, and the lack of health and veterinary infrastructure highly influenced responses to disease. The complex connections between the social needs and the economic context of these communities seem to be undermining current anthrax control and education measures. This livelihood-based decision-making may be unlikely to respond to educational intervention alone. This study provides a strong base for further research and for improvements in effective disease control. PMID:25066946

Coffin, Jeanne L; Monje, Fred; Asiimwe-Karimu, Grace; Amuguni, Hellen Janetrix; Odoch, Terence

2015-03-01

336

Phase I Study of Safety and Immunogenicity of an Escherichia coli-Derived Recombinant Protective Antigen (rPA) Vaccine to Prevent Anthrax in Adults  

Microsoft Academic Search

BackgroundThe fatal disease caused by Bacillus anthracis is preventable with a prophylactic vaccine. The currently available anthrax vaccine requires a lengthy immunization schedule, and simpler and more immunogenic options for protection against anthrax are a priority for development. In this report we describe a phase I clinical trial testing the safety and immunogenicity of an anthrax vaccine using recombinant Escherichia

Bruce K. Brown; Josephine Cox; Anita Gillis; Thomas C. VanCott; Mary Marovich; Mark Milazzo; Tanya Santelli Antonille; Lindsay Wieczorek; Kelly T. McKee; Karen Metcalfe; Raburn M. Mallory; Deborah Birx; Victoria R. Polonis; Merlin L. Robb

2010-01-01

337

Synthesis and radiolabeling of a somatostatin analog for multimodal imaging  

NASA Astrophysics Data System (ADS)

A new multimodal imaging agent for imaging the somatostatin receptor has been synthesized and evaluated in vitro and in vivo. A somatostatin analog, conjugated to both 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid (DOTA) and cypate (BS-296), was synthesized entirely on the solid phase (Fmoc) and purified by RP-HPLC. DOTA was added as a ligand for radiometals such as 64Cu or 177Lu for either radio-imaging or radiotherapy respectively. Cytate, a cypatesomatostatin analog conjugate, has previously demonstrated the ability to visualize somatostatin receptor rich tumor xenografts and natural organs by optical imaging techniques. BS-296 exhibited low nanomolar inhibitory capacity toward the binding of radiolabeled somatostatin analogs in cell membranes enriched in the somatostatin receptor, demonstrating the high affinity of this multimodal imaging peptide and indicating its potential as a molecular imaging agent. 64Cu, an isotope for diagnostic imaging and radiotherapy, was selected as the isotope for radiolabeling BS-296. BS-296 was radiolabeled with 64Cu in high specific activity (200 ?Ci/?g) in 90% radiochemical yield. Addition of 2,5-dihydroxybenzoic acid (gentisic acid) prevented radiolysis of the sample, allowing for study of the 64Cu -BS-296 the day following radiolabeling. Furthermore, inclusion of DMSO at a level of 20% was found not to interfere with radiolabeling yields and prevented the adherence of 64Cu -BS-296 to the walls of the reaction vessel.

Edwards, W. Barry; Liang, Kexian; Xu, Baogang; Anderson, Carolyn J.; Achilefu, Samuel

2006-02-01

338

Toxins and drug discovery.  

PubMed

Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. PMID:25448391

Harvey, Alan L

2014-12-15

339

Marine neurotoxins: Ingestible toxins  

Microsoft Academic Search

Opinion statement  Fish and shellfish account for a significant portion of food-borne illnesses throughout the world. In general, three classes\\u000a of diseases result from seafood consumption—intoxication, allergies, and infections. In this review, the authors discuss several\\u000a seafood-borne toxins, including domoic acid, which acts on the central nervous system. In addition, the authors discuss ciguatoxin-,\\u000a brevetoxin-, saxitoxin-, tetrodotoxin-, and scombroid-related histamine toxicity,

Elijah W. Stommel; Michael R. Watters

2004-01-01

340

Identification of Genomic Signatures for the Design of Assays for the Detection and Monitoring of Anthrax Threats  

E-print Network

of Anthrax Threats S. Draghici, P. Khatri, Y. Liu, K.J. Chase, E.A. Bode, D.A. Kulesh, L.P. Wasieloski, D OF ASSAYS FOR THE DETECTION AND MONITORING OF ANTHRAX THREATS SORIN DRAGHICI1, , PURVESH KHATRI1

341

Genome Sequence of Bacillus anthracis Isolated from an Anthrax Burial Site in Pollino National Park, Basilicata Region (Southern Italy).  

PubMed

A Bacillus anthracis strain was isolated from a burial-site in Pollino National Park where a bovine died of anthrax and was buried in 2004. We report the first genome sequence of B. anthracis isolated in the Basilicata region (southern Italy), which is the highest risk area of anthrax infection in Italy. PMID:25792059

Fasanella, Antonio; Braun, Peter; Grass, Gregor; Hanczaruk, Matthias; Aceti, Angela; Serrecchia, Luigina; Leonzio, Giuseppe; Tolve, Francesco; Georgi, Enrico; Antwerpen, Markus

2015-01-01

342

Genome Sequence of Bacillus anthracis Isolated from an Anthrax Burial Site in Pollino National Park, Basilicata Region (Southern Italy)  

PubMed Central

A Bacillus anthracis strain was isolated from a burial-site in Pollino National Park where a bovine died of anthrax and was buried in 2004. We report the first genome sequence of B. anthracis isolated in the Basilicata region (southern Italy), which is the highest risk area of anthrax infection in Italy. PMID:25792059

Fasanella, Antonio; Braun, Peter; Grass, Gregor; Hanczaruk, Matthias; Aceti, Angela; Serrecchia, Luigina; Leonzio, Giuseppe; Tolve, Francesco; Georgi, Enrico

2015-01-01

343

Evidence of Local Persistence of Human Anthrax in the Country of Georgia Associated with Environmental and Anthropogenic Factors  

PubMed Central

Background Anthrax is a soil-borne disease caused by the bacterium Bacillus anthracis and is considered a neglected zoonosis. In the country of Georgia, recent reports have indicated an increase in the incidence of human anthrax. Identifying sub-national areas of increased risk may help direct appropriate public health control measures. The purpose of this study was to evaluate the spatial distribution of human anthrax and identify environmental/anthropogenic factors associated with persistent clusters. Methods/Findings A database of human cutaneous anthrax in Georgia during the period 2000–2009 was constructed using a geographic information system (GIS) with case data recorded to the community location. The spatial scan statistic was used to identify persistence of human cutaneous anthrax. Risk factors related to clusters of persistence were modeled using a multivariate logistic regression. Areas of persistence were identified in the southeastern part of the country. Results indicated that the persistence of human cutaneous anthrax showed a strong positive association with soil pH and urban areas. Conclusions/Significance Anthrax represents a persistent threat to public and veterinary health in Georgia. The findings here showed that the local level heterogeneity in the persistence of human cutaneous anthrax necessitates directed interventions to mitigate the disease. High risk areas identified in this study can be targeted for public health control measures such as farmer education and livestock vaccination campaigns. PMID:24040426

Kracalik, Ian T.; Malania, Lile; Tsertsvadze, Nikoloz; Manvelyan, Julietta; Bakanidze, Lela; Imnadze, Paata; Tsanava, Shota; Blackburn, Jason K.

2013-01-01

344

[Cytolethal distending toxins].  

PubMed

Cytolethal distending toxins (CDT) are intracellularly acting proteins which interfere with the eukaryotic cell cycle. They are produced by Gram-negative bacteria with affinity to mucocutaneous surfaces and could play a role in the pathogenesis of various mammalian diseases. The functional toxin is composed of three proteins: CdtB entering the nucleus and by its nuclease activity inducing nuclear fragmentation and chromatin disintegration, CdtA, and CdtC, the two latter being responsible for toxin attachment to the surface of the target cell. Cytotoxic effect of CDT leads to the cell cycle arrest before the cell enters mitosis and to further changes (cell distension and death, apoptosis) depending on the cell type. Thus, CDT may function as a virulence factor in pathogenic bacteria that produce it and thus may contribute to the initiation of certain diseases. Most important are inflammatory bowel diseases caused by intestinal bacteria, periodontitis with Aggregatibacter actinomycetemcomitans as the aetiologic agent and ulcus molle where Haemophilus ducreyi is the causative agent. PMID:25025680

Curová, K; Kme?ová, M; Siegfried, L

2014-06-01

345

Emerging role of radiolabeled nanoparticles as an effective diagnostic technique  

PubMed Central

Nanomedicine is emerging as a promising approach for diagnostic applications. Nanoparticles are structures in the nanometer size range, which can present different shapes, compositions, charges, surface modifications, in vitro and in vivo stabilities, and in vivo performances. Nanoparticles can be made of materials of diverse chemical nature, the most common being metals, metal oxides, silicates, polymers, carbon, lipids, and biomolecules. Nanoparticles exist in various morphologies, such as spheres, cylinders, platelets, and tubes. Radiolabeled nanoparticles represent a new class of agent with great potential for clinical applications. This is partly due to their long blood circulation time and plasma stability. In addition, because of the high sensitivity of imaging with radiolabeled compounds, their use has promise of achieving accurate and early diagnosis. This review article focuses on the application of radiolabeled nanoparticles in detecting diseases such as cancer and cardiovascular diseases and also presents an overview about the formulation, stability, and biological properties of the nanoparticles used for diagnostic purposes. PMID:22809406

2012-01-01

346

Bacillus anthracis lethal toxin induces TNF-?–independent hypoxia-mediated toxicity in mice  

PubMed Central

Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1?. No changes in TNF-? occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-?–independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin. PMID:12952916

Moayeri, Mahtab; Haines, Diana; Young, Howard A.; Leppla, Stephen H.

2003-01-01

347

An Adenovirus-Vectored Nasal Vaccine Confers Rapid and Sustained Protection against Anthrax in a Single-Dose Regimen  

PubMed Central

Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine. PMID:23100479

Jex, Edward; Feng, Tsungwei; Sivko, Gloria S.; Baillie, Leslie W.; Goldman, Stanley; Van Kampen, Kent R.; Tang, De-chu C.

2013-01-01

348

Ricin detection: tracking active toxin.  

PubMed

Ricin is a plant toxin with high bioterrorism potential due to its natural abundance and potency in inducing cell death. Early detection of the active toxin is essential for developing appropriate countermeasures. Here we review concepts for designing ricin detection methods, including mechanism of action of the toxin, advantages and disadvantages of current detection assays, and perspectives on the future development of rapid and reliable methods for detecting ricin in environmental samples. PMID:25481398

Bozza, William P; Tolleson, William H; Rosado, Leslie A Rivera; Zhang, Baolin

2015-01-01

349

Recombinant Toxins for Cancer Treatment  

NASA Astrophysics Data System (ADS)

Recombinant toxins target cell surface receptors and antigens on tumor cells. They kill by mechanisms different from conventional chemotherapy, so that cross resistance to conventional chemotherapeutic agents should not be a problem. Furthermore, they are not mutagens and should not induce secondary malignancies or accelerate progression of benign malignancies. They can be mass-produced cheaply in bacteria as homogeneous proteins. Either growth factor-toxin fusions or antibody-toxin fusions can be chosen, depending on the cellular target.

Pastan, Ira; Fitzgerald, David

1991-11-01

350

In vitro binding of anthrax protective antigen on bacteriophage T4 capsid surface through Hoc-capsid interactions: A strategy for efficient display of large full-length proteins  

SciTech Connect

An in vitro binding system is described to display large full-length proteins on bacteriophage T4 capsid surface at high density. The phage T4 icosahedral capsid features 155 copies of a nonessential highly antigenic outer capsid protein, Hoc, at the center of each major capsid protein hexon. Gene fusions were engineered to express the 83-kDa protective antigen (PA) from Bacillus anthracis fused to the N-terminus of Hoc and the 130-kDa PA-Hoc protein was expressed in Escherichia coli and purified. The purified PA-Hoc was assembled in vitro on hoc {sup -} phage particles. Binding was specific, stable, and of high affinity. This defined in vitro system allowed manipulation of the copy number of displayed PA and imposed no significant limitation on the size of the displayed antigen. In contrast to in vivo display systems, the in vitro approach allows all the capsid binding sites to be occupied by the 130-kDa PA-Hoc fusion protein. The PA-T4 particles were immunogenic in mice in the absence of an adjuvant, eliciting strong PA-specific antibodies and anthrax lethal toxin neutralizing antibodies. The in vitro display on phage T4 offers a novel platform for potential construction of customized vaccines against anthrax and other infectious diseases.

Shivachandra, Sathish B. [Department of Biology, 103 McCort Ward Hall, Catholic University of America, 620 Michigan Ave., NE, Washington, DC 20064 (United States); Rao, Mangala [Division of Retrovirology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910 (United States); Janosi, Laszlo [Division of Retrovirology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910 (United States); Sathaliyawala, Taheri [Department of Biology, 103 McCort Ward Hall, Catholic University of America, 620 Michigan Ave., NE, Washington, DC 20064 (United States); Matyas, Gary R. [Division of Retrovirology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910 (United States); Alving, Carl R. [Division of Retrovirology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910 (United States); Leppla, Stephen H. [Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, NIH, 30 Convent Dr., Bethesda, MD 20892 (United States); Rao, Venigalla B. [Department of Biology, 103 McCort Ward Hall, Catholic University of America, 620 Michigan Ave., NE, Washington, DC 20064 (United States)]. E-mail: rao@cua.edu

2006-02-05

351

Anthrax Sampling and Decontamination: Technology Trade-Offs  

SciTech Connect

The goal of this project was to answer the following questions concerning response to a future anthrax release (or suspected release) in a building: 1. Based on past experience, what rules of thumb can be determined concerning: (a) the amount of sampling that may be needed to determine the extent of contamination within a given building; (b) what portions of a building should be sampled; (c) the cost per square foot to decontaminate a given type of building using a given method; (d) the time required to prepare for, and perform, decontamination; (e) the effectiveness of a given decontamination method in a given type of building? 2. Based on past experience, what resources will be spent on evaluating the extent of contamination, performing decontamination, and assessing the effectiveness of the decontamination in abuilding of a given type and size? 3. What are the trade-offs between cost, time, and effectiveness for the various sampling plans, sampling methods, and decontamination methods that have been used in the past?

Price, Phillip N.; Hamachi, Kristina; McWilliams, Jennifer; Sohn, Michael D.

2008-09-12

352

Whole Proteome Analysis of Mouse Lymph Nodes in Cutaneous Anthrax  

PubMed Central

This study aimed to characterize a soluble proteome of popliteal lymph nodes during lymphadenitis induced by intradermal injection of Bacillus anthracis Sterne spores in mice using tandem LC-MS/MS and reverse-phase protein microarray with antibodies specific to epitopes of phosphorylated proteins. More than 380 proteins were detected in the normal intra-nodal lymph, while the infectious process resulted in the profound changes in the protein abundances and appearance of 297 unique proteins. These proteins belong to an array of processes reflecting response to wounding, inflammation and perturbations of hemostasis, innate immune response, coagulation and fibrinolysis, regulation of body fluid levels and vascular disturbance among others. Comparison of lymph and serum revealed 83 common proteins. Also, using 71 antibodies specific to total and phosphorylated forms of proteins we carried initial characterization of circulating lymph phosphoproteome which brought additional information regarding signaling pathways operating in the lymphatics. The results demonstrate that the proteome of intra-nodal lymph serves as a sensitive sentinel of the processes occurring within the lymph nodes during infection. The acute innate response of the lymph nodes to anthrax is accompanied by cellular damage and inflammation with a large number of up- and down-regulated proteins many of which are distinct from those detected in serum. MS data are available via ProteomeXchange with identifier PXD001342. PMID:25329596

Zhou, Weidong; Mueller, Claudius; Liotta, Lance; Popov, Serguei G.

2014-01-01

353

Vaccination against Anthrax with Attenuated Recombinant Strains of Bacillus anthracis That Produce Protective Antigen  

PubMed Central

The protective efficacy of several live, recombinant anthrax vaccines given in a single-dose regimen was assessed with Hartley guinea pigs. These live vaccines were created by transforming ?ANR and ?Sterne, two nonencapsulated, nontoxinogenic strains of Bacillus anthracis, with four different recombinant plasmids that express the anthrax protective antigen (PA) protein to various degrees. This enabled us to assess the effect of the chromosomal background of the strain, as well as the amount of PA produced, on protective efficacy. There were no significant strain-related effects on PA production in vitro, plasmid stability in vivo, survival of the immunizing strain in the host, or protective efficacy of the immunizing infection. The protective efficacy of the live, recombinant anthrax vaccine strains correlated with the anti-PA antibody titers they elicited in vivo and the level of PA they produced in vitro. PMID:9916059

Barnard, John P.; Friedlander, Arthur M.

1999-01-01

354

Pathogenic ecology: Where have all the pathogens gone? Anthrax: a classic case  

NASA Astrophysics Data System (ADS)

Pathogenic ecology is the natural relationship to animate and inanimate components of the environment that support the sustainment of a pathogen in the environment or prohibit its sustainment, or their interactions with an introduced pathogen that allow for the establishment of disease in a new environment. The anthrax bacterium in the spore form has been recognized as a highly likely biological warfare or terrorist agent. The purpose of this work was to determine the environmental reservoir of Bacillus anthracis between outbreaks of anthrax and to examine the potential factors influencing the conversion of the Bacillus anthracis from a quiescent state to the disease causing state. Here we provide environmental and laboratory data for the cycling of Bacillus anthracis in plants to reconcile observations that contradict the soil borne hypothesis of anthrax maintenance in the environment.

Kiel, Johnathan; Walker, Wes W.; Andrews, Carrie J.; De Los Santos, Amy; Adams, Roy N.; Bucholz, Matthew W.; McBurnett, Shelly D.; Fuentes, Vladimir; Rizner, Karon E.; Blount, Keith W.

2009-05-01

355

Influence of protein formulation and carrier solution on asymmetrical flow field-flow fractionation: a case study of the plant-produced recombinant anthrax protective antigen pp-PA83.  

PubMed

Asymmetrical flow field-flow fractionation (afFFF) was used to investigate the properties of a plant-produced anthrax toxin protective antigen, pp-PA83. The afFFF fractogram consisted of two main peaks with molar masses similar to the molecular mass of pp-PA83 monomer. afFFF carrier solutions strongly influenced the ratio and the intensity of the two main peaks. These differences indicate that conformation changes in the pp-PA83 molecule occurred during the afFFF analysis. Similar fractograms were obtained for different pp-PA83 formulations when the afFFF carrier solution and the protein formulation were the same (or very similar). The data show that in specific cases, afFFF could be used to study protein conformation and document the importance of studying the influence of the carrier solution on afFFF. PMID:25417936

Palais, Caroline; Chichester, Jessica A; Manceva, Slobodanka; Yusibov, Vidadi; Arvinte, Tudor

2015-02-01

356

Two anthrax cases with soft tissue infection, severe oedema and sepsis in Danish heroin users  

PubMed Central

Background Anthrax had become extremely rare in Europe, but in 2010 an outbreak of anthrax among heroin users in Scotland increased awareness of contaminated heroin as a source of anthrax. We present the first two Danish cases of injectional anthrax and discuss the clinical presentations, which included both typical and more unusual manifestations. Case presentations The first patient, a 55-year old man with HIV and hepatitis C virus co-infection, presented with severe pain in the right thigh and lower abdomen after injecting heroin into the right groin. Computed tomography and ultrasonographic examination of the abdomen and right thigh showed oedematous thickened peritoneum, distended oedematous mesentery and subcutaneous oedema of the right thigh. At admission the patient was afebrile but within 24 hours he progressed to severe septic shock and abdominal compartment syndrome. Cultures of blood and intraperitoneal fluid grew Bacillus anthracis. The patient was treated with meropenem, clindamycin, ciprofloxacin and metronidazole. Despite maximum supportive care including mechanical ventilation, vasopressor treatment and continuous veno-venous hemodiafiltration the patient died on day four. The second patient, a 39-year old man with chronic hepatitis C virus infection, presented with fever and a swollen right arm after injecting heroin into his right arm. The arm was swollen from the axilla to the wrist with tense and discoloured skin. He was initially septic with low blood pressure but responded to crystalloids. During the first week, swelling progressed and the patient developed massive generalised oedema with a weight gain of 40 kg. When blood cultures grew Bacillus anthracis antibiotic treatment was changed to meropenem, moxifloxacin and metronidazole, and on day 7 hydroxycloroquin was added. The patient responded to treatment and was discharged after 29 days. Conclusions These two heroin-associated anthrax cases from Denmark corroborate that heroin contaminated with anthrax spores may be a continuous source of injectional anthrax across Europe. Clinicians and clinical microbiologists need to stay vigilant and suspect anthrax in patients with a history of heroin use who present with soft tissue or generalised infection. Marked swelling of affected soft tissue or unusual intra-abdominal oedema should strengthen clinical suspicion. PMID:24004900

2013-01-01

357

Bacterial insecticidal toxins.  

PubMed

Over the years it has been important for humans to control the populations of harmful insects and insecticides have been used for this purpose in agricultural and horticultural sectors. Synthetic insecticides, owing to their various side effects, have been widely replaced by biological insecticides. In this review we attempt to describe three bacterial species that are known to produce insecticidal toxins of tremendous biotechnological, agricultural, and economic importance. Bacillus thuringiensis (BT) accounts for 90% of the bioinsecticide market and it produces insecticidal toxins referred to as delta endotoxins. The other two bacteria belong to the genera Photorhabdus and Xenorhabdus, which are symbiotically associated with entomopathogenic nematodes of the families Heterorhabditidae and Steinernematidae respectively. Whereas, Xenorhabdus and Photorhabdus exist in a mutualistic association with the entomopathogenic nematodes, BT act alone. BT formulations are widely used in the field against insects; however, over the years there has been a gradual development of insect resistance against BT toxins. No resistance against Xenorhabdus or Photorhabdus has been reported to date. More recently BT transgenic crops have been prepared; however, there are growing concerns about the safety of these genetically modified crops. Nematodal formulations are also used in the field to curb harmful insect populations. Resistance development to entomopathogenic nematodes is unlikely due to the physical macroscopic nature of infection. Xenorhabdus and Photorhabdus transgenes have not yet been prepared; but are predicted to be available in the near future. In this review we start with an overview of the synthetic insecticides and then discuss Bacillus thuringiensis, Xenorhabdus nematophilus, and Photorhabdus luminescens in greater detail. PMID:15116762

Chattopadhyay, Abanti; Bhatnagar, N B; Bhatnagar, Rakesh

2004-01-01

358

Radiolabeling of Cramoll 1,4: Evaluation of the Biodistribution  

PubMed Central

The cramoll 1,4 is a well-studied lectin. However, few studies about its biodistribution have been done before. In this study, we radiolabeled the cramol 1,4 with Tc-99m and analyzed the biodistribution. The results showed that the cramol has an abnormal uptake by the bowel with reflections on its clearance mechanism. PMID:21760823

Ferreira de Carvalho Patricio, Beatriz; Lima-Ribeiro, Maria Helena Madruga; dos Santos Correia, Maria Tereza; dos Anjos Carneiro-Leão, Ana Maria; de Souza Albernaz, Marta; Barboza, Thiago; de Souza, Sergio Augusto Lopes; Santos-Oliveira, Ralph

2011-01-01

359

Advancing role of radiolabeled antibodies in the therapy of cancer  

Microsoft Academic Search

This review focuses on the use of radiolabeled antibodies in the therapy of cancer, termed radioimmunotherapy (RAIT). Basic problems concerned with the choice of antibody, radionuclide, and physiology of the tumor and host are discussed, followed by a review of the pertinent clinical publications of various radioantibody constructs in the treatment of hematopoietic and solid tumors of diverse histopathology, grade,

David M. Goldenberg

2003-01-01

360

Botulinum toxin, Quo Vadis?  

PubMed

Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves Soluble N-ethylmaleimide-sensitive factor-Attachment protein REceptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX also inhibits exocytosis of vesicles containing norepinephrine, glutamate, substance P and calcitonin gene-related peptide (CGRP) and inhibits expression of the vanilloid receptor. Clinical applications of BTX, which include the treatment of overactive skeletal and smooth muscles, hypersecretory and painful disorders, have increased exponentially since it was first used clinically to treat strabismus more than two decades ago. In this editorial, we discuss reports of new therapeutic indications of BTX, and propose new areas for research. PMID:17499937

Lim, Erle C H; Seet, Raymond C S

2007-01-01

361

Method for Delivering Radiolabeled Single-Chain Fv Antibody to the Brain  

Microsoft Academic Search

Radiolabeled antibody has attractive features as a therapeutic agent or diagnostic reagent. However, it is difficult for radiolabeled antibody to enter the cen- tral nervous system (CNS). The purpose of this study was to develop a method of delivering radiolabeled single-chain Fv (scFv) antibody into the CNS with the transactivator of transcription (TAT), one of the pro- tein transduction domains.

Nakajima Osamu; Hachisuka Akiko; Okunuki Haruyo; Takagi Kayoko; Teshima Reiko; Sawada Jun-ichi

2004-01-01

362

TOXINS FROM CYANOBACTERIA IN WATER  

EPA Science Inventory

This project is part of a larger U. S. Environmental Protection Agency (EPA) effort, which includes the Office of Water, to investigate algal toxins in surface water supplies and drinking water. Toxins produced by cyanobacteria (blue-green algae) are among the most potent known ...

363

Botulinum toxin: Bioweapon & magic drug  

PubMed Central

Botulinum neurotoxins, causative agents of botulism in humans, are produced by Clostridium botulinum, an anaerobic spore-former Gram positive bacillus. Botulinum neurotoxin poses a major bioweapon threat because of its extreme potency and lethality; its ease of production, transport, and misuse; and the need for prolonged intensive care among affected persons. A single gram of crystalline toxin, evenly dispersed and inhaled, can kill more than one million people. The basis of the phenomenal potency of botulinum toxin is enzymatic; the toxin is a zinc proteinase that cleaves neuronal vesicle associated proteins responsible for acetylcholine release into the neuromuscular junction. As a military or terrorist weapon, botulinum toxin could be disseminated via aerosol or by contamination of water or food supplies, causing widespread casualties. A fascinating aspect of botulinum toxin research in recent years has been development of the most potent toxin into a molecule of significant therapeutic utility. It is the first biological toxin which is licensed for treatment of human diseases. In the late 1980s, Canada approved use of the toxin to treat strabismus, in 2001 in the removal of facial wrinkles and in 2002, the FDA in the United States followed suit. The present review focuses on both warfare potential and medical uses of botulinum neurotoxin. PMID:21149997

Dhaked, Ram Kumar; Singh, Manglesh Kumar; Singh, Padma; Gupta, Pallavi

2010-01-01

364

Capsules, Toxins and AtxA as Virulence Factors of Emerging Bacillus cereus Biovar anthracis.  

PubMed

Emerging B. cereus strains that cause anthrax-like disease have been isolated in Cameroon (CA strain) and Côte d'Ivoire (CI strain). These strains are unusual, because their genomic characterisation shows that they belong to the B. cereus species, although they harbour two plasmids, pBCXO1 and pBCXO2, that are highly similar to the pXO1 and pXO2 plasmids of B. anthracis that encode the toxins and the polyglutamate capsule respectively. The virulence factors implicated in the pathogenicity of these B. cereus bv anthracis strains remain to be characterised. We tested their virulence by cutaneous and intranasal delivery in mice and guinea pigs; they were as virulent as wild-type B. anthracis. Unlike as described for pXO2-cured B. anthracis, the CA strain cured of the pBCXO2 plasmid was still highly virulent, showing the existence of other virulence factors. Indeed, these strains concomitantly expressed a hyaluronic acid (HA) capsule and the B. anthracis polyglutamate (PDGA) capsule. The HA capsule was encoded by the hasACB operon on pBCXO1, and its expression was regulated by the global transcription regulator AtxA, which controls anthrax toxins and PDGA capsule in B. anthracis. Thus, the HA and PDGA capsules and toxins were co-regulated by AtxA. We explored the respective effect of the virulence factors on colonisation and dissemination of CA within its host by constructing bioluminescent mutants. Expression of the HA capsule by itself led to local multiplication and, during intranasal infection, to local dissemination to the adjacent brain tissue. Co-expression of either toxins or PDGA capsule with HA capsule enabled systemic dissemination, thus providing a clear evolutionary advantage. Protection against infection by B. cereus bv anthracis required the same vaccination formulation as that used against B. anthracis. Thus, these strains, at the frontier between B. anthracis and B. cereus, provide insight into how the monomorphic B. anthracis may have emerged. PMID:25830379

Brézillon, Christophe; Haustant, Michel; Dupke, Susann; Corre, Jean-Philippe; Lander, Angelika; Franz, Tatjana; Monot, Marc; Couture-Tosi, Evelyne; Jouvion, Gregory; Leendertz, Fabian H; Grunow, Roland; Mock, Michèle E; Klee, Silke R; Goossens, Pierre L

2015-04-01

365

Capsules, Toxins and AtxA as Virulence Factors of Emerging Bacillus cereus Biovar anthracis  

PubMed Central

Emerging B. cereus strains that cause anthrax-like disease have been isolated in Cameroon (CA strain) and Côte d’Ivoire (CI strain). These strains are unusual, because their genomic characterisation shows that they belong to the B. cereus species, although they harbour two plasmids, pBCXO1 and pBCXO2, that are highly similar to the pXO1 and pXO2 plasmids of B. anthracis that encode the toxins and the polyglutamate capsule respectively. The virulence factors implicated in the pathogenicity of these B. cereus bv anthracis strains remain to be characterised. We tested their virulence by cutaneous and intranasal delivery in mice and guinea pigs; they were as virulent as wild-type B. anthracis. Unlike as described for pXO2-cured B. anthracis, the CA strain cured of the pBCXO2 plasmid was still highly virulent, showing the existence of other virulence factors. Indeed, these strains concomitantly expressed a hyaluronic acid (HA) capsule and the B. anthracis polyglutamate (PDGA) capsule. The HA capsule was encoded by the hasACB operon on pBCXO1, and its expression was regulated by the global transcription regulator AtxA, which controls anthrax toxins and PDGA capsule in B. anthracis. Thus, the HA and PDGA capsules and toxins were co-regulated by AtxA. We explored the respective effect of the virulence factors on colonisation and dissemination of CA within its host by constructing bioluminescent mutants. Expression of the HA capsule by itself led to local multiplication and, during intranasal infection, to local dissemination to the adjacent brain tissue. Co-expression of either toxins or PDGA capsule with HA capsule enabled systemic dissemination, thus providing a clear evolutionary advantage. Protection against infection by B. cereus bv anthracis required the same vaccination formulation as that used against B. anthracis. Thus, these strains, at the frontier between B. anthracis and B. cereus, provide insight into how the monomorphic B. anthracis may have emerged. PMID:25830379

Corre, Jean-Philippe; Lander, Angelika; Franz, Tatjana; Monot, Marc; Couture-Tosi, Evelyne; Jouvion, Gregory; Leendertz, Fabian H.; Grunow, Roland; Mock, Michèle E.; Klee, Silke R.; Goossens, Pierre L.

2015-01-01

366

Mechanisms of NK Cell-Macrophage Bacillus anthracis Crosstalk: A Balance between Stimulation by Spores and Differential Disruption by Toxins  

PubMed Central

NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-? production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-? production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-? production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-? secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-? secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms. PMID:22253596

Klezovich-Bénard, Maria; Corre, Jean-Philippe; Jusforgues-Saklani, Hélène; Fiole, Daniel; Burjek, Nick; Tournier, Jean-Nicolas; Goossens, Pierre L.

2012-01-01

367

Toxin-Based Therapeutic Approaches  

PubMed Central

Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin. PMID:22069564

Shapira, Assaf; Benhar, Itai

2010-01-01

368

Botulinum toxin: dosing and dilution.  

PubMed

In the United States, the popularity of botulinum toxins as agents to treat muscle hypertonia has grown significantly over the last decade, despite lack of approval from the Food and Drug Administration for the indication of spasticity. Botox (botulinum toxin type A) and Myobloc (botulinum toxin type B) are Food and Drug Administration-approved for other indications, such as cervical dystonia. Another commercial preparation of type A, Dysport, has yet to reach the United States market as of this writing. Although botulinum toxin's efficacy in influencing spastic hypertonia is well accepted, the impact of certain clinical issues, such as dosing and dilution, on treatment outcome is not well established by published studies. This article will review important articles and selected abstracts on the use of botulinum toxin, specifically for spastic hypertonia in adults, with emphasis on current clinical practices as they relate to dosing and dilution. PMID:15448575

Francisco, Gerard E

2004-10-01

369

Toxin production by Campylobacter spp.  

PubMed Central

Of all the virulence factors that were proposed for Campylobacter jejuni and related species to cause disease in humans, the discovery of toxin production was the most promising but led to a rather confusing and even disappointing stream of data. The discussion of whether proteinaceous exotoxins are relevant in disease remains open. One important reason for this lack of consensus is the anecdotal nature of the literature reports. To provide a basis for an unbiased opinion, this review compiles all described exotoxins, compares their reported properties, and provides a summary of animal model studies and clinical data. The toxins are divided into enterotoxins and cytotoxins and are sorted according to their biochemical properties. Since many Campylobacter toxins have been compared with toxins of other species, some key examples of the latter are also discussed. Future directions of toxin research that appear promising are defined. PMID:9227862

Wassenaar, T M

1997-01-01

370

Immunoproteomically identified GBAA_0345, alkyl hydroperoxide reductase subunit C is a potential target for multivalent anthrax vaccine.  

PubMed

Anthrax is caused by the spore-forming bacterium Bacillus anthracis, which has been used as a weapon for bioterrorism. Although current vaccines are effective, they involve prolonged dose regimens and often cause adverse reactions. High rates of mortality associated with anthrax have made the development of an improved vaccine a top priority. To identify novel vaccine candidates, we applied an immunoproteomics approach. Using sera from convalescent guinea pigs or from human patients with anthrax, we identified 34 immunogenic proteins from the virulent B. anthracis H9401. To evaluate vaccine candidates, six were expressed as recombinant proteins and tested in vivo. Two proteins, rGBAA_0345 (alkyl hydroperoxide reductase subunit C) and rGBAA_3990 (malonyl CoA-acyl carrier protein transacylase), have afforded guinea pigs partial protection from a subsequent virulent-spore challenge. Moreover, combined vaccination with rGBAA_0345 and rPA (protective antigen) exhibited an enhanced ability to protect against anthrax mortality. Finally, we demonstrated that GBAA_0345 localizes to anthrax spores and bacilli. Our results indicate that rGBAA_0345 may be a potential component of a multivalent anthrax vaccine, as it enhances the efficacy of rPA vaccination. This is the first time that sera from patients with anthrax have been used to interrogate the proteome of virulent B. anthracis vegetative cells. PMID:24273028

Kim, Yeon Hee; Kim, Kyung Ae; Kim, Yu-Ri; Choi, Min Kyung; Kim, Hye Kyeong; Choi, Ki Ju; Chun, Jeong-Hoon; Cha, Kiweon; Hong, Kee-Jong; Lee, Na Gyong; Yoo, Cheon-Kwon; Oh, Hee-Bok; Kim, Tae Sung; Rhie, Gi-eun

2014-01-01

371

Pertussis toxin-sensitive G-protein mediates the alpha 2-adrenergic receptor inhibition of melatonin release in photoreceptive chick pineal cell cultures  

SciTech Connect

The avian pineal gland is a photoreceptive organ that has been shown to contain postjunctional alpha 2-adrenoceptors that inhibit melatonin synthesis and/or release upon receptor activation. Physiological response and (32P)ADP ribosylation experiments were performed to investigate whether pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) were involved in the transduction of the alpha 2-adrenergic signal. For physiological response studies, the effects of pertussis toxin on melatonin release in dissociated cell cultures exposed to norepinephrine were assessed. Pertussis toxin blocked alpha 2-adrenergic receptor-mediated inhibition in a dose-dependent manner. Pertussis toxin-induced blockade appeared to be noncompetitive. One and 10 ng/ml doses of pertussis toxin partially blocked and a 100 ng/ml dose completely blocked norepinephrine-induced inhibition. Pertussis toxin-catalyzed (32P)ADP ribosylation of G-proteins in chick pineal cell membranes was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Membranes were prepared from cells that had been pretreated with 0, 1, 10, or 100 ng/ml pertussis toxin. In the absence of pertussis toxin pretreatment, two major proteins of 40K and 41K mol wt (Mr) were labeled by (32P)NAD. Pertussis toxin pretreatment of pineal cells abolished (32P) radiolabeling of the 40K Mr G-protein in a dose-dependent manner. The norepinephrine-induced inhibition of both cAMP efflux and melatonin release, as assessed by RIA of medium samples collected before membrane preparation, was also blocked in a dose-dependent manner by pertussis toxin. Collectively, these results suggest that a pertussis toxin-sensitive 40K Mr G-protein labeled by (32P)NAD may be functionally associated with alpha 2-adrenergic signal transduction in chick pineal cells.

Pratt, B.L.; Takahashi, J.S.

1988-07-01

372

AN ENVIRONMENTAL TECHNOLOGY VERIFICATION (ETV) TESTING OF THREE IMMUNOASSAY TEST KITS FOR ANTHRAX, BOTULINUM TOXIN AND RICIN  

EPA Science Inventory

Immunoassay test kits are based on immunoassay methods, where specific antibodies are used to detect and measure the contaminants of interest. Immunoassay test kits rely on the reaction of a contaminant or antigen with a selective antibody to give a product that can be measures....

373

Combination Therapy with Antibiotics and Anthrax Immune Globulin Intravenous (AIGIV) Is Potentially More Effective than Antibiotics Alone in Rabbit Model of Inhalational Anthrax  

PubMed Central

Background We have evaluated the therapeutic efficacy of AIGIV when given in combination with levofloxacin and the effective window of treatment to assess the added benefit provided by AIGIV over standard antibiotic treatment alone in a New Zealand white rabbit model of inhalational anthrax. Methods Rabbits were exposed to lethal dose of aerosolized spores of Bacillus anthracis (Ames strain) and treated intravenously with either placebo, (normal immune globulin intravenous, IGIV) or 15 U/kg of AIGIV, along with oral levofloxacin treatment at various time points (30–96 hours) after anthrax exposure. Results The majority of treated animals (>88%) survived in both treatment groups when treatment was initiated within 60 hours of post-exposure. However, reduced survival of 55%, 33% and 25% was observed for placebo + levofloxacin group when the treatment was initiated at 72, 84 and 96 hours post-exposure, respectively. Conversely, a survival rate of 65%, 40% and 71% was observed in the AIGIV + levofloxacin treated groups at these time points. Conclusions The combination of AIGIV with antibiotics provided an improvement in survival compared to levofloxacin treatment alone when treatment was delayed up to 96 hours post-anthrax exposure. Additionally, AIGIV treatment when given as an adjunct therapy at any of the time points tested did not interfere with the efficacy of levofloxacin. PMID:25226075

Kammanadiminti, Srinivas; Patnaikuni, Ravi Kumar; Comer, Jason; Meister, Gabriel; Sinclair, Chris; Kodihalli, Shantha

2014-01-01

374

Food toxin detection with atomic force microscope  

Technology Transfer Automated Retrieval System (TEKTRAN)

Externally introduced toxins or internal spoilage correlated pathogens and their metabolites are all potential sources of food toxins. To prevent and protect unsafe food, many food toxin detection techniques have been developed to detect various toxins for quality control. Although several routine m...

375

The Critical Role of Pathology in the Investigation of Bioterrorism-Related Cutaneous Anthrax  

PubMed Central

Cutaneous anthrax is a rare zoonotic disease in the United States. The clinical diagnosis traditionally has been established by conventional microbiological methods, such as culture and gram staining. However, these methods often yield negative results when patients have received antibiotics. During the bioterrorism event of 2001, we applied two novel immunohistochemical assays that can detect Bacillus anthracis antigens in skin biopsy samples even after prolonged antibiotic treatment. These assays provided a highly sensitive and specific method for the diagnosis of cutaneous anthrax, and were critical in the early and rapid diagnosis of 8 of 11 cases of cutaneous anthrax during the outbreak investigation. Skin biopsies were obtained from 10 of these 11 cases, and histopathological findings included various degrees of ulceration, hemorrhage, edema, coagulative necrosis, perivascular inflammation, and vasculitis. Serology was also an important investigation tool, but the results required several weeks because of the need to test paired serum specimens. Other tests, including culture, special stains, and polymerase chain reaction assay, were less valuable in the diagnosis and epidemiological investigation of these cutaneous anthrax cases. This report underscores the critical role of pathology in investigating potential bioterrorism events and in guiding epidemiological studies, a role that was clearly demonstrated in 2001 when B. anthracis spores were intentionally released through the United States postal system. PMID:14578189

Shieh, Wun-Ju; Guarner, Jeannette; Paddock, Christopher; Greer, Patricia; Tatti, Kathleen; Fischer, Marc; Layton, Marci; Philips, Michael; Bresnitz, Eddy; Quinn, Conrad P.; Popovic, Tanja; Perkins, Bradley A.; Zaki, Sherif R.

2003-01-01

376

MONITORING METHOD OF COW ANTHRAX BASED ON GIS AND SPATIAL STATISTICAL  

E-print Network

information system (GIS) is a computer application system, which possesses the ability of manipulating spatial for randomness. The GIS computer application software ArcGIS9.1 was used to overcome the lack of data of samplingMONITORING METHOD OF COW ANTHRAX BASED ON GIS AND SPATIAL STATISTICAL ANALYSIS Lin Li 1 , Yong Yang

Boyer, Edmond

377

Anthrax molecular epidemiology and forensics: using the appropriate marker for different evolutionary scales  

Microsoft Academic Search

Precise identification of Bacillus anthracis isolates has aided forensic and epidemiological analyses of natural anthrax cases, bioterrorism acts and industrial scale accidents by state-sponsored bioweapons programs. Because there is little molecular variation among B. anthracis isolates, identifying and using rare variation is crucial for precise strain identification. We think that mutation is the primary diversifying force in a clonal, recently

Paul Keim; Matthew N. Van Ert; Talima Pearson; Amy J. Vogler; Lynn Y. Huynh; David M. Wagner

2004-01-01

378

Early statistical detection of anthrax outbreaks by tracking over-the-counter medication sales  

Microsoft Academic Search

The recent series of anthrax attacks has reinforced the importance of biosurveillance systems for the timely detection of epidemics. This paper describes a statistical framework for monitoring grocery data to detect a large-scale but localized bioterrorism attack. Our system illustrates the potential of data sources that may be more timely than traditional medical and public health data. The system includes

Anna Goldenberg; Galit Shmueli; Richard A. Caruana; Stephen E. Fienberg

2002-01-01

379

Recent advances in the development of an improved, human anthrax vaccine  

Microsoft Academic Search

Human anthrax vaccines currently licensed in the United States and Western Europe consist of alum-precipitated or aluminum hydroxide-adsorbed supernatant material from fermentor cultures of toxigenic, nonencapsulated strains of Bacillus anthracis. These vaccines have several drawbacks, including the need for frequent boosters, the apparent inability to protect adequately against certain strains of B. anthracis, and occasional local reactogenicity.

Bruce E. Ivins; Susan L. Welkos

1988-01-01

380

Potentiation of anthrax vaccines using protective antigen-expressing viral replicon vectors.  

PubMed

DNA vaccines require improvement for human use because they are generally weak stimulators of the immune system in humans. The efficacy of DNA vaccines can be improved using a viral replicon as vector to administer antigen of pathogen. In this study, we comprehensively evaluated the conventional non-viral DNA, viral replicon DNA or viral replicon particles (VRP) vaccines encoding different forms of anthrax protective antigen (PA) for specific immunity and protective potency against anthrax. Our current results clearly suggested that these viral replicon DNA or VRP vaccines derived from Semliki Forest virus (SFV) induced stronger PA-specific immune responses than the conventional non-viral DNA vaccines when encoding the same antigen forms, which resulted in potent protection against challenge with the Bacillus anthracis strain A16R. Additionally, the naked PA-expressing SFV replicon DNA or VRP vaccines without the need for high doses or demanding particular delivery regimens elicited robust immune responses and afforded completely protective potencies, which indicated the potential of the SFV replicon as vector of anthrax vaccines for use in clinical application. Therefore, our results suggest that these PA-expressing SFV replicon DNA or VRP vaccines may be suitable as candidate vaccines against anthrax. PMID:25102364

Wang, Hai-Chao; An, Huai-Jie; Yu, Yun-Zhou; Xu, Qing

2015-02-01

381

Early Stastical Detection of Anthrax Out-breaks by Tracking Over-the-Counter Medication Sales  

Microsoft Academic Search

The recent series of anthrax attacks has reinforced the importance of biosurveillance systems for the timely detection of epidemics. This paper describes a statistical framework for monitoring grocery data to detect a large-scale but localized bioterrorism attack. Our system illustrates the potential of data sources that may be more timely than traditional medical and public health data. The system includes

A Goldenberg; G Shmueli

2002-01-01

382

Defining a serological correlate of protection in rabbits for a recombinant anthrax vaccine  

Microsoft Academic Search

In these studies, a serological correlate of protection against anthrax was identified in New Zealand white (NZW) rabbits that had been given one or two injections of various amounts of recombinant protective antigen (rPA) combined with aluminum hydroxide adjuvant (Alhydrogel). Rabbits were subsequently challenged by the aerosol route with spores of the Ames isolate of Bacillus anthracis. Results suggested that

S. F Little; B. E Ivins; P. F Fellows; M. L. M Pitt; S. L. W Norris; G. P Andrews

2004-01-01

383

Comparison of the immunological memory after DNA vaccination and protein vaccination against anthrax in sheep  

Microsoft Academic Search

Currently available live spore vaccines against anthrax in animals have many drawbacks, one of which is their presumed inability to induce a long lasting immunity. In the present study we compared the immunological memory after a protein vaccination with DNA vaccinations in sheep. The antigen used was the protective antigen (PA83) of Bacillus anthracis. Sheep were vaccinated three times with

Ulrike K. Hahn; Michaela Aichler; Reinhard Boehm; Wolfgang Beyer

2006-01-01

384

Analysis of Anthrax and Plague Biowarfare Vaccine Interactions with Human Monocyte-Derived Dendritic Cells1  

Microsoft Academic Search

The anti-biowarfare anthrax and plague vaccines require repeated dosing to achieve adequate protection. To test the hypothesis that this limited immunogenicity results from the nature of vaccine interactions with the host innate immune system, we inves- tigated molecular and cellular interactions between vaccines, dendritic cells (DCs), and T cells and explored the potential for adjuvants (pertussis) to boost induction of

Anna Skowera; Esther C. de Jong; Joost H. N. Schuitemaker; Jennifer S. Allen; Simon C. Wessely; Gareth Griffiths; Martien Kapsenberg; Mark Peakman

385

The Anthrax Vaccine and Research: Reactions from Postal Workers and Public Health Professionals  

PubMed Central

During the 2001 anthrax attacks, public health agencies faced operational and communication decisions about the use of antibiotic prophylaxis and the anthrax vaccine with affected groups, including postal workers. This communication occurred within an evolving situation with incomplete and uncertain data. Guidelines for prophylactic antibiotics changed several times, contributing to confusion and mistrust. At the end of 60 days of taking antibiotics, people were offered an additional 40 days' supply of antibiotics, with or without the anthrax vaccine, the former constituting an investigational new drug protocol. Using data from interviews and focus groups with 65 postal workers in 3 sites and structured interviews with 16 public health professionals, this article examines the challenges for public health professionals who were responsible for communication with postal workers about the vaccine. Multiple factors affected the response, including a lack of trust, risk perception, disagreement about the recommendation, and the controversy over the military's use of the vaccine. Some postal workers reacted with suspicion to the vaccine offer, believing that they were the subjects of research, and some African American workers specifically drew an analogy to the Tuskegee syphilis study. The consent forms required for the protocol heightened mistrust. Postal workers also had complex and ambivalent responses to additional research on their health. The anthrax attacks present us with an opportunity to understand the challenges of communication in the context of uncertain science and suggest key strategies that may improve communications about vaccines and other drugs authorized for experimental use in future public health emergencies. PMID:19117431

Thomas, Tammy; Kumar, Supriya

2008-01-01

386

Mediating the Anthrax Attacks: Media Accuracy and Agenda Setting During a Time of Moral Panic  

Microsoft Academic Search

This study examines factors affecting individuals' attitudes toward the media and susceptibility to agenda setting at times of moral panic. Sixty-three percent of respondents in a survey conducted a few weeks after the 9\\/11 attacks perceived the media anthrax coverage as accurate. Results suggest geographic location and gender, in addition to attitudes toward media accuracy, are strong predictors of agenda

Shahira Fahmy; Thomas J. Johnson

2007-01-01

387

Facilitation of Risk Communication During the Anthrax Attacks of 2001: The Organizational Backstory  

Microsoft Academic Search

The anthrax attacks of 2001 created risk communication problems that cannot be fully understood without appreci- ating the dynamics among organizations. Case studies of communication in New Jer- sey, consisting of interviews with a range of participants, found that existing organiza- tional and professional net- works facilitated trust among decisionmakers. This inter- personal trust improved com- munication among agencies and

Caron Chess; Lee Clarke

2007-01-01

388

The dissemination of anthrax from imported wool: Kidderminster 1900–14  

PubMed Central

Background: A century ago anthrax was a continuing health risk in the town of Kidderminster. The distribution of cases in people and in animals provides an indication of the routes by which spores were disseminated. The response to these cases provides an insight into attitudes to an occupational and environmental risk at the time and can be compared with responses in more recent times. Aims: To assess the distribution of anthrax cases associated with the use of contaminated wool and to review the response to them. Methods: The area studied was Kidderminster, Worcestershire, England, from 1900 to 1914. Data sources were national records of the Factory Inspectorate and local records from the infirmary, Medical Officer of Health and inquest reports, and county agricultural records, supplemented by contemporary and later review articles. Case reports and summary data were analysed, and discussions and actions taken to improve precautions reviewed. Results: There were 36 cases of anthrax, with five deaths, one of which was the sole case of the internal form of the disease. Cases of cutaneous anthrax were most frequently found in those handling raw wool, but they also occurred in workers at later stages of the spinning process and in people with little or no recorded exposure to contaminated wool. Limited precautionary measures were in place at the start of the study period. Some improvements were made, especially in the treatment of infections, but wool with a high risk of anthrax contamination continued to be used and cases continued to arise. Major changes were made to the disposal of waste and to agricultural practice in contaminated areas to curtail outbreaks in farm animals. Conclusions: The introduction of anthrax as a contaminant of imported wool led not only to cases in the highly exposed groups of workers but also to cases in other members of the population and in farm animals. The measures taken during the study period reduced fatalities from cutaneous anthrax but did not eliminate the disease. Public concern about the cases was muted. PMID:14739375

Carter, T

2004-01-01

389

Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice?†  

PubMed Central

Mechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores of Bacillus anthracis Ames, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genome-wide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C×DF2 population revealed a significant QTL (designated Rpai1 for resistance to pulmonary anthrax infection, locus 1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains. PMID:21628518

Yadav, Jagjit S.; Pradhan, Suman; Kapoor, Renuka; Bangar, Hansraj; Burzynski, Benjamin B.; Prows, Daniel R.; Levin, Linda

2011-01-01

390

Internal radiation dosimetry for clinical testing of radiolabeled monoclonal antibodies  

SciTech Connect

In gauging the efficacy of radiolabeled monoclonal antibodies in cancer treatment, it is important to know the amount of radiation energy absorbed by tumors and normal tissue per unit administered activity. This paper describes methods for estimating absorbed doses to human tumors and normal tissues, including intraperitoneal tissue surfaces, red marrow, and the intestinal tract from incorporated radionuclides. These methods use the Medical Internal Radiation Dose (MIRD) scheme; however, they also incorporate enhancements designed to solve specific dosimetry problems encountered during clinical studies, such as patient-specific organ masses obtained from computerized tomography (CT) volumetrics, estimates of the dose to tumor masses within normal organs, and multicellular dosimetry for studying dose inhomogeneities in solid tumors. Realistic estimates of absorbed dose are provided within the short time requirements of physicians so that decisions can be made with regard to patient treatment and procurement of radiolabeled antibodies. Some areas in which further research could improve dose assessment are also discussed. 16 refs., 3 figs.

Fisher, D.R.; Durham, J.S.; Hui, T.E.; Hill, R.L.

1990-11-01

391

In a “nutshell”: intrinsically radio-labeled quantum dots  

PubMed Central

Quantum dots (QDs) have many intriguing properties suitable for biomedical imaging applications. The poor tissue penetration of optical imaging in general, including those using QDs, has motivated the development of various QD-based dual-modality imaging agents. In this issue of AJNMMI (http://www.ajnmmi.us), Sun et al. reported the synthesis and in vitro/in vivo characterization of intrinsically radio-labeled QDs (r-QDs), where 109Cd was incorporated into the core/shell of QDs of various compositions. These r-QDs emit in the near-infrared range, have long circulation half-life, are quite stable with low cytotoxicity, exhibit small size and low accumulation in the reticuloendothelial system, and can allow for accurate measurement of their biodistribution in mice. With these desirable features demonstrated in this study, future development and optimization will further enhance the biomedical potential of intrinsically radio-labeled QDs. PMID:23133808

Cai, Weibo; Hong, Hao

2012-01-01

392

Dual-radiolabeled nanoparticle SPECT probes for bioimaging  

NASA Astrophysics Data System (ADS)

A gold nanoparticle was radiolabeled with 125I and 111In and functionalized with an MMP9-cleavable peptide to form a multispectral SPECT imaging contrast agent. Peptide cleavage from the nanoprobe by MMP9 was observed in vitro, and distinct pharmacokinetic properties of the contrast agent were observed between tumors with high or low MMP9 expression.A gold nanoparticle was radiolabeled with 125I and 111In and functionalized with an MMP9-cleavable peptide to form a multispectral SPECT imaging contrast agent. Peptide cleavage from the nanoprobe by MMP9 was observed in vitro, and distinct pharmacokinetic properties of the contrast agent were observed between tumors with high or low MMP9 expression. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05269b

Black, Kvar C. L.; Akers, Walter J.; Sudlow, Gail; Xu, Baogang; Laforest, Richard; Achilefu, Samuel

2014-12-01

393

Epsilon toxin: a fascinating pore-forming toxin.  

PubMed

Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric ?-pore-forming toxins including aerolysin and Clostridium septicum alpha toxin, which are characterized by the formation of a pore through the plasma membrane of eukaryotic cells consisting in a ?-barrel of 14 amphipatic ? strands. By contrast to aerolysin and C. septicum alpha toxin, ETX is a much more potent toxin and is responsible for enterotoxemia in animals, mainly sheep. ETX induces perivascular edema in various tissues and accumulates in particular in the kidneys and brain, where it causes edema and necrotic lesions. ETX is able to pass through the blood-brain barrier and stimulate the release of glutamate, which accounts for the symptoms of nervous excitation observed in animal enterotoxemia. At the cellular level, ETX causes rapid swelling followed by cell death involving necrosis. The precise mode of action of ETX remains to be determined. ETX is a powerful toxin, however, it also represents a unique tool with which to vehicle drugs into the central nervous system or target glutamatergic neurons. PMID:21535407

Popoff, Michel R

2011-12-01

394

Method to directly radiolabel antibodies for diagnostic imaging and therapy  

DOEpatents

The invention is a novel method and kit for directly radiolabeling proteins such as antibodies or antibody fragments for diagnostic and therapeutic purposes. The method comprises incubating a protein-containing solution with a solution of sodium ascorbate; adding a required quantity of reduced radionuclide to the incubated protein. A kit is also provided wherein the protein and/or reducing agents may be in lyophilized form.

Thakur, Mathew L. (Cherry Hill, NJ)

1994-01-01

395

Method to directly radiolabel antibodies for diagnostic imaging and therapy  

DOEpatents

The invention is a novel method and kit for directly radiolabeling proteins such as antibodies or antibody fragments for diagnostic and therapeutic purposes. The method comprises incubating a protein-containing solution with a solution of sodium ascorbate; adding a required quantity of reduced radionuclide to the incubated protein. A kit is also provided wherein the protein and/or reducing agents may be in lyophilized form.

Thakur, Mathew L. (Cherry Hill, NJ)

1991-01-01

396

Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics  

Microsoft Academic Search

Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [18F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), in an integrated microfluidic device. Five sequential processes-[18F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection-proceeded with high radiochemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple

Chung-Cheng Lee; Guodong Sui; Arkadij Elizarov; Chengyi Jenny Shu; Young-Shik Shin; Alek N. Dooley; Jiang Huang; Antoine Daridon; Paul Wyatt; David Stout; Hartmuth C. Kolb; Owen N. Witte; Nagichettiar Satyamurthy; James R. Heath; Michael E. Phelps; Stephen R. Quake; Hsian-Rong Tseng

2005-01-01

397

Binding kinetics of Clostridium difficile toxins A and B to intestinal brush border membranes from infant and adult hamsters  

SciTech Connect

This study was undertaken to determine if the relative resistance of neonates and infants to Clostridium difficile-associated intestinal disease can be related to age-dependent differences in intestinal receptors for C. difficile toxins A and B. Brush border membranes (BBMs) from the small intestines of adult and infant hamsters were examined for their ability to bind radiolabeled toxins A and B. (125I)toxin A bound to both infant and adult hamster BBMs at physiological temperature, whereas (125I)toxin B did not bind to the BBMs under any of the conditions examined. The number of (125I)toxin A molecules bound at saturation was approximately 4 x 10(10) per micrograms of membrane protein for adult BBMs and 1 x 10(11) per micrograms of membrane protein for infant BBMs. Scatchard plot analysis suggested the presence of a single class of toxin A binding sites on both infant and adult hamster BBMs. Maximal binding capacity and Kd values were 0.63 pmol/mg of protein and 66.7 nM, respectively, for the infant BBMs, and 0.24 pmol/mg of protein and 27 nM, respectively, for the adult BBMs. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analyses of extracted BBM proteins revealed differences in the proteins of infant and adult BBMs. However, there were not any detectable differences in the protein bands which bound (125I)toxin A between infant and adult hamsters. The results from these investigations indicate that differences in the binding kinetics of toxins A and/or B to infant and adult hamster BBMs do not account for the observed differences in their susceptibility to C. difficile-associated intestinal disease.

Rolfe, R.D. (Texas Tech Univ. Health Sciences Center, Lubbock (USA))

1991-04-01

398

Intracavitary use of two radiolabeled tumor-associated monoclonal antibodies  

SciTech Connect

Six patients with metastatic breast cancer and malignant pleural effusions and 13 patients with known or suspected ovarian cancer, underwent immunoscintigraphy after intracavitary (intrapleural or intraperitoneal) administration of iodine-131-(131I) or indium-111-(111In) labeled tumor associated monoclonal antibodies HMFG2 and H17E2. This method proved to be sensitive and specific with a true-positive result in 13 out of 14 patients with tumor and a true-negative result in five out of five patients without tumor. At any one time, 65%-80% of the whole-body radioactivity was closely associated with the cavity into which the radiolabeled antibody was administered while the radioactivity in the blood was always low, (approximately 4 X 10(-3) of administered dose/ml of blood). Concentrations of radiolabeled antibody (per gram of tumor tissue) ranged from 0.02%-0.1% of the injected dose in intracavitary tumors, but only 0.002% in a retroperitoneal metastasis. The specificity of this approach was documented in four control patients with benign ovarian cysts and in two patients who were imaged using both specific and nonspecific radiolabeled antibody. We conclude that the intracavitary administration of 131I- or 111In-labeled HMFG2 and H17E2 is a favorable route of administration and offers significant advantages over previously reported intravenous administration for the localization of breast or ovarian metastases confined to the pleural or peritoneal cavities.

Malamitsi, J.; Skarlos, D.; Fotiou, S.; Papakostas, P.; Aravantinos, G.; Vassilarou, D.; Taylor-Papadimitriou, J.; Koutoulidis, K.; Hooker, G.; Snook, D.

1988-12-01

399

Changing Patterns of Human Anthrax in Azerbaijan during the Post-Soviet and Preemptive Livestock Vaccination Eras  

PubMed Central

We assessed spatial and temporal changes in the occurrence of human anthrax in Azerbaijan during 1984 through 2010. Data on livestock outbreaks, vaccination efforts, and human anthrax incidence during Soviet governance, post-Soviet governance, preemptive livestock vaccination were analyzed. To evaluate changes in the spatio-temporal distribution of anthrax, we used a combination of spatial analysis, cluster detection, and weighted least squares segmented regression. Results indicated an annual percent change in incidence of +11.95% from 1984 to 1995 followed by declining rate of ?35.24% after the initiation of livestock vaccination in 1996. Our findings also revealed geographic variation in the spatial distribution of reporting; cases were primarily concentrated in the west early in the study period and shifted eastward as time progressed. Over twenty years after the dissolution of the Soviet Union, the distribution of human anthrax in Azerbaijan has undergone marked changes. Despite decreases in the incidence of human anthrax, continued control measures in livestock are needed to mitigate its occurrence. The shifting patterns of human anthrax highlight the need for an integrated “One Health” approach that takes into account the changing geographic distribution of the disease. PMID:25032701

Kracalik, Ian; Abdullayev, Rakif; Asadov, Kliment; Ismayilova, Rita; Baghirova, Mehriban; Ustun, Narmin; Shikhiyev, Mazahir; Talibzade, Aydin; Blackburn, Jason K.

2014-01-01

400

Antibody-based biological toxin detection  

SciTech Connect

Fiber optic evanescent fluorosensors are under investigation in our laboratory for the study of drug-receptor interactions for detection of threat agents and antibody-antigen interactions for detection of biological toxins. In a direct competition assay, antibodies against Cholera toxin, Staphylococcus Enterotoxin B or ricin were noncovalently immobilized on quartz fibers and probed with fluorescein isothiocyanate (FITC) - labeled toxins. In the indirect competition assay, Cholera toxin or Botulinum toxoid A was immobilized onto the fiber, followed by incubation in an antiserum or partially purified anti-toxin IgG. These were then probed with FITC-anti-IgG antibodies. Unlabeled toxins competed with labeled toxins or anti-toxin IgG in a dose dependent manner and the detection of the toxins was in the nanomolar range.

Menking, D.E.; Goode, M.T. [Army Edgewood Research, Development and Engineering Center, Aberdeen Proving Ground, MD (United States)

1995-12-01

401

Residues involved in the pore-forming activity of the Clostridium perfringens iota toxin.  

PubMed

Clostridium perfringens iota toxin is a binary toxin that is organized into enzyme (Ia) and binding (Ib) components. Ib forms channels in lipid bilayers and mediates the transport of Ia into the target cells. Here we show that Ib residues 334-359 contain a conserved pattern of alternating hydrophobic and hydrophilic residues forming two amphipathic ?-strands involved in membrane insertion and channel formation. This stretch of amino acids shows remarkable structural and functional analogies with the ?-pore-forming domain of C. perfringens epsilon toxin. Several mutations within the two amphipathic ?-strands affected pore formation, single-channel conductance and ion selectivity (S339E-S341E, Q345H N346E) confirming their involvement in channel formation. F454 of Ib corresponds to the ?-clamp F427 of anthrax protective antigen and F428 of C2II binary toxins. The mutation F454A resulted in a loss of cytotoxicity and strong increase in single-channel conductance (500 pS as compared with 85?pS in 1 M KCl) with a slight decrease in cation selectivity, indicating that the ?-clamp is highly conserved and crucial for binary toxin activity. In contrast, the mutants Q367D, N430D, L443E had no or only minor effects on Ib properties, while T360I, T360A and T360W caused a dramatic effect on ion selectivity and single-channel conductance, indicating gross disturbance of the oligomer structure. This suggests that, at least in the iota toxin family, T360 has a structural role in the pore organization. Moreover, introduction of charged residues within the channel (S339E-S341E) or in the vestibule (Q367D, N430D and L443E) had virtually no effect on chloroquine or Ia binding, whereas F454A, T360I, T360A and T360W strongly decreased the chloroquine and Ia affinity to Ib. These results support that distinct residues within the vestibule interact with chloroquine and Ia or are responsible for channel structure, while the channel lining amino acids play a less important role. PMID:25266274

Knapp, Oliver; Maier, Elke; Waltenberger, Eva; Mazuet, Christelle; Benz, Roland; Popoff, Michel R

2015-02-01

402

A Cell-Based Approach for the Biosynthesis/Screening of Cyclic Peptide Libraries against Bacterial Toxins  

SciTech Connect

Available methods for developing and screening small drug-like molecules able to knockout toxins or pathogenic microorganisms have some limitations. In order to be useful, these new methods must provide high-throughput analysis and identify specific binders in a short period of time. To meet this need, we are developing an approach that uses living cells to generate libraries of small biomolecules, which are then screened inside the cell for activity. Our group is using this new, combined approach to find highly specific ligands capable of disabling anthrax Lethal Factor (LF) as proof of principle. Key to our approach is the development of a method for the biosynthesis of libraries of cyclic peptides, and an efficient screening process that can be carried out inside the cell.

Camarero, J A; Kimura, R; Woo, Y; Cantor, J; Steenblock, E

2007-10-24

403

Radiolabeled Apoptosis Imaging Agents for Early Detection of Response to Therapy  

PubMed Central

Since apoptosis plays an important role in maintaining homeostasis and is associated with responses to therapy, molecular imaging of apoptotic cells could be useful for early detection of therapeutic effects, particularly in oncology. Radiolabeled annexin V compounds are the hallmark in apoptosis imaging in vivo. These compounds are reviewed from the genesis of apoptosis (cell death) imaging agents up to recent years. They have some disadvantages, including slow clearance and immunogenicity, because they are protein-based imaging agents. For this reason, several studies have been conducted in recent years to develop low molecule apoptosis imaging agents. In this review, radiolabeled phosphatidylserine targeted peptides, radiolabeled bis(zinc(II)-dipicolylamine) complex, radiolabeled 5-fluoropentyl-2-methyl-malonic acid (ML-10), caspase-3 activity imaging agents, radiolabeled duramycin, and radiolabeled phosphonium cation are reviewed as promising low-molecular-weight apoptosis imaging agents. PMID:25383382

2014-01-01

404

Proc. Natl. Acad. Sci. USA Vol. 93, pp. 1253112534, October 1996  

E-print Network

Proc. Natl. Acad. Sci. USA Vol. 93, pp. 12531­12534, October 1996 Microbiology Anthrax toxin in spleen and liver, relative to nonimmunized control mice. These results indi- cate that anthrax toxin may toxin, anthrax toxin. Anthrax toxin is composed of three proteins that act in binary combinations

Starnbach, Michael

405

Frequent and seasonally variable sublethal anthrax infections are accompanied by short-lived immunity in an endemic system.  

PubMed

1. Few studies have examined host-pathogen interactions in wildlife from an immunological perspective, particularly in the context of seasonal and longitudinal dynamics. In addition, though most ecological immunology studies employ serological antibody assays, endpoint titer determination is usually based on subjective criteria and needs to be made more objective. 2. Despite the fact that anthrax is an ancient and emerging zoonotic infectious disease found worldwide, its natural ecology is not well understood. In particular, little is known about the adaptive immune responses of wild herbivore hosts against Bacillus anthracis. 3. Working in the natural anthrax system of Etosha National Park, Namibia, we collected 154 serum samples from plains zebra (Equus quagga), 21 from springbok (Antidorcas marsupialis), and 45 from African elephants (Loxodonta africana) over 2-3 years, resampling individuals when possible for seasonal and longitudinal comparisons. We used enzyme-linked immunosorbent assays to measure anti-anthrax antibody titers and developed three increasingly conservative models to determine endpoint titers with more rigorous, objective mensuration. 4. Between 52-87% of zebra, 0-15% of springbok, and 3-52% of elephants had measurable anti-anthrax antibody titers, depending on the model used. While the ability of elephants and springbok to mount anti-anthrax adaptive immune responses is still equivocal, our results indicate that zebra in ENP often survive sublethal anthrax infections, encounter most B. anthracis in the wet season, and can partially booster their immunity to B. anthracis. 5. Thus, rather than being solely a lethal disease, anthrax often occurs as a sublethal infection in some susceptible hosts. Though we found that adaptive immunity to anthrax wanes rapidly, subsequent and frequent sublethal B. anthracis infections cause maturation of anti-anthrax immunity. By triggering host immune responses, these common sublethal infections may act as immunomodulators and affect population dynamics through indirect immunological and co-infection effects. 6. In addition, with our three endpoint titer models, we introduce more mensuration rigor into serological antibody assays, even under the often-restrictive conditions that come with adapting laboratory immunology methods to wild systems. With these methods we identified significantly more zebras responding immunologically to anthrax than have previous studies using less comprehensive titer analyses. This article is protected by copyright. All rights reserved. PMID:24499424

Cizauskas, Carrie A; Bellan, Steven E; Turner, Wendy C; Vance, Russell E; Getz, Wayne M

2014-02-01

406

Bacillus anthracis Cell Wall Peptidoglycan but Not Lethal or Edema Toxins Produces Changes Consistent With Disseminated Intravascular Coagulation in a Rat Model  

PubMed Central

Background.?Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC. Methods and Results.?To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P ? .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P ? .05 for all comparisons except for PAI level). Conclusion.?DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET. PMID:23737601

Qiu, Ping; Li, Yan; Shiloach, Joseph; Cui, Xizhong; Sun, Junfeng; Trinh, Loc; Kubler-Kielb, Joanna; Vinogradov, Evgeny; Mani, Haresh; Al-Hamad, Mariam; Fitz, Yvonne; Eichacker, Peter Q.

2013-01-01

407

Special considerations for prophylaxis for and treatment of anthrax in pregnant and postpartum women.  

PubMed

In August 2012, the Centers for Disease Control and Prevention, in partnership with the Association of Maternal and Child Health Programs, convened a meeting of national subject matter experts to review key clinical elements of anthrax prevention and treatment for pregnant, postpartum, and lactating (P/PP/L) women. National experts in infectious disease, obstetrics, maternal fetal medicine, neonatology, pediatrics, and pharmacy attended the meeting, as did representatives from professional organizations and national, federal, state, and local agencies. The meeting addressed general principles of prevention and treatment for P/PP/L women, vaccines, antimicrobial prophylaxis and treatment, clinical considerations and critical care issues, antitoxin, delivery concerns, infection control measures, and communication. The purpose of this meeting summary is to provide updated clinical information to health care providers and public health professionals caring for P/PP/L women in the setting of a bioterrorist event involving anthrax. PMID:24457117

Meaney-Delman, Dana; Zotti, Marianne E; Creanga, Andreea A; Misegades, Lara K; Wako, Etobssie; Treadwell, Tracee A; Messonnier, Nancy E; Jamieson, Denise J

2014-02-01

408

Special Considerations for Prophylaxis for and Treatment of Anthrax in Pregnant and Postpartum Women  

PubMed Central

In August 2012, the Centers for Disease Control and Prevention, in partnership with the Association of Maternal and Child Health Programs, convened a meeting of national subject matter experts to review key clinical elements of anthrax prevention and treatment for pregnant, postpartum, and lactating (P/PP/L) women. National experts in infectious disease, obstetrics, maternal fetal medicine, neonatology, pediatrics, and pharmacy attended the meeting, as did representatives from professional organizations and national, federal, state, and local agencies. The meeting addressed general principles of prevention and treatment for P/PP/L women, vaccines, antimicrobial prophylaxis and treatment, clinical considerations and critical care issues, antitoxin, delivery concerns, infection control measures, and communication. The purpose of this meeting summary is to provide updated clinical information to health care providers and public health professionals caring for P/PP/L women in the setting of a bioterrorist event involving anthrax. PMID:24457117

Zotti, Marianne E.; Creanga, Andreea A.; Misegades, Lara K.; Wako, Etobssie; Treadwell, Tracee A.; Messonnier, Nancy E.; Jamieson, Denise J.

2014-01-01

409

Massive outbreak of anthrax in wildlife in the Malilangwe Wildlife Reserve, Zimbabwe.  

PubMed

A massive outbreak of anthrax in the wildlife of the Malilangwe Wildlife Reserve in Zimbabwe between August and November 2004 resulted in the death of almost all the reserve's estimated 500 kudu (Tragelaphus strepsiceros). Other species badly affected were nyala (Tragelaphus angasi), bushbuck (Tragelaphus scriptus), waterbuck (Kobus ellipsiprymnus) and roan antelope (Hippotragus equinus), which suffered losses of approximately 68 per cent, 48 per cent, 44 per cent and 42 per cent of their populations, respectively. Buffalo (Syncerus caffer) were also badly affected and although their population suffered only a 6 per cent loss, the numbers of deaths ranked second highest after kudu. To the authors' knowledge, this is the first record of anthrax in wildlife in Zimbabwe. PMID:17259452

Clegg, S B; Turnbull, P C B; Foggin, C M; Lindeque, P M

2007-01-27

410

Combating the threat of anthrax: a quantitative structure-activity relationship approach.  

PubMed

Bacterial agents or products more likely to be used as biological weapons of mass destruction are Bacillus anthracis, Francisella tularensis, Yersinia pestis, and the neurotoxin of Clostridium botulinum. Anthrax is an acute infectious disease with a high mortality rate caused by Bacillus anthracis, reinforcing the need for better adjunctive therapy and prevention strategies. In this paper, we developed 7 QSAR models on penicillin-based inhibitors of the class A and B beta-lactamases from B. anthracis and inhibitors of anthrax lethal factor to understand the chemical-biological interactions. Hydrophobic and steric factors are found to be the most important determinants of the activity. Internal (cross-validation ( q (2)), quality factor ( Q), Fischer statistics ( F), and Y-randomization) and external validation tests have validated all the QSAR models. PMID:18611038

Verma, Rajeshwar P; Hansch, Corwin

2008-01-01

411

Plasma stability and pharmacokinetics of radiolabeled deferoxamine-biotin derivatives.  

PubMed

The extraordinary high affinity of biotin for streptavidin may be exploited in a two-step in vivo approach for delivering radiolabeled biotin derivatives suitable for imaging and therapy to lesion-bound streptavidin-conjugated monoclonal antibodies. Compared to the use of directly radiolabeled monoclonal antibodies, the two-step approach is desirable because of the fast renal clearance of radiobiotin, which reduces in vivo background levels and radiation dose. Deferoxamine binds with high-affinity trivalent metals useful for imaging and radiotherapy. Three deferoxaminebiotin derivatives were synthesized, radiolabeled and their stabilities tested in vitro in dog plasma and in vivo in the dog by an avidin binding assay and high-performance liquid chromatography. Defero-desaminolysyl-biotin (DLB) was unstable, with immediate degradation evident. A plasma enzyme, biotinidase, converts biocytin to biotin. DLB closely resembles biocytin, and analysis of the urine and plasma suggested rapid degradation of DLB to biotin and desaminolsyl-deferoxamine. Defero-biotin, a direct conjugate of deferoxamine and biotin, was similarly tested and found to be more stable. Defero-acetyl-cysteinyl-biotin contains a carboxyl group adjacent to the amide bond cleavage site of biotinidase. In vitro at 24 hr in plasma, defero-acetyl-cysteinyl-biotin was 87% stable, compared to 45% and 15% for defero-biotin and DLB, respectively. The pharmacokinetics of the three derivatives were similar, with 80% of the injected doses found in the urine at 6 hr; however, only defero-acetyl-cysteinyl-biotin was present as the intact moiety. PMID:8474023

Rosebrough, S F

1993-04-01

412

Anthrax outbreak in a Swedish beef cattle herd - 1st case in 27 years: Case report  

PubMed Central

After 27 years with no detected cases, an outbreak of anthrax occurred in a beef cattle herd in the south of Sweden. The outbreak was unusual as it occurred in winter, in animals not exposed to meat-and-bone meal, in a non-endemic country. The affected herd consisted of 90 animals, including calves and young stock. The animals were kept in a barn on deep straw bedding and fed only roughage. Seven animals died during 10 days, with no typical previous clinical signs except fever. The carcasses were reportedly normal in appearance, particularly as regards rigor mortis, bleeding and coagulation of the blood. Subsequently, three more animals died and anthrax was suspected at necropsy and confirmed by culture and PCR on blood samples. The isolated strain was susceptible to tetracycline, ciprofloxacin and ampicillin. Subtyping by MLVA showed the strain to cluster with isolates in the A lineage of Bacillus anthracis. Environmental samples from the holding were all negative except for two soil samples taken from a spot where infected carcasses had been kept until they were picked up for transport. The most likely source of the infection was concluded to be contaminated roughage, although this could not be substantiated by laboratory analysis. The suspected feed was mixed with soil and dust and originated from fields where flooding occurred the previous year, followed by a dry summer with a very low water level in the river allowing for the harvesting on soil usually not exposed. In the early 1900s, animal carcasses are said to have been dumped in this river during anthrax outbreaks and it is most likely that some anthrax spores could remain in the area. The case indicates that untypical cases in non-endemic areas may be missed to a larger extent than previously thought. Field tests allowing a preliminary risk assessment of animal carcasses would be helpful for increased sensitivity of detection and prevention of further exposure to the causative agent. PMID:20122147

2010-01-01

413

Expression of protective antigen in transgenic plants: a step towards edible vaccine against anthrax  

Microsoft Academic Search

Protective antigen (PA) is the most potent molecule for vaccination against anthrax. In the present study, we have successfully integrated protective antigen gene in nuclear genome of tobacco plants by Agrobacterium mediated leaf-disc transformation method. Expression of protective antigen gene was detected by immunoblot analysis using antisera raised against purified PA. A distinct band of ?83kDa lighted up in the

Mohd. Azhar Aziz; Samer Singh; P Anand Kumar; Rakesh Bhatnagar

2002-01-01

414

The Anthrax Capsule: Role in Pathogenesis and Target for Vaccines and Therapeutics  

Microsoft Academic Search

\\u000a The polyglutamic acid capsule of Bacillus anthracis is a well-established virulence factor, conferring antiphagocytic properties on the bacillus. We have shown that the capsule\\u000a also confers partial resistance to killing by human defensins. In our research we targeted the anthrax capsule for developing\\u000a medical countermeasures, first using the capsule as a vaccine, similar to successful efforts with other bacteria, and

Arthur M. Friedlander

415

Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin  

Microsoft Academic Search

Oedema factor, a calmodulin-activated adenylyl cyclase, is important in the pathogenesis of anthrax. Here we report the X-ray structures of oedema factor with and without bound calmodulin. Oedema factor shares no significant structural homology with mammalian adenylyl cyclases or other proteins. In the active site, 3'-deoxy-ATP and a single metal ion are well positioned for catalysis with histidine 351 as

Chester L. Drum; Shui-Zhong Yan; Joel Bard; Yue-Quan Shen; Dan Lu; Sandriyana Soelaiman; Zenon Grabarek; Andrew Bohm; Wei-Jen Tang

2002-01-01

416

Attenuated Nontoxinogenic and Nonencapsulated Recombinant Bacillus anthracis Spore Vaccines Protect against Anthrax  

Microsoft Academic Search

immunization of guinea pigs with 5 3 107 spores of one of these recombinant strains, MASC-10, expressing high levels of rPA (>100 mg\\/ml) from a constitutive heterologous promoter induced high titers of neutralizing anti-PA antibodies. This immune response was long lasting (at least 12 months) and provided protection against a lethal challenge of virulent (Vollum) anthrax spores. The recombinant B.

S. Cohen; I. Mendelson; Z. Altboum; D. Kobiler; E. Elhanany; T. Bino; M. Leitner; I. Inbar; H. Rosenberg; Y. Gozes; R. Barak; M. Fisher; C. Kronman; B. Velan; A. Shafferman

2000-01-01

417

Rapid Detection of an Anthrax Biomarker by Surface-Enhanced Raman Spectroscopy  

Microsoft Academic Search

A rapid detection protocol suitable for use by first-responders to detect anthrax spores using a low-cost, battery-powered, portable Raman spectrometer has been developed. Bacillus subtilis spores, harmless simulants for Bacillus anthracis, were studied using surface-enhanced Raman spectroscopy (SERS) on silver film over nanosphere (AgFON) substrates. Calcium dipicolinate (CaDPA), a biomarker for bacillus spores, was efficiently extracted by sonication in nitric

Xiaoyu Zhang; Matthew A. Young; Olga Lyandres; Richard P. Van Duyne

2005-01-01

418

Anthrax sub-unit vaccine: The structural consequences of binding rPA83 to Alhydrogel®  

Microsoft Academic Search

An anthrax sub-unit vaccine, comprising recombinant Protective Antigen (rPA83) and aluminium hydroxide adjuvant (Alhydrogel®) is currently being developed. Here, a series of biophysical techniques have been applied to free and adjuvant bound antigen. Limited proteolysis and fluorescence identified no changes in rPA83 tertiary structure following binding to Alhydrogel and the bound rPA83 retained two structurally important calcium ions. For adsorbed

Andrei Soliakov; Ian F. Kelly; Jeremy H. Lakey; Allan Watkinson

419

Characterisation of the immune response to the UK human anthrax vaccine  

Microsoft Academic Search

The UK human anthrax vaccine consists of the alum-precipitated culture supernatant of Bacillus anthracis Sterne. In addition to protective antigen (PA), the key immunogen, the vaccine also contains a number of other bacteria- and media-derived proteins. These proteins may contribute to the transient side effects experienced by some individuals and could influence the development of the PA-specific immune response. Bacterial

Leslie Baillie; Richard Hebdon; Helen Flick-Smith; Diane Williamson

2003-01-01

420

Immunogenicity of Recombinant Protective Antigen and Efficacy against Aerosol Challenge with Anthrax  

Microsoft Academic Search

Immunization with a recombinant form of the protective antigen (rPA) from Bacillus anthracis has been carried out with rhesus macaques. Rhesus macaques immunized with 25 g or more of B. subtilis-expressed rPA bound to alhydrogel had a significantly increased immunoglobulin G (IgG) response to rPA compared with macaques receiving the existing licensed vaccine from the United Kingdom (anthrax vaccine precipitated

E. D. Williamson; I. Hodgson; N. J. Walker; A. W. Topping; M. G. Duchars; J. M. Mott; J. Estep; C. LeButt; H. C. Flick-Smith; H. E. Jones; H. Li; C. P. Quinn

2005-01-01

421

Catastrophic Incident Recovery: Long-Term Recovery from an Anthrax Event Symposium  

SciTech Connect

On March 19, 2008, policy makers, emergency managers, and medical and Public Health officials convened in Seattle, Washington, for a workshop on Catastrophic Incident Recovery: Long-Term Recovery from an Anthrax Event. The day-long symposium was aimed at generating a dialogue about restoration and recovery through a discussion of the associated challenges that impact entire communities, including people, infrastructure, and critical systems.

Lesperance, Ann M.

2008-06-30

422

Cutaneous anthrax of the hand and its reconstruction with a reverse-flow radial forearm flap.  

PubMed

Bacillus anthracis infection can lead to necrosis in tissues and may manifest as a fatal disease in human beings. The authors present a patient with a large area of skin necrosis on the dorsum of the hand that was reconstructed with a reverse flow-through radial forearm flap, and they discuss the relevant literature. To the authors' knowledge, this is the first published report of such extensive necrosis resulting from anthrax limited to the extensor retinaculum of the hand. PMID:12142604

Coban, Y Kenan; Balik, Ozgul; Boran, Cetin

2002-07-01

423

Stool Test: C. Difficile Toxin (For Parents)  

MedlinePLUS

... Pregnancy Precautions Checkups: What to Expect Stool Test: C. Difficile Toxin KidsHealth > Parents > Doctors & Hospitals > Medical Tests & Exams > Stool Test: C. Difficile Toxin Print A A A Text Size ...

424

Sodium Channel Inhibiting Marine Toxins  

NASA Astrophysics Data System (ADS)

Saxitoxin (STX), tetrodotoxin (TTX) and their many chemical relatives are part of our daily lives. From killing people who eat seafood containing these toxins, to being valuable research tools unveiling the invisible structures of their pharmacological receptor, their global impact is beyond measure. The pharmacological receptor for these toxins is the voltage-gated sodium channel which transports Na ions between the exterior to the interior of cells. The two structurally divergent families of STX and TTX analogues bind at the same location on these Na channels to stop the flow of ions. This can affect nerves, muscles and biological senses of most animals. It is through these and other toxins that we have developed much of our fundamental understanding of the Na channel and its part in generating action potentials in excitable cells.

Llewellyn, Lyndon E.

425

Efficacy and Safety of AVP-21D9, an Anthrax Monoclonal Antibody, in Animal Models and Humans  

PubMed Central

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.) PMID:24733473

Malkevich, Nina V.; Hopkins, Robert J.; Bernton, Edward; Meister, Gabriel T.; Vela, Eric M.; Atiee, George; Johnson, Virginia; Nabors, Gary S.; Aimes, Ronald T.; Ionin, Boris

2014-01-01

426

False alarms, real challenges--one university's communication response to the 2001 anthrax crisis.  

PubMed

Considerable research exists on how government agencies at the federal, state, and local levels communicated during the fall 2001 anthrax attacks. However, there is little research on how other institutions handled this crisis, in terms of their response to potential anthrax contamination (aka "white powder scares") and their approach to disseminating important health and safety information. In this article, we investigate a major university's communication response to the anthrax crisis. First, we describe its communication experiences relating to a large white powder scare that occurred in October 2001. Second, we describe the university's broader communication efforts in terms of several important elements of risk communication research, including influence of source attributes, key messages, preferred channels, responses to information requests, and organizational influences. This study underlines that an institution does not have to be directly affected by a crisis to find itself on the communication "front lines." Moreover, other institutions may find it useful to learn from the experiences of this university, so that they may communicate more effectively during future crises. PMID:16545026

Clarke, Christopher E; Chess, Caron

2006-01-01

427

Addressing residual risk issues at anthrax cleanups: how clean is safe?  

PubMed

Since the 2001 attacks in which Bacillus anthracisspores were mailed to various media offices and two U.S. Senators, considerable interest has focused on developing estimates of the risk of contracting inhalational anthrax from exposure to such spores. Credible risk estimates would have significant utility in establishing future cleanup goals for contaminated sites. To perform a meaningful risk assessment, one needs sufficient data to identify the hazards, conduct dose-response assessment, and assess exposure. This report reviews the existing data on mortality produced by Bacillus anthracisspores in laboratory animals and humans. In particular, it focuses on the 11 cases of inhalational anthrax resulting from the 2001 attacks and their impact on hazard identification activities. It also addresses factors that may contribute to increased risk among exposed populations and the sources of uncertainty in dose response analysis. The article examines the state of the science for assessing exposure levels to Bacillus anthracis spores and concludes that significant challenges exist to performing robust assessments of risk. This conclusion supports the policy position of the U.S. Environmental Protection Agency (EPA) that there should be no growth of Bacillus anthracis spores from all postremediation environmental samples, for the cleanup of a site to be judged effective and for that site to be considered safe for reoccupancy. This has been the ultimate criterion for efficacy of cleanups performed in response to the 2001 anthrax attacks. PMID:16020189

Canter, Dorothy A

428

The necrophagous fly anthrax transmission pathway: empirical and genetic evidence from wildlife epizootics.  

PubMed

Early studies confirmed Bacillus anthracis in emesis and feces of flies under laboratory conditions, but there is little empirical field evidence supporting the roles of flies in anthrax transmission. We collected samples during outbreaks of anthrax affecting livestock and native and exotic wildlife on two ranches in West Texas (2009-2010). Sampling included animal carcasses, maggots, adult flies feeding on or within several meters of carcasses, and leaves from surrounding vegetation. Microbiology and PCR were used to detect B. anthracis in the samples. Viable B. anthracis and/or PCR-positive results were obtained from all represented sample types. Genetic analysis of B. anthracis samples using multilocus variable number tandem repeat analysis (MLVA) confirmed that each ranch represented a distinct genetic lineage. Within each ranch, we detected the same genotype of B. anthracis from carcasses, maggots, and adult flies. The results of this study provide evidence supporting a transmission cycle in which blowflies contaminate vegetation near carcasses that may then infect additional browsing animals during anthrax outbreaks in the shrubland environment of West Texas. PMID:25072988

Blackburn, Jason K; Van Ert, Matthew; Mullins, Jocelyn C; Hadfield, Ted L; Hugh-Jones, Martin E

2014-08-01

429

Cutaneous absorption and decontamination of ( sup 3 H)T-2 toxin in the rat model  

SciTech Connect

Cutaneous absorption and decontamination of ({sup 3}H)T-2 mycotoxin using various treatment modalities incorporating water, detergent, sprays, and scrubbing of application sites were examined in the rat model at 5, 30, 60, and 1440 min (24 h) postexposure. Rats were killed immediately after treatment and radiolabeled T-2 remaining in full-thickness skin samples was determined. Absorption and decontamination were followed over time, and decontaminating treatment modalities were evaluated for efficacy. Less than 1% of the applied dose was absorbed in 5 min, and 50% was absorbed in 24 h. At 5 min, 99.5 {plus minus} 0.05% of nonabsorbed (residual) ({sup 3}H)T-2 was removed, and 58 {plus minus} 5.2% of residual toxin was removed at 24 h with a 2.5% detergent/water spray. When treatment modalities were evaluated at 60 min, a 2.5% detergent/water scrub followed by a detergent/water spray produced optimal decontamination by removing 81 {plus minus} 2.2% of residual toxin. All treatment modalities using detergent and/or water removed significant amounts of toxin, a dry scrub was not efficacious. Treatment should be initiated as soon as possible after exposure for best results. However, the stratum corneum acts as a reservoir for the toxin, and decontamination should be carried out even if delayed several hours or days after exposure. Dermal absorption pharmacokinetics found in these studies are similar to those described for other low-molecular-weight compounds, and the decontamination results from T-2 toxin should be applicable to other, similar toxic substances.

Bunner, B.L.; Wannemacher, R.W. Jr.; Dinterman, R.E.; Broski, F.H. (Army Biomedical Research and Development Laboratory, Fort Detrick, Frederick, MD (USA))

1989-01-01

430

Yeast killer toxins and dimorphism.  

PubMed

The differential action of four selected yeast killer toxins on the mycelial and yeast forms of four isolates of the dimorphic fungus Sporothrix schenckii was comparatively evaluated. The results confirmed that the yeast killer phenomenon is present among hyphomycetes and yeasts and that both morphological forms of S. schenckii are susceptible to the action of the same yeast killer toxin. Quantitative differences in the response to the killer action of the mycelial and yeast forms in individual strains were also observed. To avoid retroconversion of the dimorphic forms, we used a modification of the conventional killer system. PMID:2754015

Polonelli, L; Conti, S; Campani, L; Morace, G; Fanti, F

1989-06-01

431

Biokinetics and dosimetry of several radiolabelled peptides in cancer cells  

NASA Astrophysics Data System (ADS)

Radiolabelled peptides have been used as target-specific radiopharmaceuticals. The goal of this research was the in vitro assessment of the uptake, internalization, externalization, and efflux of five radiolabelled peptides in cancer cells to estimate radiation-absorbed doses from experimental biokinetic data. 177Lu-DOTA-octreotate, 188Re-lanreotide, and 99mTc-HYNIC-octreotide were studied in the AR42J cell line. The PC3 and NCIH69 cells were used for 99mTc-HYNIC-bombesin and 177Lu-DOTA-minigastrin, respectively. The cumulated activities in the membrane and cytoplasm were calculated by integration of the experimental time-activity curves and used for dosimetry calculations according to the Medical Internal Radiation Dose (MIRD) cellular methodology. The mean absorbed dose to the cell nucleus were 0.69±0.09, 0.11±0.08, 0.55±0.09, 3.45±0.48, and 3.30±0.65 Gy/Bq for 99mTc-HYNIC-bombesin, 99mTc-HYNIC-octreotide, 177Lu-DOTA-minigastrin, 177Lu-DOTA-octreotate, and 188Re-lanreotide, respectively. If radiopharmaceutical cell kinetics were not used and only uptake data were considered, the calculated doses would be overestimated up to 25 times.

Rodríguez-Cortés, J.; Ferro-Flores, G.; de Murphy, C. Arteaga; Pedraza-López, M.; Ramírez-Iglesias, M. A. T.

432

Shiga toxins induce autophagy leading to differential signaling pathways in toxin-sensitive and toxin-resistant human cells  

PubMed Central

Summary The bacterial virulence factors Shiga toxins (Stxs) are expressed by Shigella dysenteriae serotype 1 and certain Escherichia coli strains. Stxs are protein synthesis inhibitors and induce apoptosis in many cell types. Stxs induce apoptosis via prolonged ER stress signaling to activate both extrinsic and intrinsic pathways in human myeloid cells. Studies have shown that autophagy, a lysosome-dependent catabolic process, may be associated with activation of pro-survival or death processes. It is currently unknown if autophagy contributes to apoptosis or protects cells from Stxs. To study cellular responses to Stxs, we intoxicated toxin-sensitive cells (THP-1 and HK-2 cells), and toxin-resistant cells (primary human monocyte-derived macrophages) and examined toxin intracellular trafficking and autophagosome formation. Stxs translocated to different cell compartments in toxin-resistant versus toxin-sensitive cells. Confocal microscopy revealed autophagosome formation in both toxin-resistant and toxin-sensitive cells. Proteolytic cleavage of Atg5 and Beclin-1 play pivotal roles in switching non-cytotoxic autophagy to cell death signaling. We detected cleaved forms of Atg5 and Beclin-1 in Stx-treated toxin-sensitive cells, while cleaved caspases, calpains, Atg5 and Beclin-1 were not detected in toxin-resistant primary human monocytes and macrophages. These findings suggest that toxin sensitivity correlates with caspase and calpain activation, leading to Atg5 and Beclin-1 cleavage. PMID:21722286

Lee, Moo-Seung; Cherla, Rama P.; Jenson, Matthew H.; Leyva-Illades, Dinorah; Martinez-Moczygemba, Margarita; Tesh, Vernon L.

2011-01-01

433

Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin  

Microsoft Academic Search

The efficacy of a licensed human anthrax vaccine (Anthrax Vaccine Adsorbed (AVA)) was tested in guinea pigs, rabbits, and rhesus macaques against spore challenge by Bacillus anthracis isolates of diverse geographical origin. Initially, groups of Hartley guinea pigs were vaccinated at 0 and 4 weeks with AVA, then challenged intramuscularly at 10 weeks with spores from 33 isolates of B.

P. F. Fellows; M. K. Linscott; B. E. Ivins; M. L. M. Pitt; C. A. Rossi; P. H. Gibbs; A. M. Friedlander

2001-01-01

434

Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant  

PubMed Central

Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ?4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy. PMID:24554695

Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita

2014-01-01

435

Ackee Toxin : a Riboflavin Antimetabolite?  

Microsoft Academic Search

THERE has occurred in Jamaica an illness known as `vomiting sickness', characterized by vomiting, coma and death, which has been attributed to a toxin present in the ackee (Blighia sapida)1-3. In the course of routine assay for the protein values of human diets, a Jamaican meal containing this fruit was prepared, fed to rats, and the animals lost 26 per

H. C. Fox; D. S. Miller

1960-01-01

436

MCEARD - CYANOBACTERIA AND THEIR TOXINS  

EPA Science Inventory

Harmful algal blooms (HAB) of cyanobacteria, also known as blue-green algae, have recently become more spatially and temporally prevalent in the US and worldwide. Waterborne cyanobacteria and their highly potent toxins are a significant hazard for human health and the ecosystem....

437

Recombinant Toxins for Cancer Treatment  

Microsoft Academic Search

Recombinant toxins target cell surface receptors and antigens on tumor cells. They kill by mechanisms different from conventional chemotherapy, so that cross resistance to conventional chemotherapeutic agents should not be a problem. Furthermore, they are not mutagens and should not induce secondary malignancies or accelerate progression of benign malignancies. They can be mass-produced cheaply in bacteria as homogeneous proteins. Either

Ira Pastan; David Fitzgerald

1991-01-01

438

Risk Assessment of Shellfish Toxins  

PubMed Central

Complex secondary metabolites, some of which are highly toxic to mammals, are produced by many marine organisms. Some of these organisms are important food sources for marine animals and, when ingested, the toxins that they produce may be absorbed and stored in the tissues of the predators, which then become toxic to animals higher up the food chain. This is a particular problem with shellfish, and many cases of poisoning are reported in shellfish consumers each year. At present, there is no practicable means of preventing uptake of the toxins by shellfish or of removing them after harvesting. Assessment of the risk posed by such toxins is therefore required in order to determine levels that are unlikely to cause adverse effects in humans and to permit the establishment of regulatory limits in shellfish for human consumption. In the present review, the basic principles of risk assessment are described, and the progress made toward robust risk assessment of seafood toxins is discussed. While good progress has been made, it is clear that further toxicological studies are required before this goal is fully achieved. PMID:24226039

Munday, Rex; Reeve, John

2013-01-01

439

Monitoring water supplies for weaponized bacteria and bacterial toxins using rapid fluorescence-based viability and affinity assays  

NASA Astrophysics Data System (ADS)

The rapid detection of weaponized bacteria and toxins is a major problem during a biological attack. Although sensitive detection formats exist for many biowarfare agents, they often require advanced training and complex procedures. Luna has developed simple, rapid means for determining the presence of pathogens and bacterial toxins in water supplies using fluorescence-based assays that can be adapted for field use. The batteries of rapid assays are designed for i) determining cell viability and bacterial loads by exploiting metabolic markers (e.g., acid-production, redox potentials, etc) and ii) detecting bacterial toxins using fluorescent, polymerized affinity liposomes (fluorosomes). The viability assays were characterized using E. coli, S. aureus and the anthrax simulant, B. globigii. The viability assays detected bacterial loads of ~ 104 CFU/ml and with simple filtration ~ 100CFU/ml could be detected. The affinity fluorosomes were characterized using cholera toxin (CT). Affinity liposomes displaying GM1 and anti-CT antibodies could detect CT at

Van Tassell, Roger L.; Evans, Mishell

2004-03-01

440

Nemertean toxin genes revealed through transcriptome sequencing.  

PubMed

Nemerteans are one of few animal groups that have evolved the ability to utilize toxins for both defense and subduing prey, but little is known about specific nemertean toxins. In particular, no study has identified specific toxin genes even though peptide toxins are known from some nemertean species. Information about toxin genes is needed to better understand evolution of toxins across animals and possibly provide novel targets for pharmaceutical and industrial applications. We sequenced and annotated transcriptomes of two free-living and one commensal nemertean and annotated an additional six publicly available nemertean transcriptomes to identify putative toxin genes. Approximately 63-74% of predicted open reading frames in each transcriptome were annotated with gene names, and all species had similar percentages of transcripts annotated with each higher-level GO term. Every nemertean analyzed possessed genes with high sequence similarities to known animal toxins including those from stonefish, cephalopods, and sea anemones. One toxin-like gene found in all nemerteans analyzed had high sequence similarity to Plancitoxin-1, a DNase II hepatotoxin that may function well at low pH, which suggests that the acidic body walls of some nemerteans could work to enhance the efficacy of protein toxins. The highest number of toxin-like genes found in any one species was seven and the lowest was three. The diversity of toxin-like nemertean genes found here is greater than previously documented, and these animals are likely an ideal system for exploring toxin evolution and industrial applications of toxins. PMID:25432940

Whelan, Nathan V; Kocot, Kevin M; Santos, Scott R; Halanych, Kenneth M

2014-12-01