Novel Therapeutic and Prophylactic Modalities to Protect the United States Armed Forces Against Mayor Biological Threat Agents
Abstract
We found that secreted virulence factors other than anthrax toxins play important role in anthrax. Our experiments revealed several pathogenic mechanisms relevant to the activity of anthrax proteases and hemolysins in cultured cells and mice challenged with B. anthracis spores. In the reporting period the research was focused on the hemostatic abnormalities manifested in the degradation of von Willebrand factor, release of this factor in response to anthrax proteins, and degradation of the ADAMTS13 protease. The results favor a hypothesis that an anticoagulant activity of secreted pathogenic factors along with the disruption of barrier permeability could be considered as a major cause of hemorrhage during infection. Studies on host cell signaling cascades allowed identify the cell survival pathways as new potential pharmacological targets. Inhibition of AKT pathway in spore-challenged cells indicates a strong contribution of the edema toxin generated cyclic AMP to the lethal outcome of infection. We conclude that in murine model the host response to anthrax infection is an important factor contributing to lethality. This hypothesis is substantiated by the protective effect of adenosine derivative in combination with ciprofloxacin in anthrax-challenged mice. We identified B. anthracis HSP60 protein as a potential TLR2 agonist capable of binding host cell CD91 receptor and inducing host inflammatory response.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2007
- Accession Number
- ADA475509
Entities
People
- Serguei Popov
Organizations
- George Mason University