IDENTIFICATION OF NOVEL BACILLUS ANTHRACIS VIRULENCE FACTORS BY PROTEOMIC/SEROLOGICAL APPROACH AND THEIR APPLICATION IN VACCINE DEVELOPMENT

We have documented in the past proteomic/serological surveys of Bacillus anthracis, for identification of virulence factors, as well as vaccine and diagnostic marker candidates. These studies revealed proteins that can serve as novel antigens for further evaluation, based on their immunogenicity, abundance, and functional relatedness to infection. One of these, HtrA, an extracellular protease/chaperone, is abundantly expressed during infection and consequently able to serve as an early disease-biomarker of anthrax. A study of the phenotype associated with disruption of the htrA gene demonstrated that HtrA is necessary for tolerance to various stress stimuli. Most notably, htrA gene disruption resulted in a dramatic virulence attenuation in various animal models of anthrax. Immunization with sub-lethal doses of htrA-disrupted B. anthracis, elicited a protective immune response as attested by challenge with fully virulent bacterial spores. These results suggest that HtrA is essential for manifestation of B. anthracis pathogenesis and may represent the basis for the development of possible novel prophylactic and therapeutic interventions to countermeasure B. anthracis infection. An htrA disrupted Sterne (acapsular non-virulent) strain-derived live attenuated spore vaccine is currently evaluated for safety and efficacy.

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