Germination of Bacillus anthracis Spores in Macrophages

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DESCRIPTION (provided by applicant): Anthrax is caused by the inhalation, ingestion or uptake through a cut or abrasion of spores of Bacillus anthracis. An essential step in B. anthracis pathogenesis is the transformation of metabolically dormant spores into vegetative, toxin-producing bacteria. Past research has primarily focused on the mechanism of macrophage killing by anthrax toxins. Recent studies have begun to explore factors that are responsible for the germination of B. anthracis spores and their subsequent survival in the macrophages. The spores are engulfed by macrophages where they germinate and commence the synthesis of toxins. Subsequent release from macrophages leads to proliferation in the blood of vegetative bacteria and extensive toxin production. Spore germination within the macrophage is a critical but not well-understood step in the infection process. It is not currently known which vacuolar compartment or spore properties are essential for germination. Our working hypothesis is that germination requires a specific endosomal/phagosomal compartment with appropriate physical and nutritional factors recognized by engulfed spores from pathogenic isolates and that germination requires specific receptors and/or specific spore surface properties. In order to test this hypothesis, we propose two approaches: 1) initially direct or limit spores to different phagosomal compartments and then block vacuole rearrangement at distinct steps in order to examine the effects on spore uptake and germination. 2) Select for macrophage-specific, germination deficient spores and thus identify spore components essential for intracellular germination. Results from our study will define the compartment of the vacuoles required for B. anthracis germination, and the macrophage-specific germination-deficient B.anthracis mutants should help to elucidate spore components essential for germination in macrophages. These results will advance our understanding of in vivo spore germination and the properties of B. anthracis spores necessary for this process. This information could be helpful for developing pharmaceutical agents useful for preventing the germination of B. anthracis spores inside macrophages.