Bacterial Pathogenesis and Therapeutics

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The Bacterial Pathogenesis and Therapeutic theme of the NBC will be focused on understanding the molecular mechanisms of pathogenesis associated with bacterial agents that belong to the Centers for Disease Control (CDC) Category A designation. This group of Category A bacteria (B. anthracis, Y. pesfis, and F. tularensis) will be studied in the eight Subprojects. Subproject 1 " Interference with B. anthracis quorum-sensing to modulate bacterial virulence" (Martin J. Blaser MD) will determine if interference with intercellular communication within B. anthracis populations will modulate growth and virulence. Subproject 2 " Interferon in prevention of lethality from B. anthracis Lethal Factor" (Jeffrey Gold MD) will study if exogenously administered interferon can overcome the disruption in intracellular signaling and lethality by LF. Subproject 3 "The impact of B. anthracis on Interferon regulated RNA splicing" (Michael Weiden MD) will determine if B. anthracis inhibits regulated splicing reactions enhancing the interferon response. Subproject 4" Cytokine response to systemic infection with Bacillus anthracis" (Gilla Kaplan PhD) will investigate whether inhibition of the production of specific proinfiammatory cytokines reduces tissue damage and improves outcome in models of infection. Subproject 5 "Mechanism of Survival of Bacterial Spores in Human Macrophages" (Roy T. Steigbigel MD) will study the susceptibility of spores of Bacillus sp. to the killing mechanisms of phagocytic cells. Subproject 6 " Subunit immunization to Yersinia pestis" (James B. Bliska PhD) will evaluate the protective efficacy of single subunit and multivalent immunogens composed of LcrV, YopD or YopB. Subproject 7 " Inhibition of a protein tyrosine phosphatase (YopH) of Yersinia pestis" (Zhong-Yin Zhang PhD) will identify the in vivo substrates and solve crystal structures of the YopH bound to the newly identified substrates. Subproject 8 "Development of Genetic Transfer Systems for Francisella tularensis" (Martin S. Pavelka PhD) will refine plasmid systems and DNA electroporation, and develop efficient transposon mutagenesis and allelic exchange methodology for F. tularensis. In addition to the increase in knowledge about the pathogenesis of the diseases caused by these organisms, this theme will also provide novel immunogens, inhibitors to effector molecules, new genetic systems, and potential adjunct therapies to infection.