The Bacterial Pathogenesis and Therapeutic theme of the NBC will be focused on understanding themolecular mechanisms of pathogenesis associated with bacterial agents that belong to the Centers forDisease 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 willmodulate growth and virulence. Subproject 2 ' Interferon in prevention of lethality from B. anthracis LethalFactor' (Jeffrey Gold MD) will study if exogenously administered interferon can overcome the disruption inintracellular signaling and lethality by LF. Subproject 3 'The impact of B. anthracis on Interferon regulatedRNA splicing' (Michael Weiden MD) will determine if B. anthracis inhibits regulated splicing reactionsenhancing the interferon response. Subproject 4' Cytokine response to systemic infection with Bacillusanthracis' (Gilla Kaplan PhD) will investigate whether inhibition of the production of specific proinfiammatorycytokines reduces tissue damage and improves outcome in models of infection. Subproject 5 'Mechanismof Survival of Bacterial Spores in Human Macrophages' (Roy T. Steigbigel MD) will study the susceptibilityof spores of Bacillus sp. to the killing mechanisms of phagocytic cells. Subproject 6 ' Subunit immunizationto Yersinia pestis' (James B. Bliska PhD) will evaluate the protective efficacy of single subunit andmultivalent immunogens composed of LcrV, YopD or YopB. Subproject 7 ' Inhibition of a protein tyrosinephosphatase (YopH) of Yersinia pestis' (Zhong-Yin Zhang PhD) will identify the in vivo substrates and solvecrystal structures of the YopH bound to the newly identified substrates. Subproject 8 'Development ofGenetic Transfer Systems for Francisella tularensis' (Martin S. Pavelka PhD) will refine plasmid systems andDNA 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, andpotential adjunct therapies to infection.
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