Bacterial Pathogenesis and Therapeutics

NBC的细菌发病机制和治疗主题将集中在理解 与细菌病原体相关的致病分子机制 疾病控制(CDC)A类称号。这组A类细菌(炭疽杆菌，Y.Pesfis， 和F.tularensis)将在八个子项目中进行研究。 分项目1“干扰炭疽杆菌群体感应以调节细菌毒力”(Martin J. 将确定对炭疽杆菌种群内细胞间通信的干扰是否会 调节生长和毒力。子项目2：干扰素预防炭疽杆菌致死性 因子“(Jeffrey Gold MD)将研究外源性应用干扰素是否可以克服 细胞内信号转导和LF的致死性。子项目3：炭疽杆菌对干扰素调控的影响 RNA剪接“(Michael Weden MD)将确定炭疽杆菌是否抑制受调控的剪接反应 增强干扰素反应。子项目4：细胞因子对芽孢杆菌全身感染的反应 炭疽病“(Gilla Kaplan PhD)将调查是否抑制产生特定的前炎症 在感染模型中，细胞因子减少了组织损伤并改善了结果。分项目5“机制 细菌孢子在人类巨噬细胞中的存活“(Roy T.Steigbigel MD)将研究这种敏感性 芽孢杆菌的孢子。吞噬细胞的杀伤机制。次级项目6“亚单位免疫 对鼠疫耶尔森氏菌的保护作用“(James B.Bliska PhD)将评估单亚基和 由LCrV、YopD或YopB组成的多价免疫原。分项目7：抑制一种蛋白质酪氨酸 鼠疫耶尔森氏菌的磷酸酶(YopH)(张中银博士)将在体内鉴定底物并解决 YopH与新鉴定的底物结合的晶体结构。分项目8“发展 图拉氏方济氏菌遗传转移系统“(Martin S.Pavelka PhD)将完善质粒系统和 DNA电穿孔，并建立了高效的转座子诱变和等位基因交换方法。 图拉尔人。 除了对这些生物引起的疾病的发病机制的了解增加外， 这一主题还将提供新的免疫原、效应器分子的抑制剂、新的遗传系统以及 感染的潜在辅助治疗。

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.