Bacterial Pathogenesis and Therapeutics

NBC的细菌发病机制和治疗主题将侧重于了解 致病的分子机制与细菌剂，属于中心， 疾病控制中心（CDC）A类指定。这组A类细菌（B. anthracis，Y. pesfis， 和F. tularensis）将在八个分项目中进行研究。 子项目1“对B的干扰。炭疽菌群体感应调节细菌毒力”（Martin J. Blaser MD）将确定是否干扰B内的蜂窝间通信。炭疽菌群将 调节生长和毒性。子项目2“干扰素预防B致死性。致死炭疽 因子”（Jeffrey Gold医学博士）将研究外源性干扰素是否能克服干扰素的破坏。 细胞内信号传导和LF致死。次级项目3“B的影响。炭疽对干扰素调节 RNA剪接”（Michael Weiden MD）将确定是否为B。炭疽菌抑制受调节的剪接反应 增强干扰素反应。子项目4”芽孢杆菌全身感染的细胞因子反应 炭疽病”（Gilla Kaplan博士）将研究是否抑制特异性促炎性因子的产生， 细胞因子减少组织损伤并改善感染模型的结果。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 芽孢杆菌孢子对吞噬细胞的杀伤机制。次级项目6“亚单位免疫接种 鼠疫耶尔森氏菌”（詹姆斯B. Bliska博士）将评估单个亚单位的保护功效， 由LcrV、YopD或YopB组成的多价免疫原。子项目7“蛋白酪氨酸的抑制 鼠疫耶尔森氏菌磷酸酶（YopH）”（Zhong-Yin Zhang博士）将鉴定体内底物并解决 结合到新鉴定的底物的YopH的晶体结构。次级项目8“发展 土拉热弗朗西丝氏菌的遗传转移系统”（Martin S. Pavelka博士）将完善质粒系统， DNA电穿孔技术，建立了高效的转座子诱变和等位基因交换方法。 土拉热。 除了对这些生物体引起的疾病的发病机理的了解有所增加外， 这一主题还将提供新的免疫原，效应分子的抑制剂，新的遗传系统， 潜在的感染辅助治疗。

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.