Effects of mycobacterial infections induced cell death on host immune response

描述（由申请方提供）：细胞死亡途径是致病性分枝杆菌和宿主巨噬细胞之间相互作用的核心。抑制受感染宿主细胞的细胞死亡是病原性分枝杆菌的一种有据可查但知之甚少的作用。分枝杆菌可由于延迟或抑制巨噬细胞死亡而获得若干优点，包括保护生长环境的保存、参与宿主细胞中的内在杀微生物活性以及保护性免疫的最佳刺激。这种抗细胞死亡表型的遗传基础尚未完全证实或阐明。利用结核分枝杆菌转座子突变体库，我们筛选了结核分枝杆菌的促细胞死亡突变体。结核病，并能够找到负责抑制感染诱导的巨噬细胞细胞死亡的多个遗传基因座。这项资助计划研究其中的几个基因，以检查它们与毒力和免疫原性的相关性。此外，这项研究将表征分枝杆菌这一重要毒力性状的关键遗传组分，同时提供必要的洞察力和工具来研究这种复杂的宿主-病原体相互作用的细节。我们的研究还可能为改进分枝杆菌疫苗和确定新的结核病药物靶点提供新的方法。 公共卫生相关性：我们建议研究可能增强适应性免疫启动的促细胞死亡分枝杆菌突变体。该研究结果将有助于开发新的药物靶点和结核病候选疫苗。

DESCRIPTION (provided by applicant): Cell death pathways are central to the interaction between pathogenic mycobacteria and host macrophages. The inhibition of cell death of infected host cells is a well-documented, but poorly understood, action of pathogenic mycobacteria. Mycobacteria may accrue several advantages as a result of delaying or inhibiting macrophage cell death, including preservation of a protected growth environment, engagement of intrinsic microcidal activities in the host cell, and optimal stimulation of protective immunity. The genetic basis for this anti-cell death phenotype has not been fully demonstrated or elucidated. Using a Mycobacterium tuberculosis transposon mutant library, we have screened pro-cell death mutants of M. tuberculosis and were able to find multiple genetic loci that are responsible for inhibiting infection-induced cell death of macrophages. This grant proposes to study several of these genes to examine their correlation to virulence and immunogenicity. Additionally, this study will characterize key genetic components of this important virulence trait of mycobacteria, while providing insight and tools necessary to investigate the details of this complex host-pathogen interaction. Our studies may also provide novel approaches for improving mycobacterial vaccines and identifying new TB drug targets. PUBLIC HEALTH RELEVANCE: We propose to study pro-cell death mycobacterial mutants that may enhance priming of adaptive immunity. The results of the study will be useful for the development of new drug targets and TB vaccine candidates.