Effects of mycobacterial infections induced cell death on host immune response

描述（由申请人提供）：细胞死亡途径是致病性分枝杆菌和宿主巨噬细胞相互作用的核心。对感染宿主细胞的细胞死亡的抑制是一种有充分文献记载的，但对致病性分枝杆菌的作用知之甚少。分枝杆菌可以延缓或抑制巨噬细胞的死亡，包括保存受保护的生长环境，参与宿主细胞内在的杀微生物活动，以及最佳的保护性免疫刺激。这种抗细胞死亡表型的遗传基础尚未得到充分证明或阐明。利用结核分枝杆菌转座子突变文库，我们筛选了结核分枝杆菌的细胞死亡前突变体，并能够找到多个负责抑制感染诱导的巨噬细胞死亡的基因位点。该基金建议研究这些基因中的几个，以检查它们与毒力和免疫原性的相关性。此外，本研究将表征分枝杆菌这一重要毒力特征的关键遗传成分，同时为研究这种复杂的宿主-病原体相互作用的细节提供必要的见解和工具。我们的研究也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途径。

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.