Redefining the role of autophagy in bacterial disease

项目概要 除了传统的抗菌药物外，针对宿主防御途径是限制细菌感染的一种有吸引力的策略。 细菌感染的不良影响。自噬是一种受到广泛关注的途径， 细胞成分被隔离在随后被靶向的双膜囊泡中的过程 到溶酶体进行降解和回收。自噬被认为对于细胞自主防御至关重要 由于许多细菌病原体在内化后可在双膜囊泡中检测到， 过程称为异体吞噬。因此，靶向自噬的药物可能会在以下方面发挥作用： 细菌感染下游的多种疾病。在这个计划中，我们正在研究的贡献 ATG16L1 是一种自噬蛋白，在自噬体形成以及宿主对自噬体的反应中起核心作用 两种模型病原体——鼠伤寒沙门氏菌和金黄色葡萄球菌。通过研究自噬 在金黄色葡萄球菌的环境中，我们发现 ATG16L1 使哺乳动物细胞能够对细菌做出反应 通过产生外泌体来感染，外泌体是一种小分泌囊泡，通过中和来保护宿主免受感染 这种细菌产生的强力毒素。我们对沙门氏菌的研究发现，常见的 ATG16L1 T300A 等位基因以非细胞自主方式影响宿主对该病原体的易感性 方式。因此，这个竞争性续订申请的目标是阐明其机制 哺乳动物细胞利用自噬和病原体感应来控制外泌体生物发生（目标 1）并解开 ATG16L1 T300A 如何促进宿主介导的细菌感染保护的分子细节 病原体。更好地了解 ATG 如何参与非异体吞噬功能有助于弥合差距 细胞自主防御和参与宿主-微生物相互作用的复杂细胞外机制之间的关系。

PROJECT SUMMARY In addition to traditional antimicrobials, targeting host defense pathways is an attractive strategy to limit the adverse effect of bacterial infection. One such pathway that has received considerable attention is autophagy, a process where cellular constituents are sequestered in a double-membrane vesicle that is subsequently targeted to the lysosome for degradation and recycling. Autophagy is suggested to be critical for cell autonomous defense because many bacterial pathogens are detected within double-membrane vesicles upon internalization, a process referred to as xenophagy. Therefore, it is possible that drugs that target autophagy will be useful in a wide range of diseases downstream of bacterial infections. In this program, we are studying the contribution of ATG16L1, an autophagy protein that plays a central role in autophagosome formation, in the host response to two model pathogens –Salmonella enterica Typhimurium and Staphylococcus aureus. By studying autophagy in the setting of S. aureus we have discovered that ATG16L1 enable mammalian cells to respond to bacterial infections by producing exosomes, small secreted vesicles that protect the host from infection by neutralizing potent toxins produced by this bacterium. Our studies with Salmonella have discovered that the commonly found ATG16L1 T300A allele impacts the susceptibility of the host towards this pathogen in a non-cell autonomous manner. Thus, the goals of this competitive renewal application are to elucidate the mechanism(s) by which mammalian cells coopt autophagy and pathogen sensing to control exosome biogenesis (Aim 1) and to unravel the molecular details of how ATG16L1 T300A contributes to host-mediated protection from infection by bacterial pathogens. A better understanding of how ATGs participate in non-xenophagy functions can help bridge the gap between cell autonomous defense and complex extracellular mechanisms involved in host-microbe interactions.