Redefining the role of autophagy in bacterial disease

项目总结 除了传统的抗菌药外，靶向宿主防御途径是一种有吸引力的策略，以限制 细菌感染的不良反应。其中一种受到相当大关注的途径是自噬，即一种 将细胞成分隔离在随后被靶向的双层膜小泡中的过程 到溶酶体进行降解和回收。自噬被认为是细胞自主防御的关键 由于许多细菌病原体在内化时在双膜小泡中被检测到，因此 这一过程被称为异体吞噬。因此，靶向自噬的药物有可能在 广泛的疾病下游的细菌感染。在这个节目中，我们正在研究 ATG16L1是一种自噬蛋白，在自噬小体的形成中发挥核心作用，在宿主对 两种模式病原体--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产生反应 通过产生外体，即通过中和保护宿主免受感染的小分泌小泡而感染 这种细菌产生的强效毒素。我们对沙门氏菌的研究发现，通常发现的 ATG16L1 T300A等位基因以非细胞自主性方式影响宿主对该病原体的敏感性 举止。因此，本次竞争性续签申请的目的是阐明(S)通过什么机制 哺乳动物细胞选择自噬和病原体感应来控制外体的生物发生(目标1)和解开 ATG16L1 T300A对宿主介导的细菌感染保护作用的分子细节 病原体。更好地了解ATG如何参与非吞噬功能有助于弥合这一差距 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.