Redefining the role of autophagy in bacterial disease

重新定义自噬在细菌性疾病中的作用

• 批准号: 10053295
• 负责人: Ken Hashigiwa Cadwell
• 金额: $ 51.51万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-10 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053295
• 关键词: Adverse effects; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Attention; Autophagocytosis; Bacteria; Bacterial Infections; Cell Culture Techniques; Cell membrane; Cell surface; Cells; Childhood; Clinical; Communicable Diseases; Communities; Cytosol; Data; Defense Mechanisms; Development; Disease; Drug Targeting; Drug usage; Endothelium; Epithelial; Genes; Goals; Health; Host Defense; Human; Immune; In Vitro; Infection; Inflammasome; Integration Host Factors; Knockout Mice; Literature; Lysosomes; Mediating; Mediation; Membrane; Membrane Proteins; Modeling; Morbidity - disease rate; Multiple Bacterial Drug Resistance; Mus; Mutant Strains Mice; Natural Resistance; Outcome; Pathway interactions; Phagosomes; Pharmacology; Physiological; Pneumonia; Process; Proteome; Publications; Recycling; Regulation; Resistance; Resistance to infection; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Sepsis; Signal Transduction; Specificity; Staphylococcus aureus; Staphylococcus aureus infection; Streptomycin; Testing; Therapeutic; Tissues; Toxin; Vacuole; Vesicle; Virulent; alpha Toxin; antimicrobial; bacterial resistance; cell injury; cell type; enteric infection; experimental study; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; interest; methicillin resistant Staphylococcus aureus; microbicide; mortality; mutant; novel; pathogen; pathogenic bacteria; prevent; prophylactic; receptor; recruit; repaired; resistant strain; sensor

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 by which 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. Therefore, it is possible that drugs that target autophagy will be useful in a wide range of diseases downstream of bacterial infections. However, in addition to a direct microbicidal mechanism, autophagy has many substrates and cell type-specific functions that may contribute to the outcome of an infection. Thus, we chose to re-examine the role of autophagy in vivo using two model pathogens – Salmonella enterica Typhimurium and Staphylococcus aureus. We chose to investigate S. Typhimurium because previous in vitro studies extensively demonstrated that this bacterium is targeted for degradation through autophagy. In contrast, in vitro experiments indicate that S. aureus uses the autophagy machinery for intracellular survival. In preliminary data, we demonstrate that inhibiting autophagy in vivo leads to the opposite outcome that is predicted by the literature. Specifically, autophagy mutants were protected from S. Typhimurium and susceptible to S. aureus. The goal of this proposal is to elucidate the physiological mechanism by which autophagy functions during infection by these two important bacterial pathogens. In Aim 1, we will test a model in which S. Typhimurium recruits the autophagy machinery to repair the Salmonella-containing vacuole (SCV) and evade innate immune sensors. In Aim 2, we will define a novel role for autophagy in regulating the cell surface proteome of the host cells, a function that is critical in limiting damage caused by a pore-forming toxin produced by S. aureus. The results from the proposed experiments will challenge the existing paradigm on the role of autophagy in antimicrobial defense and guide the proper use of drugs that target autophagy.

项目摘要 除了传统的抗微生物剂之外，靶向宿主防御途径是一种有吸引力的策略，以限制微生物的生长。 细菌感染的副作用。其中一个受到相当关注的途径是自噬， 一种细胞成分被隔离在双膜囊泡中的过程， 靶向溶酶体进行降解和再循环。自噬被认为是细胞的关键 自主防御，因为许多细菌病原体在双膜囊泡中被检测到， 内化因此，靶向自噬的药物可能在广泛的免疫治疗中是有用的。 细菌感染下游的疾病。然而，除了直接的杀微生物机制之外， 自噬有许多底物和细胞类型特异性功能，可能有助于细胞自噬的结果。 感染因此，我们选择使用两种模式病原体-沙门氏菌-重新检查自噬在体内的作用。 肠伤寒沙门氏菌和金黄色葡萄球菌。我们选择研究S。鼠伤寒，因为以前 体外研究广泛表明，这种细菌是通过自噬降解的目标。在 相反，体外实验表明S.金黄色葡萄球菌使用自噬机制来实现细胞内存活。在 初步数据，我们证明，抑制体内自噬导致相反的结果， 文献预测的。具体地说，自噬突变体被保护免受S。氏菌和 对S.金黄色。该提案的目标是阐明其生理机制， 自噬在被这两种重要的细菌病原体感染期间起作用。在目标1中，我们将测试一个模型 其中S.鼠伤寒杆菌招募自噬机制修复含沙门氏菌的空泡（SCV） 避开先天免疫传感器在目标2中，我们将定义自噬在调节细胞中的新作用， 宿主细胞的表面蛋白质组，这是限制由成孔毒素引起的损伤的关键功能 由S.金黄色。从拟议的实验结果将挑战现有的范式对 自噬在抗菌防御中的作用，并指导正确使用靶向自噬的药物。