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: 10764559
• 负责人: Ken Hashigiwa Cadwell
• 金额: $ 55.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10764559
• 关键词: Address; Adverse effects; Affect; Alleles; Amino Acid Substitution; Attention; Autophagocytosis; Autophagosome; Bacteria; Bacterial DNA; Bacterial Infections; Binding; Biogenesis; Biological; CRISPR/Cas technology; Cell Culture Techniques; Cell Death; Cell physiology; Cells; Cellular biology; Citrobacter rodentium; Communicable Diseases; Complex; Cues; Cytokine Suppression; Cytosol; Data; Disease; Dominant-Negative Mutation; Drug Targeting; Epithelial Cells; Event; Frequencies; Funding; Genetic Screening; Goals; Heterozygote; Host Defense; Human; Immune response; Immunity; Infection; Infectious Agent; Inflammation Mediators; Inflammatory; Innate Immune Response; Intervention; Knowledge; Lysosomes; Mammalian Cell; Mediating; Mediator; Membrane; Microbe; Microscopy; Mitochondria; Modeling; Molecular; Mus; Natural Immunity; Necrosis; Norovirus; Pathogen detection; Pathway interactions; Physiological; Play; Population; Predisposition; Process; Production; Proteins; Proteomics; Recycling; Role; Salmonella; Salmonella typhimurium; Staphylococcus aureus; Staphylococcus aureus infection; Techniques; Testing; Toxin; Variant; Vesicle; Virulence; antimicrobial; cell type; cytokine; design; exosome; experimental study; extracellular; extracellular vesicles; genetic variant; host-microbe interactions; improved outcome; inhibitor; intestinal epithelium; loss of function; monocyte; mouse model; novel; pathogen; pathogenic bacteria; pharmacologic; prevent; programs; receptor; recruit; response; therapeutic target; trafficking

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.

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， 细胞成分被隔离在双膜囊泡中的过程， 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囊泡内被检测到， 这个过程被称为xenophagy。因此，靶向自噬的药物可能在治疗中有用。 细菌感染下游的各种疾病。在这个节目中，我们正在研究的贡献， ATG 16 L1是一种自噬蛋白，在自噬体形成中起核心作用，在宿主对 两种模式病原体-沙门氏菌和金黄色葡萄球菌。通过研究自噬 在S.我们已经发现ATG 16 L1能够使哺乳动物细胞对细菌应答， 感染通过产生外泌体，小分泌囊泡，保护宿主免受感染，通过中和 这种细菌产生的强毒素。我们对沙门氏菌的研究发现， ATG 16 L1 T300 A等位基因以非细胞自主的方式影响宿主对该病原体的易感性。 方式因此，此竞争性更新应用程序的目标是阐明 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（Aim 1）， ATG 16 L1 T300 A如何有助于宿主介导的保护免受细菌感染的分子细节 病原体更好地理解ATG如何参与非仇外功能有助于弥合差距 细胞自主防御与宿主-微生物相互作用中复杂的细胞外机制之间的联系。