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Membrane trafficking in innate immunity to bacterial pathogens

膜运输对细菌病原体的先天免疫

基本信息

批准号：
10238030
负责人：
Adriana Rita Mantegazza
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238030
关键词：
1-Phosphatidylinositol 4-Kinase Anti-Bacterial Agents Anti-Inflammatory Agents Antibacterial Response Antigen Presentation Antigens Attention Autophagocytosis Bacteria Bacterial Infections Binding CD4 Positive T Lymphocytes Cell membrane Cell surface Cells Chloride Channels Complex Cytoplasmic Receptors Data Defect Dendritic Cells Detection Disease model Endosomes Environment Enzymes FRAP1 gene Family Genetic Diseases Hermanski-Pudlak Syndrome Homeostasis Human Immune Immune System Diseases Immune response Immunity Immunologic Deficiency Syndromes Immunologic Receptors Impairment Inflammasome Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 Ion Channel Lead Link Lipids Lysosomes Membrane Membrane Transport Proteins Modeling Molecular Natural Immunity Nature Nucleoside Transporter Nutrient Oligopeptides Organelles Outcome Particulate Pathway interactions Pattern Phagocytes Phagosomes Phosphatidylinositols Play Positioning Attribute Process Production Property Protein Sortings Receptor Signaling Regulation Role Sentinel Signal Transduction Site Sorting - Cell Movement Stimulus TIRAP gene TLR4 gene Testing Toll-like receptors Vesicle adaptive immune response adaptive immunity cytokine fighting inorganic phosphate microbial mouse model novel pathogen pathogenic bacteria phosphatidylinositol 4-phosphate protein transport rare genetic disorder recruit response trafficking

项目摘要

SUMMARY Anti-bacterial inflammatory responses in phagocytes are initiated by recognition of common pathogen associated molecular patterns (PAMPs) by innate immune receptors. PAMP binding to membrane-associated toll-like receptors (TLRs) at distinct subcellular sites triggers site-specific responses, and bacteria that compromise phagosomal membranes additionally trigger cytoplasmic receptors, some of which assemble into multisubunit inflammasomes that process and release IL-1 family cytokines. Membrane dynamics within host phagocytes dramatically influence TLR and inflammasome localization and signaling, but host regulation of such dynamics has been relatively unexplored. Our studies in a genetic disease model identified the endosomal adaptor complex AP-3 as a central hub for intracellular trafficking pathways that regulate both TLR and inflammasome responses to phagocytosed bacteria in dendritic cells (DCs) - immune cells that link innate responses to adaptive immunity. However, AP-3 impacts these responses indirectly, reflecting AP-3's central role in endolysosomal protein sorting. We hypothesize that defining direct targets of AP-3 sorting will elucidate new membrane pathways controlling innate signaling and downstream anti-bacterial immune responses. AP-3 sorts cargoes on endosomes into vesicles bound for lysosomes, phagosomes or related organelles. We hypothesize that innate signaling defects in AP-3-deficient DCs reflect depletion of AP-3 cargoes from these organelles. Preliminary data suggest that one such cargo is PI4K2α, an enzyme that generates the lipid phosphatidylinositol-4-phosphate to recruit TLRs via their proinflammatory adaptors to membranes. Aim 1 will test whether phagosomal PI4K2α recruits TLRs to initiate pro-inflammatory signaling and antigen presentation. Other putative AP-3 cargoes include lysosomal transporters that function in lysosome homeostasis. We hypothesize that depletion of such cargoes triggers a lysosome-dependent signaling cascade that promotes inflammasome silencing by autophagy. Aim 2 will test whether and how lysosomal disruption impacts inflammasome activity, and Aim 3 will test whether depletion of specific candidate lysosomal membrane channels similarly silence inflammasomes and impact lysosome signaling and adaptive immune responses. Fulfillment of the following Specific Aims will elucidate novel pathways that are potentially targeted by genetic disease and/or by pathogen interference to compromise host immunity to bacterial pathogens. 1. To test whether TLR signaling from phagosomes and downstream responses are regulated by the AP-3-associated PtdIns-4-kinase PI4K2α. 2. To test whether impaired lysosomal function dampens inflammasome activity through nutrient- dependent signaling. 3. To test whether lysosomal membrane transporter expression influences inflammasome activation.

总结