C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis

先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤

• 批准号: 9765616
• 负责人: Victor Nizet
• 金额: $ 62.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765616
• 关键词: Affect; Antibiotic Resistance; Autophagocytosis; Bacteremia; Bacteria; Bacterial Infections; Bioinformatics; Blood Circulation; CRISPR screen; Caspase; Cells; Child; Communicable Diseases; Complement; Consequentialism; Coupled; Data; Disease; Elderly; Epithelial Cells; Epithelium; Gene Expression; Genes; Gnotobiotic; Host Defense; Human; Immune; Immunity; Immunocompromised Host; Infection; Infectious Skin Diseases; Investigation; Knowledge; Lead; Libraries; Life; Link; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Necrotizing fasciitis; Organ; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Phagocytes; Phagolysosome; Pharmacology; Pharyngitis; Physicians; Play; Process; Production; Proteins; Public Health; Reporting; Research Personnel; Respiratory System; Risk; Role; Salmonella enterica; Scientist; Sepsis; Serine Protease; Serum; Skin; Streptococcal Infections; Streptococcus pyogenes; Surface; System; Tissues; Toxic Shock Syndrome; Vaccines; Virulence; Work; bactericide; commensal microbes; complement system; experience; gut microbiome; human pathogen; in vivo; infection risk; inhibitor/antagonist; macrophage; microbiome; microbiome composition; mortality; mouse model; mutant; neutrophil; new therapeutic target; novel; pathogen; prevent; skin microbiome; transcriptome sequencing

SUMMARY Bacterial infections remain a leading cause of morbidity and mortality worldwide and a critical public health issue due to increasing antibiotic resistance and limited vaccines. Many of the most consequential bacterial infections originate at mucosal surfaces, such as the gut, respiratory tract or skin, then disseminate to other tissues via the bloodstream. Two preeminent human pathogens causing both mucosal and invasive diseases are Gram- negative Salmonella enterica (e.g., serovar Typhimurium, STm) and Gram-positive group A Streptococcus (GAS). Pivotal to innate host defense against bloodstream infection is the function of complement system proteins and their activation cascades, especially opsonization by C3, coupled with the bactericidal activity of phagocytic cells including macrophages (MΦ) and neutrophils. Pathogenic strains of STm and GAS can subvert phagolysosome function to survive intracellularly in MΦ ex vivo and in vivo, whereupon the autophagy system emerges as a critical battleground for pathogen survival/killing. This project brings together two highly experienced and productive physician-scientist investigators with complementary expertise: Gram-negative bacterial pathogenesis, mucosal immunity and gnotobiotic mouse models (MPI, M. Raffatellu) coupled to Gram- positive bacterial pathogenesis, innate immunity, and bacterial-phagocyte interactions (MPI, V. Nizet). Together we have recently discovered a novel, essential intracellular function of C3: targeting of bacteria to the autophagy system for killing in MΦ – a discovery that may challenge conclusions of countless studies of MΦ-bacterial interactions performed in the absence of active serum. Further, we have discovered that the STm serine protease PgtE, the GAS serine protease SpyCEP, and the GAS cysteine protease SpeB allow the respective pathogens to inactivate C3 and to replicate intracellularly in MΦ. Our central hypothesis is that intracellular C3-dependent autophagy is critical to host innate defense, and that the ability of invasive pathogens such as STm and GAS to counteract this process substantially increases their disease-causing potential. Recent data also indicate the microbiome plays an essential role in skin and mucosal complement production, which may represent another crucial factor by which commensal microbes affect invasive bacterial infection risk. Here we propose to continue to investigate the role of intracellular C3 during infection, to understand the ramifications of this new principle of innate immunity on host-pathogen interactions and the outcome of two of the most important human infectious diseases. Our approaches are likely to reveal new virulence genes and host immune pathways that will connect mechanisms, resolve longstanding knowledge gaps, and lead to new avenues of investigation of broad relevance to bacterial pathogenesis including potential novel therapeutic targets and leads.

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