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

基本信息

批准号：
10579831
负责人：
Victor Nizet
金额：
$ 62.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10579831
关键词：
Affect Antibiotic Resistance Autophagocytosis Autophagosome Bacteremia Bacteria Bacterial Infections Bioinformatics Blood Circulation CRISPR screen Caspase Cells Child Communicable Diseases Complement Coupled Data Disease Elderly Epithelial Cells Epithelium Gene Expression Gnotobiotic Host Defense Human Immune Immunity Immunocompromised Host Infection Infectious Skin Diseases Intestines Investigation Knowledge Libraries Life Link Macrophage Morbidity - disease rate Mucosal Immunity Mucous Membrane Mus Natural Immunity Necrotizing fasciitis Organ Outcome Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Phagocytes Phagolysosome Pharyngitis Physicians Play Process Production Productivity 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 microbiome microbiome composition mortality mouse model mutant neutrophil new therapeutic target novel pathogen pharmacologic prevent skin microbiome transcriptome sequencing virulence gene

项目摘要

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.

概括细菌感染仍然是全球发病率和死亡率的主要原因，也是一个重要的公共卫生问题由于抗生素耐药性增加和疫苗有限，许多最严重的细菌感染。起源于粘膜表面，如肠道、呼吸道或皮肤，然后通过引起粘膜疾病和侵袭性疾病的两种主要人类病原体是革兰氏阴性菌。阴性肠道沙门氏菌（例如鼠伤寒血清型，STm）和革兰氏阳性 A 组链球菌 (GAS)。宿主先天防御血流感染的关键是补体系统的功能。蛋白质及其激活级联，特别是 C3 的调理作用，以及杀菌活性吞噬细胞，包括巨噬细胞 (MΦ) 和中性粒细胞，可以破坏 STm 和 GAS 的致病菌株。吞噬溶酶体在 MΦ 离体和体内的细胞内存活，因此自噬系统该项目将两个高度结合在一起，成为病原体生存/杀死的关键战场。经验丰富、富有成效的医师科学家研究人员，具有互补的专业知识：革兰氏阴性菌细菌发病机制、粘膜免疫和 gnotobiotic 小鼠模型 (MPI, M. Raffatellu) 与 Gram- 阳性细菌发病机制、先天免疫和细菌吞噬细胞相互作用（MPI，V. Nizet）。我们最近发现了 C3 的一种新颖的、重要的细胞内功能：将细菌靶向自噬 MΦ 杀灭系统——这一发现可能挑战无数 MΦ 细菌研究的结论此外，我们发现 STm 丝氨酸蛋白酶在没有活性血清的情况下进行相互作用。 PgtE、GAS丝氨酸蛋白酶SpyCEP、GAS半胱氨酸蛋白酶SpeB允许各自的病原体使 C3 失活并在 MΦ 中进行细胞内复制我们的中心假设是细胞内 C3 依赖性。自噬对于宿主先天防御至关重要，并且 STm 和 GAS 等侵入性病原体的能力抵消这一过程会大大增加其致病潜力。微生物组在皮肤和粘膜补体的产生中发挥着重要作用，这可能代表了另一个共生微生物影响侵入性细菌感染风险的关键因素在此我们建议继续。研究细胞内 C3 在感染过程中的作用，了解这一新原理的影响先天免疫对宿主-病原体相互作用的影响以及两种最重要的人类传染病的结果我们的方法可能会揭示新的毒力基因和宿主免疫途径。机制，解决长期存在的知识差距，并带来具有广泛相关性的新调查途径细菌发病机制，包括潜在的新治疗靶点和线索。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exploration of Bacterial Bottlenecks and Streptococcus pneumoniae Pathogenesis by CRISPRi-Seq.

DOI：
10.1016/j.chom.2020.10.001
发表时间：
2021-01-13
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Liu X;Kimmey JM;Matarazzo L;de Bakker V;Van Maele L;Sirard JC;Nizet V;Veening JW
通讯作者：
Veening JW