Translation of evolution-guided insights for new models of human infectious disease

人类传染病新模型的进化指导见解的转化

• 批准号: 10050700
• 负责人: Patrick S Mitchell
• 金额: $ 51.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10050700
• 关键词: Advanced Development; Antigen-Antibody Complex; Autoimmune Diseases; CASP1 gene; Communicable Diseases; Dengue Infection; Dengue Virus; Detection; Enteral; Evolution; Exhibits; Genetic; Goals; Human; Immunity; Infection; Infectious Diseases Research; Inflammasome; Inflammatory; Laboratory mice; Link; Modeling; Molecular; Mus; Nature; Pathogenesis; Pattern; Peptide Hydrolases; Race; Recording of previous events; Recurrence; Refractory; Role; Shigella; Shigella Infections; Shigella flexneri; Signal Transduction; Stimulus; Stress; Translating; Translations; Virus Diseases; Vision; arm; autoinflammatory; base; cross-species transmission; enteric infection; host-pathogen coevolution; human model; human pathogen; improved; inflammatory disease of the intestine; innovation; insight; model design; mouse model; novel; pathogen; pathogenic bacteria; recruit; response

SUMMARY Inflammasomes are cytosolic innate immune complexes that form in response to a variety of pathogen- associated or stress-induced stimuli. Activated inflammasomes recruit Caspase-1, which initiates downstream inflammatory signaling. Genetic deletion of inflammasome components in mice has demonstrated the critical importance of inflammasomes during infection by viral, bacterial and eukaryotic pathogens. In addition, the inappropriate activation of inflammasomes has been linked to numerous auto-inflammatory and auto-immune diseases in humans. Host-pathogen coevolution is a major factor underlying the genetic and molecular determinants of cross- species transmission and infectious disease. The antagonistic nature of host-pathogen interactions can drive recurrent cycles of adaptation and counter-adaptation. These evolutionary ‘arms races’ drive rapid molecular innovation. Thus, the unique history of pathogen encounters of each lineage has driven species-specific adaptations. It should therefore not be surprising that laboratory mice are poor models of many human-specific or human-adapted pathogens. In this proposal I outline my vision to leverage the species-specific nature of host-pathogen interactions to develop improved models of human immunity and pathogenesis. Using a combination of evolution-guided and mechanism-focused approaches, I have made the following discoveries: 1) the Dengue virus (DENV) protease NS2B3 activates the human (but not mouse) NLRP1 inflammasome. DENV is the first known pathogen that activates human NLRP1. This finding supports a formerly unrecognized role for NLRP1 in host immunity and pathogenesis to DENV infection. 2) the enteric bacterial pathogen Shigella antagonizes the human (but not mouse) NAIP/NLRC4 inflammasome. Based on this finding, I have found that NLRC4-deficient mice are highly susceptible to enteric infection and. exhibit hallmarks of intestinal inflammation. Thus, I have established the first mouse model of Shigellosis. This proposal seeks to boldly expand on these observations using innovative approaches to generate new or significantly refine models of human infectious disease. I propose to 1) establish a new model of DENV immunity and pathogenesis, and 2) advance the development of the Shigellosis mouse model. Both DENV and Shigella are important human pathogens, which combined cause >200 million infections per year. Improved DENV infection models is a clear but unmet need, and until my Shigellosis mouse model, mice were thought to be refractory to Shigella enteric infection. Thus, the successful completion of the stated goals will significantly impact human infectious disease research.

总结 炎性小体是细胞溶质先天免疫复合物，其响应于多种病原体而形成， 相关的或压力引起的刺激。活化的炎性小体募集Caspase-1，其启动下游 炎症信号小鼠中炎性小体成分的基因缺失已经证明了 炎性小体在病毒、细菌和真核病原体感染过程中的重要性。此外该 炎性小体的不适当激活与许多自身炎症和自身免疫性疾病有关， 人类的疾病。 宿主-病原体协同进化是交叉感染的遗传和分子决定因素， 物种传播和传染病。宿主-病原体相互作用的拮抗性质可以驱动 适应和反适应的循环。这些进化的“军备竞赛”推动了快速的分子 创新因此，每个谱系的病原体遭遇的独特历史驱动了物种特异性 适应因此，实验室小鼠是许多人类特异性肿瘤的不良模型，这并不奇怪。 或人类适应的病原体。在这份提案中，我概述了我的愿景，以利用物种特异性的性质， 宿主-病原体相互作用，以开发人类免疫和发病机制的改进模型。 通过结合使用进化引导和机制聚焦的方法，我做了以下工作 发现：1）登革病毒（DENV）蛋白酶NS 2B 3激活人（而不是小鼠）NLRP 1 炎性小体DENV是第一个已知的激活人类NLRP 1的病原体。这一发现支持了 NLRP 1在宿主免疫和DENV感染发病机制中的作用以前未被认识。2)肠溶 细菌病原体志贺氏菌拮抗人（而不是小鼠）NAIP/NLRC 4炎性体。基于 根据这一发现，我发现NLRC 4缺陷小鼠对肠道感染高度敏感。表现出 肠道炎症的标志因此，我建立了第一个小鼠志贺氏菌病模型。 这项建议旨在大胆地扩大这些意见，使用创新的方法，以产生新的 或显著改进人类传染病的模型。我建议1）建立一个新的DENV模型 免疫学和发病机制的研究; 2）推进了志贺氏菌病小鼠模型的建立。DENV和 志贺氏菌属是重要的人类病原体，每年合并引起> 2亿例感染。改进 DENV感染模型是一个明确但未满足的需求，直到我的志贺氏菌病小鼠模型，小鼠被认为是 对志贺氏菌肠道感染是难治的。因此，成功地完成所述目标将大大 影响人类传染病研究。