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

摘要 炎性小体是一种细胞质的天然免疫复合体，对各种病原体- 相关的或应激诱导的刺激。激活的炎症体招募Caspase-1，Caspase-1启动下游 炎症信号。小鼠炎症体成分的基因缺失已经证明了关键 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， 炎症小体的不适当激活与许多自体炎症和自身免疫有关。 人类的疾病。 寄主-病原菌的共同进化是交叉致病的遗传和分子决定因素的主要因素。 物种传播和传染病。宿主-病原体相互作用的对抗性可以推动 适应和反适应的循环循环。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导致了特定物种的 改编。因此，实验室小鼠是许多人类特有的糟糕模型也就不足为奇了。 或者人类适应的病原体。在这份提案中，我概述了我的愿景，即利用 宿主和病原体的相互作用，以发展人类免疫和发病机制的改进模型。 结合使用进化导向和机制导向的方法，我做了以下工作 发现：1)登革病毒(DENV)蛋白酶NS2B3激活人(但不是小鼠)NLRP1 炎症者。DENV是第一个已知的激活人类NLRP1的病原体。这一发现支持一种 NLRP1在宿主免疫和DENV感染发病机制中的作用以前不为人所知。2)肠道 细菌病原体志贺氏菌能拮抗人(但不是小鼠)NAIP/NLRC4炎症体。基于 这一发现，我发现NLRC4基因缺陷的小鼠对肠道感染高度敏感。陈列品 肠道炎症的特征。因此，我建立了第一个志贺氏菌病小鼠模型。 这项提议寻求大胆地扩展这些观察结果，使用创新的方法来产生新的 或者大幅改进人类传染病的模型。我建议1)建立一个新的DENV模式 2)促进志贺氏菌病小鼠模型的建立。DENV和 志贺氏菌是重要的人类病原体，每年导致2亿人感染。改进 DENV感染模型是一个明确但没有得到满足的需求，在我的志贺氏菌病小鼠模型之前，小鼠被认为是 对志贺氏菌肠道感染耐药。因此，所述目标的成功完成将显著 影响人类传染病研究。

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.