RESEARCH PROJECT 2

项目2：宿主先天途径的遗传鉴定 控制细菌致病 摘要 哺乳动物先天免疫系统的吞噬细胞，特别是巨噬细胞和中性粒细胞，形成了第一个 它们是细菌感染的防线，并配备了强大的机制来限制细菌生长和 铲除入侵者。然而，细菌病原体已经进化出阻止这些杀戮的机制。 吞噬细胞的机制，并在人体组织中持续存在。除了具有直接的抗菌活性外， 巨噬细胞和中性粒细胞也会启动和形成强大的炎症反应， 影响疾病。事实上，这项研究中涉及的每种病原体引发的炎症途径- 结核分枝杆菌(Mtb)、金黄色葡萄球菌(SA)和沙眼衣原体(CT)-主要 在细菌在组织中的持久性和促进疾病方面的作用。病原体必须按顺序颠覆这些细胞 但决定感染结果的宿主基因和细胞途径并不是 完全清楚。这项提议的总体思想是使用公正的、系统的方法来探索 病原体和先天免疫细胞之间的相互作用，并利用这一信息来预测 细菌感染性，将在人体样本中以迭代的方式进行测试，以模拟宿主在 感染。我们建议系统地鉴定先天免疫基因网络，它是发病的基础。 这三种重要细菌病原体感染的临床相关模型系统。使用强大的 在体外感染和小鼠模型中基于CRISPR的基因敲除策略，加上创新的 在临床样本中识别与功能相关的多态性的方法，我们试图显著地 增加我们对人类感染生物学的理解。我们预计，这些见解，再加上 HPMI中心的其他要素将指出具有治疗相关性的新漏洞。

PROJECT 2: GENETIC IDENTIFICATION OF HOST INNATE PATHWAYS THAT CONTROL BACTERIAL PATHOGENESIS SUMMARY Phagocytes of the mammalian innate immune system, in particular macrophages and neutrophils, form the first line of defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and eradicate invaders. Bacterial pathogens, however, have evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues. In addition to having direct antimicrobial activity, macrophages and neutrophils also initiate and shape powerful inflammatory responses that dramatically influence disease. Indeed, the inflammatory pathways elicited by each of the pathogens involved in this study - Mycobacterium tuberculosis (Mtb), Staphylococcus aureus (SA), and Chlamydia trachomatis (CT) - play major roles in bacterial persistence in tissues and in promoting disease. Pathogens must subvert these cells in order to grow and persist, but the host genes and cellular pathways that dictate the outcome of infection are not entirely clear. The broad idea of this proposal is to use unbiased, systematic approaches to probe the intimate interactions between pathogen and innate immune cells, and to use this information to make predictions about bacterial infectivity that will be tested in human samples in an iterative fashion to model host response during infection. We propose to systematically identify innate immune gene networks that underlie pathogenesis in clinically relevant model systems of infections with these three important bacterial pathogens. Using powerful CRISPR-based knockout strategies in both ex vivo infections and in mouse models, coupled with innovative approaches to identify functionally relevant polymorphisms in clinical samples, we seek to dramatically increase our understanding of infection biology of humans. We anticipate that these insights, coupled with the other elements of the HPMI Center, will point to novel vulnerabilities with therapeutic relevance.