The function of CARD9 in innate immune responses

先天免疫在启动免疫反应和清除病原体方面起着至关重要的作用 微生物感染。使用模式识别受体，包括细胞表面受体，如Toll样受体 受体(TLR)或细胞内受体，如结节样受体(NLRs)，宿主细胞感知和响应 到微生物感染，这触发了各种信号事件的激活，导致抗微生物和 炎症反应。了解各种微生物感染诱导的信号通路将 提供对宿主防御机制的分子洞察，并提供潜在的治疗靶点 用于抗微生物感染。我们实验室和其他实验室最近的研究表明，CARD9，一种Caspase 含有募集结构域(CARD)的适配蛋白在先天免疫中发挥重要作用 通过调节核因子-kB和MAP激酶的反应。有趣的是，我们发现CARD9 与含细菌的吞噬小体有物理联系，并直接参与清除 巨噬细胞中的受感染细菌。然而，CARD9参与的分子机制是 对这些反应的监管仍有待确定。为了进一步研究CARD9的生物学功能， 我们提出了两个特定的目标来研究CARD9介导抗菌素的分子机制 使用我们最近产生的CARD9缺陷(CARD9-/-)小鼠进行反应。我们的具体目标是： (1)确定CARD9参与细胞内清除的分子机制 细菌；(2)鉴定介导依赖于CARD9的抗细菌和真菌的CARD9相互作用蛋白 回应。总之，这些研究将揭示一种未知的宿主防御机制，并提供 深入了解抗微生物免疫反应。

Innate immunity plays a crucial role in initiating the immune responses and pathogen clearance upon microbial infection. Using pattern recognition receptors including cell surface receptor such as Toll-like receptors (TLRs) or intracellular receptors such as NOD-like receptors (NLRs), host cells sense and respond to microbial infection, which triggers the activation of various signaling events, leading to anti-microbial and inflammatory responses. Understanding the signaling pathways induced by various microbial infections will provide the molecular insights into the host defense machinery and provide the potential therapeutic targets for anti-microbial infection. Recent studies from our lab and others indicate that CARD9, a Caspase Recruitment Domain (CARD)-containing adaptor protein, plays an important role in innate immune responses through regulation of NF-kB and MAP kinases. Interestingly, we have found that CARD9 physically associates with bacteria-containing phagosomes and is directly involved in the clearance of infected bacteria in macrophages. However, the molecular mechanism by which CARD9 is involved in the regulation of these responses remains to be determined. To further study the biological function of CARD9, we propose two specific aims to investigate the molecular mechanism by which CARD9 mediates antimicrobial responses using our recently generated CARD9-deficient (Card9-/-) mice. Our specific aims are: (1) to determine the molecular mechanism by which CARD9 is involved in the clearance of intracellular bacteria; (2) to identify CARD9-interacting proteins that mediate CARD9-dependent anti-bacterial and fungal responses. Together, these studies will reveal an unknown host defense mechanism and provide the novel insight into anti-microbial immune responses.