Pathogen recognition and induction of innate immunity and inflammation against

项目1的重点是了解登革病毒（DENV），西尼罗河病毒（WNV）和日本脑炎病毒（JEV）如何被宿主细胞识别以触发先天免疫和炎症反应，并定义这些细胞内在和细胞外在反应如何协同控制感染。DENV、WNV和JEV是遗传相关的黄病毒，并且是全球最重要的节肢动物传播病毒之一。这些病毒不断出现，可导致人类严重出血性疾病（DENV）或神经系统疾病（WNV和JEV）。目前尚无获批的抗病毒治疗药物可用于治疗黄病毒感染。此外，没有针对数十亿高危人群的DENV或WNV感染的批准疫苗，并且目前的JEV疫苗显示出有限的保护持久性。我们的初步研究表明，对黄病毒感染的易感性由先天免疫/I型干扰素（IFN）防御控制，所述防御由RIG-I样受体（RLR）、RIG-I和MDA 5对黄病毒RNA的病原体相关分子模式（PAMP）识别触发。此外，我们已经确定了Nod样受体蛋白（NLRP）3在病毒诱导的炎症反应中炎症体信号传导/IL-1 β产生中的主要作用。这些研究表明，RLR和NLRP 3信号通路的病毒触发将先天免疫和炎症反应联系起来，以抑制黄病毒感染。 本提案中的研究将（1）鉴定在DENV、WNV和JEV感染期间触发先天免疫的RLR信号传导的病毒PAMP;（2）确定嗜神经黄病毒、WNV和JEV的NLRP 3活化和IL-1D产生的触发物;和（3）确定先天免疫/IFN应答和IL-12的连接和效应器作用的分子机制。控制黄病毒的l β炎症反应 感染

Project 1 is focused on understanding how Dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) are recognized by the host cell to trigger innate immune and inflammatory responses, and on defining how these cell-intrinsic and cell-extrinsic responses synergize to control infection. DENV, WNV, and JEV are genetically related flaviviruses and among the most important arthropod-borne viruses globally. These viruses are continually emerging and can cause severe hemorrhagic (DENV) or neurological disease (WNV and JEV) in humans. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. Moreover, there are no approved vaccines against DENV or WNV infection forthe billions of at-risk people, and the current JEV vaccines demonstrate limited durability of protection. Our preliminary studies indicate that susceptibility to flavivirus infection is controlled by innate immune/type I interferon (IFN) defenses triggered by pathogen-associated molecular pattern (PAMP) recognition of flavivirus RNA by RlG-l-like receptors (RLRs), RIG-I and MDA5. Additionally, we have identified a major role forthe Nod-like receptor protein (NLRP)3 in inflammasome signaling/IL-lbeta production in the virus-induced inflammatory response. These studies show that viral triggering of RLR and NLRP3 signaling pathways links innate immune and inflammatory responses to suppress flavivirus infection. The studies in this proposal will (1) Identify the viral PAMPs that trigger RLR signaling of innate immunity during DENV, WNV, and JEV infection; (2) Define the trigger(s) of NLRP3 activation and IL-1 D production by the neurotropic flaviviruses, WNV and JEV; and (3) Determine the molecular mechanisms of linkage and effector actions of innate immune/lFN responses and IL-lbeta inflammatory responses that control flavivirus infection