Pathogen recognition and induction of innate immunity and inflammation against

项目1的重点是了解登革热病毒(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固有免疫和炎症反应，并确定这些细胞内在和细胞外在反应如何协同作用来控制感染。DENV、WNV和JEV是遗传上相关的黄病毒，也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，可在人类中引起严重出血性(DENV)或神经系统疾病(WNV和JEV)。目前还没有批准的抗病毒治疗剂可用于治疗黄病毒感染。此外，目前还没有批准的针对数十亿高危人群感染DENV或WNV的疫苗，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，黄病毒感染的易感性是由病原体相关分子模式(PAMP)通过RLG-L样受体(RLRs)、RIG-I和MDA5识别黄病毒RNA而触发的先天性免疫/I型干扰素防御系统。此外，我们还发现了NOD样受体蛋白(NLRP)3在炎症体信号转导中的重要作用，以及在病毒诱导的炎症反应中产生IL-1β的作用。这些研究表明，病毒触发的RLR和NLRP3信号通路将先天免疫和炎症反应联系起来，以抑制黄病毒感染。 这项研究将(1)确定在DENV、WNV和JEV感染期间触发天然免疫RLR信号的病毒PAMP；(2)确定嗜神经性黄病毒、WNV和JEV激活NLRP3和产生IL-1 D的触发器(S)；以及(3)确定控制黄病毒的天然免疫/LFN反应和IL-1β炎症反应之间的联系和效应作用的分子机制 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