Role of TLR4 in Coronavirus Infection

描述(申请人提供)：人类冠状病毒(HCoV)是正链RNA病毒，估计约占普通感冒病例的30%。一种新的HCoV作为严重急性呼吸综合征(SARS)的病原体的出现证明了冠状病毒可能导致严重的呼吸道疾病并对人类健康造成重大影响。虽然SARS-CoV自最初暴发以来没有在人类种群中重新出现，但最近从蝙蝠等自然哺乳动物宿主中分离到的相关冠状病毒表明，未来可能会再次发生强毒冠状病毒在动物与人之间的传播。更全面地了解肺部冠状病毒感染后呼吸道的免疫反应，将提高我们有效应对未来新出现的冠状病毒感染爆发的能力。动物模型对于了解人类冠状病毒感染的发病机制至关重要，对于评估疫苗和其他潜在的免疫干预措施的效果也很重要。经鼻感染C3H小鼠的小鼠肝炎病毒株1(MHV-1)可引起一种致死率高的急性呼吸道疾病，在病理上与人类SARS病例有许多相似之处。与野生型对照相比，C3H/HeJ小鼠在编码Toll样受体4(TLR4)的基因上存在自然突变，破坏了其正常功能，与野生型对照相比，经鼻感染MHV-1后，发病率和死亡率大大增加。与易感的C3H小鼠相比，C57BL/6小鼠在鼻内感染MHV-1后不会发生疾病。然而，以C57BL/6为背景的I型干扰素受体缺陷小鼠感染MHV-1，导致病毒在多个组织中的复制失控，表明I型干扰素在介导MHV-1感染的早期控制中具有重要的先天免疫作用。综上所述，这些数据表明，先天免疫在呼吸道冠状病毒感染的早期控制中起着至关重要的作用，但目前对体内早期诱导对冠状病毒的先天免疫反应的宿主传感器通路知之甚少。这项建议的总体目标是确定先天免疫反应如何影响随后对肺部冠状病毒感染的适应性免疫反应的发展。这项建议将检查以下具体目标：1)确定TLR4缺乏导致C3H小鼠鼻内感染MHV-1后死亡率增加的原因；2)确定哪些宿主病原体识别受体识别耐药C57BL/6小鼠鼻内感染MHV-1。从这项研究中获得的知识将有助于更好地了解有效控制冠状病毒感染所需的早期事件，并为呼吸道冠状病毒感染的治疗干预提供新的方法。人类冠状病毒导致人类呼吸道感染，可能导致类似普通感冒的轻微疾病，以及可能致命的严重呼吸道疾病。这项建议的总体目标是确定最初的先天免疫反应如何影响随后对肺部冠状病毒感染的适应性免疫反应的发展。这些信息将为呼吸道冠状病毒感染的治疗干预提供新的方法，并有助于未来冠状病毒疫苗的设计。

DESCRIPTION (provided by applicant): Human coronaviruses (HCoVs) are positive-stranded RNA viruses that are estimated to account for approximately 30% of cases of the common cold. The emergence of a novel HCoV as the etiologic agent of severe acute respiratory syndrome (SARS) demonstrated the potential of coronaviruses to induce severe respiratory disease and cause a significant impact human heath. Although SARS-CoV has not re-emerged within the human population since its initial outbreak, the recent isolation of related coronaviruses from natural mammalian reservoirs such as bats suggest that animal-to-human transmission of a virulent coronavirus may occur again in the future. A more complete understanding of the immune response in the respiratory tract following pulmonary coronavirus infection would enhance our ability to effectively treat future outbreaks of emerging coronavirus infections. Animal models are critical to understanding the pathogenesis of human coronavirus infections and are important for evaluating the efficacy of vaccines and other potential immune interventions. Intranasal mouse hepatitis virus strain 1 (MHV-1) infection of C3H mice produces an acute respiratory disease with a high lethality rate that shares several pathological similarities with human SARS cases. C3H/HeJ mice that harbor a natural mutation in the gene that encodes toll-like receptor 4 (TLR4) that disrupts its normal function, exhibit greatly increased morbidity and mortality after intranasal MHV-1 infection as compared to wild-type controls. In contrast to susceptible C3H mice, C57BL/6 mice do not develop disease following intranasal MHV-1 infection. However, MHV-1 infection of type I IFN receptor-deficient mice on the C57BL/6 background results in uncontrolled virus replication in multiple tissues demonstrating the important role for innate immunity and type I IFN in mediating the early control of MHV-1 infection. Taken together these data indicate that innate immunity plays a crucial role in the early control of respiratory coronavirus infection, however the host sensor pathways responsible for the early induction of the innate immune response to coronaviruses in vivo are currently poorly understood. The overall goal of this proposal is to define how the innate immune response influences the development of the subsequent adaptive immune response to pulmonary coronavirus infections. This proposal will examine the following Specific Aims: 1) determine the why TLR4 deficiency results in enhanced mortality after intranasal MHV-1 infection of C3H mice and 2) determine which host pathogen recognition receptors recognize intranasal MHV-1 infection in resistant C57BL/6 mice. The knowledge gained from this study will provide a better understanding of the early events required for effective control of coronavirus infection and also provide novel approaches for the therapeutic intervention of respiratory coronavirus infections. Human coronaviruses cause respiratory tract infections in humans that can result in mild disease similar to the common cold as well as potentially fatal cases of severe respiratory disease. The overall goal of this proposal is to define how the initial innate immune response influences the development of the subsequent adaptive immune response to pulmonary coronavirus infections. This information will provide novel approaches for therapeutic intervention of respiratory coronavirus infections and aid in the design of future coronavirus vaccines.