Role of TLR4 in Coronavirus Infection

TLR4 在冠状病毒感染中的作用

基本信息

批准号：
7701085
负责人：
Steven M Varga
金额：
$ 22.41万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7701085
关键词：
Accounting Acute Animal Model Animals B-Lymphocytes C3H/HeJ Mouse C57BL/6 Mouse CD8B1 gene Cells Characteristics Chiroptera Common Cold Coronavirus Coronavirus Infections Data Development Disease Disease Outbreaks Event Exhibits Family Future Gastrointestinal tract structure Genes Genome Goals Gram-Negative Bacterial Infections Human Immune Immune response Immunobiology Inbred C3H Mice Infection Infectious Agent Injury Interferon Type I Intervention Knowledge Laboratories Ligands Lipopolysaccharides Lung Lung diseases Mediating Methodology Morbidity - disease rate Murine hepatitis virus Mus Mutation Natural Immunity Neuraxis Pathogen detection Pathogenesis Pathologic Pathway interactions Phylogenetic Analysis Play Population RNA Viruses Research Resistance Respiratory System Respiratory Tract Infections Respiratory syncytial virus RSV proteins Respiratory tract structure Role Severe Acute Respiratory Syndrome Signal Transduction T-Lymphocyte T-Lymphocyte Epitopes Therapeutic Intervention Tissues Vaccines Virulent Virus Virus Diseases Virus Replication Work base design human coronavirus immunopathology in vivo information gathering innovation mortality novel novel strategies pathogen prevent receptor respiratory response sensor toll-like receptor 4 transmission process type I interferon receptor vaccine efficacy

项目摘要

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.

描述（由申请人提供）：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%。新型 HCoV 作为严重急性呼吸综合征 (SARS) 病原体的出现证明了冠状病毒有可能诱发严重呼吸道疾病并对人类健康造成重大影响。尽管SARS-CoV自首次爆发以来尚未在人群中重新出现，但最近从蝙蝠等自然哺乳动物宿主中分离出的相关冠状病毒表明，未来可能会再次发生强毒冠状病毒从动物到人类的传播。更全面地了解肺部冠状病毒感染后呼吸道的免疫反应将增强我们有效治疗未来新发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免疫干预措施的功效也很重要。 C3H小鼠鼻内感染小鼠肝炎病毒1株（MHV-1）会产生一种致死率很高的急性呼吸道疾病，其病理学与人类SARS病例有一些相似之处。与野生型对照相比，编码 Toll 样受体 4 (TLR4) 的基因存在天然突变，破坏其正常功能的 C3H/HeJ 小鼠在鼻内 MHV-1 感染后表现出发病率和死亡率大大增加。与易感 C3H 小鼠相比，C57BL/6 小鼠在鼻内 MHV-1 感染后不会发病。然而，C57BL/6 背景下 I 型 IFN 受体缺陷小鼠的 MHV-1 感染导致多个组织中病毒复制不受控制，这表明先天免疫和 I 型 IFN 在介导 MHV-1 感染的早期控制中发挥着重要作用。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发挥着至关重要的作用，然而，目前对体内负责早期诱导对冠状病毒的先天免疫反应的宿主传感器途径知之甚少。该提案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。该提案将研究以下具体目标：1) 确定为什么 TLR4 缺陷导致 C3H 小鼠鼻内 MHV-1 感染后死亡率增加；2) 确定哪些宿主病原体识别受体识别耐药 C57BL/6 小鼠鼻内 MHV-1 感染。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方法。人类冠状病毒会引起人类呼吸道感染，可能导致类似于普通感冒的轻微疾病，也可能导致致命的严重呼吸道疾病。该提案的总体目标是确定初始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方法，并有助于设计未来的冠状病毒疫苗。