Role of the MHV S Protein Fc Receptor Activity in Immune Evasion in the CNS

MHV S 蛋白 Fc 受体活性在中枢神经系统免疫逃避中的作用

• 批准号: 7530148
• 负责人: JULIAN L LEIBOWITZ
• 金额: $ 7.33万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530148
• 关键词: Address; Affinity; Antibodies; Antigens; Binding; Complement; Coronavirus; Cultured Cells; Demyelinating Diseases; Disease; Exhibits; Fc Receptor; Genes; Hepatitis Viruses; Herpesviridae; Human; Immune; Immune response; Immune system; Immunoglobulin G; Infection; Link; Molecular; Molecular Mimicry; Monoclonal Antibodies; Mouse Protein; Multiple Sclerosis; Murine hepatitis virus; Mus; Mutation; Numbers; Pathogenesis; Play; Predisposition; Proteins; Public Health; Research; Role; SARS coronavirus; Simplexvirus; Study models; System; Testing; Time; Viral Proteins; Virus; Virus Diseases; human coronavirus; human disease; mouse model; mutant; positional cloning; receptor; recombinant virus; respiratory

DESCRIPTION (provided by applicant): The objective of this proposal is to determine the role of the Fc receptor-like activity of the mouse hepatitis virus (MHV) S protein in the pathogenesis of the demyelinating disease induced by this virus. We have demonstrated that the spike (S) proteins of MHV and certain other coronaviruses (but not all) was a molecular mimic of the Fc? receptor II (Fc?RII). The MHV S protein non-specifically binds IgG with low to modest affinity and was recognized by a monoclonal antibody raised against the low affinity Fc?RII. Herpesviruses, in particular herpes simplex viruses, also encode genes which have an Fc receptor activity and it has been shown that this activity plays a role in immune evasion by HSV type 1. We hypothesize that the Fc?RII activity of the MHV S protein also plays a role in immune evasion and/or immunopathogenesis during infection with MHV. In this proposal we intend to utilize recently developed reverse genetic systems for MHV-A59 to determine the role of this activity in the demyelinating disease produced in mice by infection with this virus, and to investigate if this activity facilitates immune evasion by this virus. The specific aims of this proposal are: (1) To identify residues in the MHV S protein that are essential for molecular mimicry of the Fc?RII; (2) To isolate MHV-A59 recombinant viruses carrying mutations in the S protein that inactivate its Fc?RII activity. These mutants will be characterized and compared with the parental isogenic MHV-A59 as to their replication in cell culture, their susceptibility to neutralization by antibody in the presence and absence of complement, and their ability to persist in the CNS and produce disease in mice. A number of human diseases have been linked to persistent infections of the CNS and others such as multiple sclerosis (MS) are suspected to be triggered by viral infections. PUBLIC HEALTH RELEVANCE: The MHV mouse model is a widely studied model for MS. Although the mechanism is not completely understood, MHV is able to avoid complete elimination from the CNS by the immune system. The proposed studies are relevant to increasing our understanding of mechanisms by which MHV evades immunological elimination from the CNS. This proposal addresses the role of a functional activity of an important MHV protein in evading the host immune response and producing disease. This functional activity, binding antibody by its non-antigen recognizing Fc end (molecular mimicry of the Fc receptor), is also present in human herpesviruses, and may also illuminate the persistence of these viruses in the CNS. In addition, two of three other coronaviruses tested also exhibited molecular mimicry of the Fc receptor. Thus, the results obtained from this research may be relevant to other human coronavirus diseases such as the lower respiratory illnesses caused SARS-CoV and the HCoV-NL3.

描述（由申请方提供）：本提案的目的是确定小鼠肝炎病毒（MHV）S蛋白的Fc受体样活性在该病毒诱导的脱髓鞘疾病发病机制中的作用。我们已经证明，刺突（S）蛋白的MHV和某些其他冠状病毒（但不是所有）是一个分子模拟的Fc？受体II（Fc？RII）。MHV S蛋白非特异性结合IgG低到中等的亲和力，并通过单克隆抗体对低亲和力Fc？RII.疱疹病毒，特别是单纯疱疹病毒，也编码具有Fc受体活性的基因，并且已经显示该活性在1型HSV的免疫逃避中起作用。我们假设Fc？MHV S蛋白的RII活性也在MHV感染期间的免疫逃避和/或免疫发病机制中起作用。在这个提议中，我们打算利用最近开发的反向遗传系统MHV-A59，以确定这种活性的作用，在脱髓鞘疾病产生的小鼠感染这种病毒，并调查这种活动是否有利于免疫逃避这种病毒。该建议的具体目标是：（1）确定MHV S蛋白中Fc的分子模拟所必需的残基？（2）分离携带S蛋白突变的MHV-A59重组病毒，使其与Fc结合; RII活动。将对这些突变体进行表征，并与亲本等基因MHV-A59进行比较，包括它们在细胞培养物中的复制、它们在存在和不存在补体的情况下对抗体中和的敏感性以及它们在CNS中持续存在并在小鼠中产生疾病的能力。许多人类疾病与CNS的持续感染有关，而其他疾病如多发性硬化症（MS）则被怀疑是由病毒感染引发的。公共卫生关系：MHV小鼠模型是广泛研究的MS模型。尽管机制尚未完全了解，但MHV能够避免通过免疫系统从CNS完全消除。拟议的研究与增加我们对MHV逃避CNS免疫消除机制的理解有关。这一建议解决了一个重要的MHV蛋白的功能活性在逃避宿主免疫反应和产生疾病的作用。这种通过非抗原识别Fc末端（Fc受体的分子模拟）结合抗体的功能活性也存在于人疱疹病毒中，也可能说明这些病毒在CNS中的持久性。此外，测试的三种其他冠状病毒中有两种也表现出Fc受体的分子模拟。因此，从这项研究中获得的结果可能与其他人类冠状病毒疾病有关，如SARS-CoV和HCoV-NL 3引起的下呼吸道疾病。