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（由申请人提供）：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引起的脱髓鞘疾病的发病机制中的作用。我们已经证明 MHV 和某些其他冠状病毒（但不是全部）的刺突 (S) 蛋白是 Fc? 的分子模拟物？受体 II (Fc?RII)。 MHV S 蛋白以低至中等亲和力非特异性结合 IgG，并被针对低亲和力 FcRII 产生的单克隆抗体识别。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，并且已表明该活性在 1 型 HSV 的免疫逃避中发挥作用。我们假设 MHV S 蛋白的 Fc?RII 活性也在 MHV 感染期间的免疫逃避和/或免疫发病机制中发挥作用。在本提案中，我们打算利用最近开发的 MHV-A59 反向遗传系统来确定该活性在小鼠因感染该病毒而产生的脱髓鞘疾病中的作用，并研究该活性是否促进该病毒的免疫逃避。该提案的具体目标是： (1) 鉴定 MHV S 蛋白中对 Fc?RII 分子模拟至关重要的残基； (2)分离携带S蛋白突变使其Fc?RII活性失活的MHV-A59重组病毒。这些突变体将被表征，并与亲本同基因 MHV-A59 进行比较，包括它们在细胞培养物中的复制、它们在补体存在和不存在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。许多人类疾病与中枢神经系统的持续感染有关，而多发性硬化症 (MS) 等其他疾病则被怀疑是由病毒感染引发的。公共卫生相关性：MHV 小鼠模型是广泛研究的多发性硬化症模型。尽管其机制尚不完全清楚，但 MHV 能够避免被免疫系统从 CNS 中完全消除。拟议的研究有助于加深我们对 MHV 逃避中枢神经系统免疫消除机制的理解。该提案阐述了重要 MHV 蛋白的功能活性在逃避宿主免疫反应和产生疾病中的作用。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类疱疹病毒中，并且也可能说明这些病毒在中枢神经系统中的持续存在。此外，测试的其他三种冠状病毒中的两种也表现出 Fc 受体的分子模拟。因此，这项研究获得的结果可能与其他人类冠状病毒疾病有关，例如引起 SARS-CoV 和 HCoV-NL3 的下呼吸道疾病。