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: 7619047
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619047
• 关键词: Address; Affinity; Antibodies; Antigens; Binding; Cell Culture Techniques; Complement; Coronavirus; Demyelinating Diseases; Disease; Exhibits; Fc Receptor; Genes; Herpesviridae; Human; Immune; Immune response; Immune system; Immunoglobulin G; Infection; Link; Molecular; Molecular Mimicry; Monoclonal Antibodies; Multiple Sclerosis; Murine hepatitis virus; Mus; Mutation; Pathogenesis; Play; Predisposition; Proteins; Research; Role; SARS coronavirus; Simplexvirus; Study models; System; Testing; Time; Viral Proteins; Virus; Virus Diseases; human coronavirus; human disease; mouse model; mutant; positional cloning; public health relevance; 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）：本申请的目的是确定小鼠肝炎病毒（MHV） S蛋白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MHV和某些其他冠状病毒（但不是全部）的刺突(S)蛋白是Fc？受体II （Fc?RII）。MHV S蛋白非特异性结合低至中等亲和力的IgG，并被一种针对低亲和力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，并且已证明该活性在HSV 1型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/或免疫发病中起作用。在这项提议中，我们打算利用最近开发的MHV-A59的反向遗传系统来确定这种活性在感染这种病毒的小鼠产生的脱髓鞘疾病中的作用，并研究这种活性是否促进了这种病毒的免疫逃避。本提案的具体目的是：(1)鉴定MHV S蛋白中对Fc？RII;(2)分离携带S蛋白突变的MHV-A59重组病毒，使其Fc？RII活动。这些突变体将被表征并与亲本等基因MHV-A59进行比较，以确定它们在细胞培养中的复制，它们在存在和缺乏补体的情况下对抗体中和的敏感性，以及它们在中枢神经系统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小鼠模型是一种广泛研究的ms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中枢神经系统完全消除。拟议的研究与增加我们对MHV逃避中枢神经系统免疫消除的机制的理解有关。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中的作用。这种功能活性，通过其非抗原识别Fc端（Fc受体的分子模拟）结合抗体，也存在于人类疱疹病毒中，并且也可能阐明这些病毒在中枢神经系统中的持久性。此外，测试的其他三种冠状病毒中有两种也表现出Fc受体的分子模拟。因此，本研究的结果可能与其他人类冠状病毒疾病有关，如SARS-CoV和HCoV-NL3引起的下呼吸道疾病。

项目成果

Identification of novel functional regions within the spike glycoprotein of MHV-A59 based on a bioinformatics approach.

• DOI: 10.1016/j.virusres.2014.05.023
• 发表时间: 2014-08-30
• 期刊: Virus research
• 影响因子: 5
• 作者: Kaufman G;Liu P;Leibowitz JL
• 通讯作者: Leibowitz JL