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

基本信息

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
项目类别：
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

项目摘要

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）：该提案的目的是确定小鼠肝炎病毒（MHV）蛋白在该病毒引起的脱髓鞘疾病的发病机理中的FC受体样活性的作用。我们已经证明了MHV的尖峰蛋白和某些其他冠状病毒（但不是全部）是FC的分子模仿？受体II（FC？rii）。 MHV的蛋白非特异性结合IgG具有低至适中的亲和力，并通过针对低亲和力FC？RII的单克隆抗体识别。疱疹病毒，尤其是单纯疱疹病毒，还编码具有FC受体活性的基因，并且已经表明，这种活性在HSV 1型1类中在免疫逃避中起作用。我们假设MHV S蛋白的FC rii活性也在免疫逃避和/或免疫促进性的Intection the MHV中起作用。在该提案中，我们打算利用最近开发的MHV-A59反向遗传系统来确定这种活性在通过感染该病毒的小鼠中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。该提案的具体目的是：（1）鉴定MHV蛋白中的残基，这些残基对于FC RII的分子模仿至关重要；（2）分离出在S蛋白中携带突变的MHV-A59重组病毒，从而使其FC？RII活性失活。这些突变体将被表征并与父母的同基因MHV-A59进行比较，以在细胞培养中复制，在存在和不存在补体的情况下对抗体进行中和的敏感性以及在CNS中持续存在并在小鼠中产生疾病的能力。许多人类疾病已与中枢神经系统的持续感染以及其他多发性硬化症（MS）有关，被怀疑是由病毒感染触发的。公共卫生相关性：MHV鼠标模型是MS的广泛研究模型。尽管该机制尚未完全理解，但MHV能够避免免疫系统从中枢神经系统中完全消除。拟议的研究与我们对MHV逃避中枢神经系统免疫学消除的机制的理解有关。该建议探讨了重要的MHV蛋白在逃避宿主免疫反应和产生疾病中的功能活性的作用。这种功能活性是通过其非抗原识别Fc末端（FC受体的分子模仿）结合的抗体，也存在于人疱疹病毒中，并且也可能阐明CNS中这些病毒的持久性。此外，测试的其他三个冠状病毒中的两个也表现出FC受体的分子模仿。因此，从这项研究获得的结果可能与其他人类冠状病毒疾病有关，例如下呼吸道疾病引起SARS-COV和HCOV-NL3。