Herpes simplex virus-1 evasion of CD1d antigen presentation pathway

单纯疱疹病毒-1逃避CD1d抗原呈递途径

基本信息

批准号：
9054767
负责人：
Weiming Yuan
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-10 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054767
关键词：
Acute Adaptor Signaling Protein Address Animal Model Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antiviral Agents Antiviral Therapy Bacteria Binding Blindness CD1d antigen Cell physiology Cell surface Cells Down-Regulation Drug Targeting Encephalitis Endosomes Evolution Family Genes Glycoproteins Goals Health Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Immune Immune response Immune system Immunity Infection Investigation Kinesin Knock-in Mouse Life Light Lipids MHC Class I Genes Maps Mediating Modeling Molecular Motor Mus Mutagenesis Mutation Natural Immunity Natural Killer Cells Outcome Parasites Play Point Mutation Prevention Proteins Proto-Oncogene Proteins c-akt Public Health Reagent Recycling Regulatory T-Lymphocyte Role Simplexvirus Site Structure Surface System T cell regulation T-Cell Activation T-Lymphocyte Testing Therapeutic Tumor Immunity Vaccines Viral Viral Pathogenesis Viral Physiology Viral Proteins Viral Tumor Antigens Viral Vaccines Virus Virus Diseases adaptive immunity antimicrobial comparative design fungus improved in vivo innovation killer T cell latent infection member mouse model mutant novel novel strategies pathogen prevent prototype tool tumor virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Herpesvirus infection is a major public health problem. Herpes simplex virus-1 (HSV-1), as the model virus for a-herpesvirus family, is the leading pathogen for infection-caused blindness and encephalitis. To establish infection and escape critical components of the immune systems to remain latent in host cells, the virus has evolved sophisticated immune evasion strategies. CD1d-restricted innate-like NKT cells play critical anti-microbial functions against different pathogens, including viruses, bacteria, fungi, and parasites. However, it remains unclear how pathogens including viruses evade the potent anti-microbial functions of NKT cells during infection and latency. The specific emphasis of this proposal is how HSV-1 modulates human CD1d expression in antigen-presenting cells to inhibit NKT cell function. We have originally discovered that upon infection, HSV-1 rapidly suppresses CD1d expression on the cell surface and inhibits the activation of NKT cells and their immunoregulatory function. Recently, we have identified that two viral factors, glycoprotein B (gB) and protein kinase US3, are required for optimal downregulation of CD1d surface expression. In particular, gB targets and relocates CD1d molecules to the TGN, while US3 blocks CD1d recycling and facilitates more gB-mediated CD1d relocalization to the TGN. Remarkably, this immune evasion mechanism only targets human, but not mouse, CD1d suggesting it is a result of viral co- evolution with human host. To dissect the in vivo roles of tis immune evasion mechanism, we have successfully generated a human CD1d knock-in mouse. We propose three interrelated specific aims. First, we will delineate the molecular details of the gB-CD1d interaction and map the interaction domains in these proteins. Second, we will examine the molecular and cellular mechanism by which the viral protein US3 cooperates with gB to down-regulate CD1d. Finally, we will investigate how gB and US3 proteins inhibit NKT cell function using our new mouse model. We will specifically examine how the down-regulation of CD1d inhibits the initial activation and recruitment of NKT cells to the infection site. Further identification of the NKT cell effector function inhibited by the evasins will provide novel leads or therapeutic means to treat and prevent HSV-1 infection. This proposal is highly innovative and its successful outcome should serve as a major discovery that will significantly impact our understanding of herpesvirus-mediated immune evasion as well as potentially provide the means for developing effective vaccines and antiviral drugs.

描述（由申请人提供）：疱疹病毒感染是一个主要的公共卫生问题。单纯疱疹病毒-1（HSV-1）作为A HERPESVIRUS家族的模型病毒，是引起感染失明和脑炎的领先病原体。为了建立免疫系统的感染和逃避关键成分以保持宿主细胞的潜在，该病毒已经发展出复杂的免疫逃避策略。 CD1D限制的先天性NKT细胞对不同的病原体（包括病毒，细菌，真菌和寄生虫）起着关键的抗菌功能。但是，尚不清楚包括病毒在内的病原体如何逃避在感染和潜伏期期间NKT细胞的有效抗微生物功能。该建议的具体重点是HSV-1如何调节抗原呈递细胞中的人CD1D表达以抑制NKT细胞功能。我们最初发现，在感染后，HSV-1会迅速抑制细胞表面的CD1D表达，并抑制NKT细胞的激活及其免疫调节功能。最近，我们确定了两个病毒因子B糖蛋白B（GB）和蛋白激酶US3是最佳下调CD1D表面表达所必需的。特别是，GB靶标并将CD1D分子重新定位到TGN，而US3阻断了CD1D回收利用并促进了更多GB介导的CD1D重新定位到TGN。值得注意的是，这种免疫逃避机制仅针对人类，而不是小鼠CD1D，这表明这是与人类宿主的病毒式共同进化的结果。为了剖析TIS免疫逃避机制的体内作用，我们成功地产生了人类CD1D敲击小鼠。我们提出了三个相互关联的特定目标。首先，我们将描述GB-CD1D相互作用的分子细节，并绘制这些蛋白质中的相互作用域。其次，我们将检查病毒蛋白US3与GB合作以下调CD1D的分子和细胞机制。最后，我们将研究GB和US3蛋白如何使用我们的新小鼠模型抑制NKT细胞功能。我们将特别研究CD1D的下调如何抑制NKT细胞对感染部位的初始激活和募集。 EVASIN抑制的NKT细胞效应功能的进一步鉴定将提供新颖的铅或治疗手段，以治疗和预防HSV-1感染。该提议具有很高的创新性，其成功的结果应成为一个重大发现，这将极大地影响我们对疱疹病毒介导的免疫逃避的理解，并有可能为开发有效的疫苗和抗病毒药提供手段。