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

• 批准号: 8652945
• 负责人: Weiming Yuan
• 金额: $ 41.1万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-10 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652945
• 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

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型（HSV-1）是疱疹病毒科的模式病毒，是引起感染性失明和脑炎的主要病原体。为了建立感染和逃避免疫系统的关键组成部分，以保持潜伏在宿主细胞中，病毒已经进化出复杂的免疫逃避策略。CD 1d限制性天然样NKT细胞对不同病原体（包括病毒、细菌、真菌和寄生虫）发挥关键的抗微生物功能。然而，目前尚不清楚包括病毒在内的病原体如何在感染和潜伏期间逃避NKT细胞的有效抗微生物功能。该提案的具体重点是HSV-1如何调节抗原呈递细胞中的人CD 1d表达以抑制NKT细胞功能。我们最初发现，在感染后，HSV-1迅速抑制细胞表面的CD 1d表达，并抑制NKT细胞的活化及其免疫调节功能。最近，我们已经确定了两个病毒因子，糖蛋白B（g B）和蛋白激酶US 3，需要最佳的下调CD 1d表面表达。特别是，gB靶向并重新定位CD 1d分子至TGN，而US 3阻断CD 1d再循环并促进更多gB介导的CD 1d重新定位至TGN。值得注意的是，这种免疫逃避机制仅靶向人，而不是小鼠，CD 1d表明它是病毒与人类宿主共同进化的结果。为了剖析这种免疫逃避机制在体内的作用，我们成功地产生了人CD 1d基因敲入小鼠。我们提出了三个相互关联的具体目标。首先，我们将描绘gB-CD 1d相互作用的分子细节，并绘制这些蛋白质中的相互作用结构域。其次，我们将研究病毒蛋白US 3与gB合作下调CD 1d的分子和细胞机制。最后，我们将使用我们的新小鼠模型研究gB和US 3蛋白如何抑制NKT细胞功能。我们将专门研究CD 1d的下调如何抑制NKT细胞的初始激活和募集到感染部位。进一步鉴定由evasins抑制的NKT细胞效应子功能将为治疗和预防HSV-1感染提供新的线索或治疗手段。这一提议具有高度创新性，其成功的结果应该成为一个重大发现，将显著影响我们对疱疹病毒介导的免疫逃避的理解，并可能为开发有效的疫苗和抗病毒药物提供手段。