Keratinocyte innate immune responses after herpes simplex virus infection

单纯疱疹病毒感染后角质形成细胞的先天免疫反应

• 批准号: 8488595
• 负责人: William Joseph Muller
• 金额: $ 4.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8488595
• 关键词: Adult; Binding; Biological Assay; Candidate Disease Gene; Cell Surface Receptors; Cell membrane; Cells; DNA; Data; Epithelial Cells; Generations; Genes; Glycoproteins; Heparitin Sulfate; Herpesviridae; Herpesvirus 1; Histopathology; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; In Vitro; Infection; Laboratories; Latent Virus; Lead; Ligands; Lymphocyte; Lymphocyte Activation; Measures; Mediating; Mediator of activation protein; Membrane Fusion; Microarray Analysis; Morbidity - disease rate; Mouse Strains; Mucous Membrane; Mus; Neonatal; Neurologic; PVRL1; Pathway interactions; Population; Primary Cell Cultures; Proteins; RNA; Research; Serotyping; Signal Pathway; Signal Transduction; Simplexvirus; Site; Skin; Surface; Testing; Tissues; Transcription Factor AP-1; Translations; Tumor Necrosis Factor Receptor; Universities; Viral; Viral Proteins; Virus; Virus Diseases; Work; gene induction; keratinocyte; knock-down; member; mortality; mutant; receptor; response; skin disorder; time use; transcription factor; transmission process; viral DNA

Herpes simplex virus (HSV) is a common cause of infection, with about 60% of US adults seropositive for HSV-1 and 20% for HSV-2 [1]. Infection with either serotype can cause neurologic morbidity and mortality in susceptible populations, especially after neonatal transmission [2]. HSV infection is generally initiated at either mucosal or skin surfaces, and shedding from skin and mucosa after reactivation of latent virus is a primary mode of transmission [3, 4]. Infection of susceptible cells is initiated after binding of one of several specific cell surface receptors to viral ligands, with subsequent fusion of the viral envelope with the cell membrane and delivery of viral DNA into the cell [5, 6]. Although several viral proteins are capable of mediating attachment, binding of the gD glycoprotein to one of its receptors is required for subsequent membrane fusion and productive HSV infection. Cell surface receptors for gD include herpes virus entry mediator (HVEM), nectin-1 or -2, and specific sites in heparan sulfate [6]. HVEM is a member of the tumor necrosis factor (TNF) receptor superfamily of proteins [7]. HVEM is expressed in many tissues, but its natural function appears to be in regulating immune responses. Although lymphocytes are not thought to be significant targets of HSV infection, the known natural ligands of HVEM enhance or inhibit lymphocyte activation [8], suggesting that the gD-HVEM interaction could influence lymphocyte-mediated immunity to HSV. However, our recent data suggests that innate immune signaling initiated by epithelial cells is altered by the interaction of HSV with HVEM [9]. We do not have a mechanistic understanding of this effect, and our ongoing studies are directed at elucidating a mechanism. The purpose of this proposed study is to generate additional data on the influence ofthe HSV gD-HVEM interaction on the generation of early innate responses in keratinocytes, the first cells to encounter HSV after primary infection. The overall hypothesis is that signaling pathways downstream of HVEM are altered upon engagement with HSV, leading to an innate immune response that provides an initial advantage for viral replication. This study takes advantage of viral mutants in our laboratory which are deficient in their ability to engage HVEM for entry (described in [9] and [10]), and will add Skin Disease Research Center (SDRC) expertise in keratinocyte culture and histopathology.

单纯疱疹病毒（HSV）是一种常见的感染原因，约60%的美国成年人HSV-1和HSV-2血清阳性[1]。任何一种血清型的感染都可能导致易感人群的神经系统发病和死亡，尤其是在新生儿传播后[2]。 HSV感染通常在粘膜或皮肤表面开始，潜伏病毒再活化后从皮肤和粘膜脱落是主要的传播方式[3，4]。易感细胞的感染在几种特异性细胞表面受体之一与病毒配体结合后开始，随后病毒包膜与细胞膜融合并将病毒DNA递送到细胞中[5，6]。尽管几种病毒蛋白能够介导附着，但随后的膜融合和生产性HSV感染需要gD糖蛋白与其受体之一的结合。gD的细胞表面受体包括疱疹病毒进入介体（HVEM）、nectin-1或-2和硫酸乙酰肝素中的特异性位点[6]。 HVEM是肿瘤坏死因子（TNF）受体蛋白超家族的成员[7]。HVEM在许多组织中表达，但其天然功能似乎是调节免疫反应。尽管淋巴细胞不被认为是HSV感染的重要靶标，但HVEM的已知天然配体增强或抑制淋巴细胞活化[8]，表明gD-HVEM相互作用可能影响淋巴细胞介导的对HSV的免疫。然而，我们最近的数据表明，由上皮细胞启动的先天免疫信号传导通过HSV与HVEM的相互作用而改变[9]。我们对这种效应没有机械的理解，我们正在进行的研究旨在阐明一种机制。本研究的目的是生成关于HSV gD-HVEM相互作用对角质形成细胞（初次感染后第一个遇到HSV的细胞）中早期先天性应答产生的影响的额外数据。总体假设是HVEM下游的信号传导途径在与HSV接合时改变，导致先天免疫应答，其为病毒免疫提供初始优势。 复制的本研究利用了我们实验室中缺乏HVEM进入能力的病毒突变体（见[9]和[10]），并将增加皮肤病研究中心（SDRC）在角质形成细胞培养和组织病理学方面的专业知识。