Merkel cell polyomavirus infection and the host immune response

默克尔细胞多瘤病毒感染与宿主免疫反应

• 批准号: 10001428
• 负责人: Jianxin You
• 金额: $ 17.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001428
• 关键词: 3-Dimensional; Architecture; Cancer Etiology; Cell Culture System; Cell Culture Techniques; Cells; Chronic; Clinical; Cutaneous T-cell lymphoma; DNA biosynthesis; Dermal; Development; Disease; Environment; Equilibrium; Event; Failure; Fibroblasts; Future; Gene Expression; General Population; Genes; Genetic Transcription; Goals; Grant; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunocompetent; Immunologics; Immunosuppression; Immunotherapy; Incidence; Individual; Infection; Knowledge; Life Cycle Stages; Malignant Neoplasms; Merkel Cells; Merkel cell carcinoma; Modeling; Molecular; Myelogenous; Oncogenic; Oncogenic Viruses; Patients; Phase; Physiological; Polyomavirus; Polyomavirus Infections; Production; Protein Array Analysis; Proteins; Resistance; Risk Factors; Role; Skin; Skin Cancer; Survival Rate; System; T-Lymphocyte; Time; Tropism; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Visualization; burden of illness; checkpoint therapy; chemotherapy; chronic infection; empowered; genetic signature; genome-wide; immune function; immunosuppressed; laser capture microdissection; latent infection; melanoma; mortality; multidisciplinary; novel; novel strategies; novel virus; prevent; response; targeted treatment; transcriptome sequencing; tumor; tumorigenesis; tumorigenic; viral DNA; whole genome

Viral infection contributes to nearly 15% of human cancers worldwide. Many of the oncogenic viruses are prone to cause cancer in immunosuppressed individuals but maintain asymptomatic infection in the general population, underscoring the critical role of the host immune system in preventing oncogenic virus-induced cancers. The importance of host immunity is clearly demonstrated in Merkel cell polyomavirus (MCPyV) and associated cancers. MCPyV is a novel human polyomavirus that has been shown to cause Merkel cell carcinoma (MCC). MCC is one of the most aggressive skin cancers with a disease-associated mortality rate between 33-46% that exceeds the rate of melanoma and less than 45% five-year survival rate. While the incidence of MCC has tripled over the past twenty years, there is no effective chemotherapy available for metastatic MCC. MCPyV infection is widespread in the general population, suggesting that the virus has evolved a mechanism to evade host immune eradication. Immune suppression is one of the most important risk factors for MCPyV-associated MCC, indicating that failure of human hosts to control MCPyV infection can increase the likelihood of MCPyV-related tumorigenesis. In immune competent patients, MCC tumor continues to develop despite the production of T cells recognizing MCPyV-encoded proteins. Recently developed immunotherapies showed promising results but the responses are short-lived. The abilities of MCPyV- associated MCCs to escape immunological destruction and to resist immunotherapy argue that this virus-induced tumorigenesis is empowered by an immune evasion mechanism. Identification of immune effectors that normally restrict MCPyV propagation may reveal mechanism for MCPyV oncogenesis and inform strategies to reduce its disease burden. However, very little in known about how MCPyV interacts with the immune system. This topic was impossible to study because MCPyV tropism was previously unknown, making it technically difficult to cultivate MCPyV. We recently identified human dermal fibroblasts as the host cells for MCPyV and established the first cell infection model for this oncogenic virus. Using this system, we observed, for the first time, the induction of immune gene expression triggered by MCPyV infection. In this grant, we will determine the molecular mechanisms by which MCPyV induces immune response (Aim 1) and characterize this response genome-wide using the ex vivo skin culture that mimics the physiological environment of the human skin (Aim 2). Through revealing the largely unknown interplay between MCPyV and the host immune system, our goal is to understand how immunoevasion contributes to MCPyV persistence and MCC oncogenesis. Elucidating specific aspects of host immunity that normally restrict MCPyV infection could unveil novel strategies for preventing and treating the devastating MCC cancer.

病毒感染导致全球近15%的人类癌症。许多致癌病毒易于在免疫抑制个体中引起癌症，但在一般人群中保持无症状感染，这强调了宿主免疫系统在预防致癌病毒诱导的癌症中的关键作用。宿主免疫的重要性在默克尔细胞多瘤病毒（MCPyV）和相关癌症中清楚地得到证明。MCPyV是一种新型人类多瘤病毒，已被证明会导致默克尔细胞癌（MCC）。MCC是最具侵袭性的皮肤癌之一，与疾病相关的死亡率在33-46%之间，超过了黑色素瘤的死亡率，但五年生存率低于45%。虽然MCC的发病率在过去二十年中增加了两倍，但对于转移性MCC没有有效的化疗。MCPyV感染在一般人群中广泛存在，表明该病毒已进化出逃避宿主免疫根除的机制。免疫抑制是MCPyV相关MCC最重要的风险因素之一，表明人类宿主未能控制MCPyV感染可增加MCPyV相关肿瘤发生的可能性。在有免疫能力的患者中，尽管产生了识别MCPyV编码蛋白的T细胞，但MCC肿瘤继续发展。最近开发的免疫疗法显示出有希望的结果，但反应是短暂的。MCPyV相关MCC逃避免疫破坏和抵抗免疫疗法的能力表明，这种病毒诱导的肿瘤发生是由免疫逃避机制赋予的。鉴定通常限制MCPyV传播的免疫效应物可以揭示MCPyV肿瘤发生的机制，并为减少其疾病负担的策略提供信息。然而，很少有人知道MCPyV如何与免疫系统相互作用。这个课题是不可能研究的，因为MCPyV的嗜性以前是未知的，使得在技术上难以培养MCPyV。我们最近鉴定了人皮肤成纤维细胞作为MCPyV的宿主细胞，并建立了这种致癌病毒的第一个细胞感染模型。使用该系统，我们首次观察到由MCPyV感染引发的免疫基因表达的诱导。在这项研究中，我们将确定MCPyV诱导免疫应答的分子机制（目标1），并使用模拟人类皮肤生理环境的离体皮肤培养物（目标2）在全基因组范围内表征这种应答。通过揭示MCPyV和宿主免疫系统之间的相互作用，我们的目标是了解免疫逃避如何有助于MCPyV的持久性和MCC肿瘤发生。阐明通常限制MCPyV感染的宿主免疫的特定方面可以揭示预防和治疗毁灭性MCC癌症的新策略。