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

基本信息

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
项目类别：
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

项目摘要

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.

全球近 15% 的人类癌症是由病毒感染引起的。许多致癌病毒容易在免疫抑制个体中引起癌症，但在普通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发的癌症中的关键作用。默克尔细胞多瘤病毒 (MCPyV) 和相关癌症清楚地证明了宿主免疫的重要性。 MCPyV 是一种新型人类多瘤病毒，已被证明可引起默克尔细胞癌 (MCC)。 MCC 是最具侵袭性的皮肤癌之一，其疾病相关死亡率为 33-46%，超过黑色素瘤，五年生存率低于 45%。尽管 MCC 的发病率在过去二十年中增加了两倍，但目前尚无针对转移性 MCC 的有效化疗方法。 MCPyV 感染在普通人群中广泛存在，表明该病毒已经进化出一种逃避宿主免疫清除的机制。免疫抑制是 MCPyV 相关 MCC 的最重要危险因素之一，表明人类宿主未能控制 MCPyV 感染会增加 MCPyV 相关肿瘤发生的可能性。在免疫能力强的患者中，尽管产生了识别 MCPyV 编码蛋白的 T 细胞，但 MCC 肿瘤仍在继续发展。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治疗的能力表明，这种病毒诱导的肿瘤发生是由免疫逃避机制增强的。识别通常限制 MCPyV 传播的免疫效应器可能会揭示 MCPyV 肿瘤发生的机制，并为减轻其疾病负担的策略提供信息。然而，人们对 MCPyV 如何与免疫系统相互作用知之甚少。这个课题是不可能研究的，因为 MCPyV 的趋向性以前是未知的，这使得培养 MCPyV 在技术上很困难。我们最近确定了人真皮成纤维细胞作为 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 MCPyV 感染引发的免疫基因表达的诱导。在这笔资助中，我们将确定 MCPyV 诱导免疫反应的分子机制（目标 1），并使用模拟人类皮肤生理环境的离体皮肤培养物在全基因组范围内表征这种反应（目标 2）。通过揭示 MCPyV 与宿主免疫系统之间很大程度上未知的相互作用，我们的目标是了解免疫逃避如何促进 MCPyV 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能会揭示预防和治疗毁灭性 MCC 癌症的新策略。