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.

病毒感染在全球范围内造成近15％的人类癌症。许多致癌病毒容易引起免疫抑制个体的癌症，但在普通人群中保持无症状感染，强调了宿主免疫系统在防止致癌病毒引起的癌症中的关键作用。在默克尔细胞多瘤病毒（MCPYV）和相关的癌症中清楚地证明了宿主免疫的重要性。 MCPYV是一种新型的人类多瘤病毒，已被证明会引起默克尔细胞癌（MCC）。 MCC是最具侵略性的皮肤癌之一，与疾病相关的死亡率在33-46％之间，超过黑色素瘤率，五年生存率小于45％。尽管过去二十年来MCC的发病率增加了两倍，但没有有效的化学疗法可用于转移性MCC。 MCPYV感染在普通人群中广泛存在，这表明该病毒已经发展出一种逃避宿主免疫消除的机制。免疫抑制是与MCPYV相关的MCC最重要的危险因素之一，表明人宿主无法控制MCPYV感染的失败会增加与MCPYV相关的肿瘤发生的可能性。在免疫能力的患者中，尽管产生了识别MCPYV编码蛋白的T细胞，但MCC肿瘤仍在继续发展。最近开发的免疫疗法显示出令人鼓舞的结果，但反应是短暂的。 MCPYV相关的MCC避免免疫学破坏并抵抗免疫疗法的能力表明，这种病毒诱导的肿瘤发生的能力是由免疫逃避机制增强的。通常限制MCPYV传播的免疫效应子的鉴定可能揭示了MCPYV肿瘤发生的机制，并为减轻其疾病负担的策略提供了信息。但是，关于MCPYV如何与免疫系统相互作用的知之甚少。这个主题是不可能研究的，因为MCPYV Tropism以前是未知的，因此在技术上很难培养MCPYV。我们最近将人类皮肤成纤维细胞确定为MCPYV的宿主细胞，并建立了该致癌病毒的第一个细胞感染模型。我们首次使用该系统观察到MCPYV感染触发的免疫基因表达的诱导。在这笔赠款中，我们将确定MCPYV诱导免疫反应的分子机制（AIM 1），并使用模仿人类皮肤生理环境的离体皮肤培养物来表征这种反应的整个基因组（AIM 2）。通过揭示MCPYV与宿主免疫系统之间的很大未知的相互作用，我们的目标是了解免疫抗性如何有助于MCPYV的持久性和MCC的造成效果。阐明通常限制MCPYV感染的宿主免疫的特定方面可以公布防止和治疗毁灭性MCC癌症的新型策略。