Merkel cell polyomavirus infection and the host immune response

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的个体中致癌，但在普通人群中保持无症状感染，这突显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)及其相关癌症中得到了明确的证明。MCPyV是一种新的人类多瘤病毒，已被证明可导致默克尔细胞癌(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，五年生存率不到45%。虽然MCC的发病率在过去20年中增加了两倍，但目前还没有有效的化疗方法来治疗转移性MCC。MCPyV感染在普通人群中普遍存在，这表明该病毒已经进化出一种逃避宿主免疫根除的机制。免疫抑制是MCPyV相关MCC最重要的危险因素之一，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。在免疫功能正常的患者中，尽管产生了识别MCPyV编码蛋白的T细胞，MCC肿瘤仍在继续发展。最近开发的免疫疗法显示了令人振奋的结果，但反应是短暂的。MCPyV相关的MCC逃避免疫破坏和抵抗免疫治疗的能力认为，这种病毒诱导的肿瘤发生是由免疫逃避机制增强的。识别正常情况下限制MCPyV传播的免疫效应分子可能揭示MCPyV的致癌机制，并为减少其疾病负担提供策略。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MCPyV的培养在技术上是困难的。我们最近鉴定了人真皮成纤维细胞是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。利用该系统，我们首次观察到了MCPyV感染对免疫基因表达的诱导作用。在这项资助中，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体外皮肤培养在全基因组范围内表征这种反应(目标2)。通过揭示MCPyV和宿主免疫系统之间鲜为人知的相互作用，我们的目标是了解免疫逃避如何促进MCPyV的持续和MCC的发生。阐明宿主免疫的特定方面通常限制MCPyV感染，可以揭示预防和治疗毁灭性MCC癌症的新策略。

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.