Merkel cell polyomavirus infection, host response, and viral oncogenic mechanism

默克尔细胞多瘤病毒感染、宿主反应和病毒致癌机制

基本信息

批准号：
10365419
负责人：
Jianxin You
金额：
$ 38.16万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365419
关键词：
3-Dimensional Architecture Award Biological Assay Biological Response Modifiers Cell Culture System Cell Culture Techniques Cell Proliferation Cellular Tropism Clustered Regularly Interspaced Short Palindromic Repeats DNA Data Dermal Development Dominant-Negative Mutation Elderly Equilibrium Etiology Event Failure Fibroblasts Genes Genetic Transcription Genome Goals Host Defense Mechanism Human Immune Immune response Immune signaling Immune system Immunity Immunocompromised Host Immunosuppression In Vitro Incidence Individual Infection Innate Immune Response Innate Immune System Interferons Knock-out Knowledge Malignant Neoplasms Mediating Merkel Cells Merkel cell carcinoma Modeling Molecular Mus Natural Immunity Nucleic Acids Oncogenic Oncogenic Viruses Pathologic Pathway interactions Pattern Play Polyomavirus Polyomavirus Infections Population Premalignant Cell Research Risk Role Signal Pathway Signal Transduction Signaling Protein Skin Skin Cancer Stimulator of Interferon Genes Supporting Cell System Testing Tropism Tumor Suppressor Proteins UV carcinogenesis Viral Viral Genome Virus Virus Diseases Virus Replication Xenograft Model antagonist chronic infection cytokine driver mutation effective therapy epidemiology study gene function immunosuppressed innate immune pathways innate immune sensing metaplastic cell transformation mortality multidisciplinary novel novel strategies pathogen prevent sensor tool tumor tumorigenesis virus related cancer

项目摘要

Project Summary Merkel cell polyomavirus (MCPyV), the most recently discovered tumor virus, can cause a highly aggressive form of skin cancer called Merkel cell carcinoma (MCC). While the incidence of MCC has tripled over the past twenty years, there is no effective therapy for metastatic MCCs, highlighting the need to better understand MCPyV oncogenic mechanism in order to develop more successful therapies. MCPyV asymptomatically infects most of the human population, but tends to cause MCC in the elderly and immunocompromised individuals. These observations suggest that host immunity plays a critical role in controlling MCPyV-induced tumorigenesis. However, very little is known about the innate immune response elicited by MCPyV. Neither is it clear how a dysregulated immune system contributes to MCC tumorigenesis. This is largely because MCPyV tropism was previously unknown and there was a lack of biologically relevant culture system for MCPyV. Recently, we discovered that human dermal fibroblasts (HDFs) support productive MCPyV infection and established the first in vitro as well as ex vivo infection models for MCPyV. Using these systems, we demonstrated that MCPyV infection activates STING-mediated innate immune responses, which in turn restrict viral amplification and spread. In addition, we discovered that STING is silenced in MCPyV(+) MCC tumors, revealing that loss of STING function is needed to drive MCC tumorigenesis. Our studies suggest that disruption of STING function may cause pathologic rampant replication of MCPyV to promote viral genome integration into the host genome, which is a key event in MCPyV- driven tumorigenesis. In addition, loss of STING function may allow MCPyV-induced pre-cancerous cells to circumvent its tumor suppressive effects, thus stimulating cell proliferation and tumorigenesis. Building on these observations, we hypothesize that STING functions not only as a key antiviral immune mediator for controlling MCPyV infection but also a prime tumor suppressor that blocks MCPyV-driven tumorigenesis. To test this hypothesis, we will combine the in vitro and ex vivo MCPyV infection models with 3D “artificial human skin” reconstructed in mice to examine the impact of STING innate immune sensing pathways on MCPyV infection (Aim 1) and to determine how disruption of STING signaling impacts MCPyV-driven MCC tumorigenesis (Aim 2). Through revealing the largely unknown interplay between MCPyV and the innate immune system, our ultimate goal is to understand how poorly controlled MCPyV infection leads to MCC development. Identification of immune effectors that normally restrict MCPyV propagation could also unveil novel strategies for preventing and treating the devastating MCC cancers.

项目概要默克尔细胞多瘤病毒（MCPyV）是最近发现的肿瘤病毒，可引起高度侵袭性皮肤癌称为默克尔细胞癌 (MCC)，而 MCC 的发病率却很高。过去二十年中，转移性 MCC 的数量增加了两倍，但目前尚无有效的治疗方法，这凸显了需要更好地了解MCPyV致癌机制才能开发更成功 MCPyV 无症状感染大多数人群，但往往会导致 MCC。老年人和免疫功能低下的人这些观察结果表明宿主免疫力。在控制 MCPyV 诱导的肿瘤发生中发挥着关键作用，然而，人们对此知之甚少。 MCPyV 引发的先天免疫反应也不清楚免疫失调是如何发生的。系统有助于 MCC 肿瘤发生，这主要是因为 MCPyV 趋向性以前是存在的。未知，并且缺乏 MCPyV 的生物学相关培养系统。发现人真皮成纤维细胞 (HDF) 支持生产性 MCPyV 感染，并且我们使用这些系统建立了第一个体外和离体 MCPyV 感染模型。证明 MCPyV 感染激活 STING 介导的先天免疫反应，此外，我们发现 STING 被沉默。 MCPyV(+) MCC 肿瘤，揭示 STING 功能的丧失是驱动 MCC 肿瘤发生所必需的。我们的研究表明，STING 功能的破坏可能会导致病理性的猖獗复制 MCPyV 促进病毒基因组整合到宿主基因组中，这是 MCPyV 中的关键事件- 此外，STING 功能的丧失可能导致 MCPyV 诱导癌前病变。细胞规避其肿瘤抑制作用，从而刺激细胞增殖和肿瘤发生。基于这些观察，我们认为 STING 的功能不仅是一种关键的抗病毒药物控制 MCPyV 感染的免疫介质，也是阻断 MCPyV 感染的主要肿瘤抑制因子为了检验这一假设，我们将结合体外和离体 MCPyV。在小鼠体内重建 3D“人造皮肤”感染模型，以检查 STING 的影响先天免疫途径感知 MCPyV 感染（目标 1）并确定如何破坏 STING 信号传导影响 MCPyV 驱动的 MCC 肿瘤发生（目标 2）。 MCPyV 和先天免疫系统之间的未知相互作用，我们的最终目标是了解控制不佳的 MCPyV 感染如何导致 MCC 的发展免疫效应物的鉴定。通常限制 MCPyV 传播的药物也可能揭示预防和治疗的新策略毁灭性的 MCC 癌症。