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

• 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
• 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

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.

项目摘要 最近发现的肿瘤病毒Merkel细胞多瘤病毒（MCPYV）可能会引起高度 侵略性的皮肤癌称为默克尔细胞癌（MCC）。虽然MCC的事件有 在过去的二十年中，没有有效的转移MCC疗法 需要更好地了解MCPYV致癌机制，以发展更成功 疗法。 MCPYV不对称地感染了大多数人口，但倾向于引起MCC 老年和免疫功能低下的个体。这些观察结果表明宿主免疫 在控制MCPYV诱导的肿瘤发生中起关键作用。但是，对 McPyv引起的先天免疫反应。也不清楚免疫失调如何 系统有助于MCC肿瘤发生。这主要是因为McPyv Tropism以前是 未知，对于MCPYV缺乏生物学相关的培养系统。最近，我们 发现人真皮成纤维细胞（HDFS）支持生产性mcpyv感染和 建立了MCPYV的第一个体外和离体感染模型。使用这些系统，我们 证明MCPYV感染激活了刺激介导的先天免疫反应，这在 转动限制病毒扩增并扩散。此外，我们发现Sting在 MCPYV（+）MCC肿瘤，表明驱动MCC肿瘤发生需要失去刺激功能。 我们的研究表明，刺痛功能的破坏可能导致病理猖ramp的复制 MCPYV促进病毒基因组整合到宿主基因组中，这是MCPYV-的关键事件 驱动的肿瘤发生。此外，刺激功能的丧失可能允许MCPYV诱导的癌症 细胞规避其肿瘤抑制作用，从而刺激细胞增殖和肿瘤发生。 在这些观察结果的基础上，我们假设Sting不仅可以作为关键抗病毒功能 免疫介质控制MCPYV感染，但也是阻塞的主要肿瘤抑制剂 MCPYV驱动的肿瘤发生。为了检验这一假设，我们将结合体外和离体MCPYV 在小鼠中重建具有3D“人造人皮肤”的感染模型，以检查刺激的影响 MCPYV感染（AIM 1）上的先天免疫感应途径，并确定如何破坏 STING信号传导会影响MCPYV驱动的MCC肿瘤发生（AIM 2）。通过揭示大部分 MCPYV与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MCPYV感染导致MCC的发展程度较差。鉴定免疫作用 通常限制MCPYV的传播也可能会推出防止和治疗的新型策略 毁灭性的MCC癌症。