Mouse Model of Human Papillomavirus Pathogenesis

人类乳头瘤病毒(HPV)感染导致的癌症约占所有人类癌症的5%。一组高危的α-HPV是宫颈癌、其他肛门生殖道癌以及头颈癌的病原体。在一种罕见的遗传性皮肤疾病--疣状表皮发育不良(EV)患者中，以及在快速增长的器官移植患者和其他慢性免疫抑制患者中，β-HPV会导致皮肤鳞状细胞癌(CSCCs)。在慢性鳞状细胞癌中也检测到了伽马-HPV。尽管市场上有预防感染大多数癌症相关的甲型HPV的预防性疫苗，但美国的疫苗接种率一直很低，而且由于癌症在最初感染几年到几十年后出现，接种疫苗不会立即对HPV癌症发病率产生影响。此外，这些疫苗不提供对贝塔和伽马-HPV感染的保护，因此，它们不会影响由这些HPV引发的cSCC。由癌症相关的α和β-HPV编码的E6和E7蛋白通过与宿主细胞信号蛋白结合并在功能上颠覆宿主细胞信号蛋白而具有致癌活性和功能。由于HPV不会在异种宿主中复制，因此很少有研究探讨乳头瘤病毒E6和E7细胞靶点与病毒致病和体内致癌的相关性。感染普通实验室小鼠品系的小鼠乳头瘤病毒1型(MmuPV1)的发现，终于使乳头瘤病毒的发病机制和致癌研究得以在体内和在遗传上可处理的宿主中进行。这项建议利用了Lambert团队和Munger实验室的专业知识，前者建立了皮肤和粘膜部位的MmuPV1感染/发病模型，后者识别了MmuPV1E6和E7相关的细胞蛋白，并在基于细胞的分析中验证了其中许多相互作用。我们的建议是基于这样的假设，即MmuPV1是研究HPV发病机制和癌症发生的模型，这些见解将是确定抗病毒治疗靶点的关键。我们将研究MmuPV1E6抑制Notch和转化生长因子-β信号转导，E7分别通过RIG-I/MAVS和cGAS/STING颠覆视网膜母细胞瘤肿瘤抑制基因RB1，以及E6和E7介导的天然免疫信号在皮肤发病和癌变中的作用。

Human papillomavirus (HPV) infections cause approximately 5% of all human cancers. A group of “high-risk” alpha-HPVs are etiologic agents of cervical carcinoma, other anogenital cancers and as well as head and neck cancers. The beta-HPVs cause cutaneous squamous cell carcinomas (cSCCs) in patients with a rare hereditary skin disorder, epidermodysplasia verruciformis (EV), and in the rapidly growing population of organ-transplant and other chronically immunosuppressed patients. The gamma-HPVs have also been detected in cSCCs. Even though prophylactic vaccines that protect from infections with most cancer-associated alpha-HPVs are on the market, US vaccination rates have remained low, and because cancers arise years to decades after the initial infection, vaccination will not have an immediate impact on HPV cancer rates. Moreover, these vaccines do not offer protection from beta- and gamma-HPV infections and, hence, they will not impact cSCCs triggered by these HPVs. The E6 and E7 proteins encoded by the cancer-associated alpha- and beta-HPVs have oncogenic activities and function by binding to and functionally subverting host cellular signaling proteins. Because HPVs do not replicate in heterologous hosts, there have only been very few studies that probed the relevance of papillomavirus E6 and E7 cellular targets for viral pathogenesis and carcinogenesis in vivo. The discovery of Mus musculus Papillomavirus 1 (MmuPV1), which infects common laboratory mouse strains, finally allows papillomavirus pathogenesis and carcinogenesis studies in vivo and in a genetically tractable host. This proposal leverages the expertise of the Lambert group who has established an MmuPV1 infection/pathogenesis model for cutaneous and mucosal sites and the Munger lab who has identified MmuPV1 E6- and E7-associated cellular proteins and validated many of these interactions in cell-based assays. Our proposal is based on the hypothesis that MmuPV1 is a model to investigate HPV pathogenesis and carcinogenesis, and these insights will be key to identifying targets for antiviral therapy. We will investigate the importance of MmuPV1 E6 inhibiting NOTCH and TGF-beta signaling, and E7 subverting the retinoblastoma tumor suppressor RB1, as well as E6 and E7 mediated subversion of innate immune signaling by the RIG-I/MAVS and cGAS/STING, respectively, for cutaneous pathogenesis and carcinogenesis.