Mouse Model of Human Papillomavirus Pathogenesis

人乳头瘤病毒（HPV）感染导致约5%的人类癌症。一组“高危”α-HPV是宫颈癌、其他肛门生殖器癌以及头颈癌的病原体。β-HPV在患有罕见遗传性皮肤病疣状表皮发育不良（EV）的患者中以及在快速增长的器官移植和其他慢性免疫抑制患者群体中引起皮肤鳞状细胞癌（cSCC）。在cSCC中也检测到γ-HPV。尽管市场上有预防性疫苗可以防止大多数癌症相关的α-HPV感染，但美国的疫苗接种率仍然很低，而且由于癌症在初次感染后数年至数十年才出现，因此疫苗接种不会对HPV癌症率产生直接影响。此外，这些疫苗不提供对β-和γ-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蛋白具有致癌活性，并通过结合和功能性破坏宿主细胞信号传导蛋白而发挥功能。由于HPV在异源宿主中不复制，因此只有很少的研究探讨了乳头瘤病毒E6和E7细胞靶点与体内病毒致病和致癌的相关性。感染常见实验室小鼠品系的小家鼠乳头瘤病毒1（MmuPV 1）的发现，终于允许在体内和遗传上易处理的宿主中进行乳头瘤病毒发病机制和致癌作用的研究。该提案利用了Lambert小组的专业知识，该小组已经建立了皮肤和粘膜部位的MmuPV 1感染/发病机制模型，Munger实验室已经鉴定了MmuPV 1 E6和E7相关的细胞蛋白，并在基于细胞的测定中验证了许多这些相互作用。我们的建议是基于MmuPV 1是研究HPV发病机制和致癌作用的模型的假设，这些见解将是确定抗病毒治疗靶点的关键。我们将研究MmuPV 1 E6抑制NOTCH和TGF-β信号传导，E7破坏视网膜母细胞瘤肿瘤抑制因子RB 1，以及E6和E7分别通过RIG-I/MAVS和cGAS/STING介导的先天免疫信号传导的破坏对于皮肤发病机制和致癌作用的重要性。

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.