A Novel In Vivo Infection Model To Study Papillomavirus-Mediated Disease of the Female Reproductive Tract

Abstract

Papillomaviruses exhibit species-specific tropism, thereby limiting understanding and research of several aspects of HPV infection and carcinogenesis. The discovery of a murine papillomavirus (MmuPV1) provides the opportunity to study papillomavirus infections in a tractable, in vivo laboratory model. MmuPV1 infects and causes disease in the cutaneous epithelium, as well as the mucosal epithelia of the oral cavity and anogenital tract. In this report, we describe a murine model of MmuPV1 infection and neoplastic disease in the female reproductive tracts of wild-type immunocompetent FVB mice. Low-grade dysplastic lesions developed in reproductive tracts of FVB mice infected with MmuPV1 for 4 months, and mice infected for 6 months developed significantly worse disease, including squamous cell carcinoma (SCC). We also tested the contribution of estrogen and/or UV radiation (UVR), two cofactors we previously identified as being involved in papillomavirus-mediated disease, to cervicovaginal disease. Similar to HPV16 transgenic mice, exogenous estrogen treatment induced high-grade precancerous lesions in the reproductive tracts of MmuPV1-infected mice by 4 months and together with MmuPV1 efficiently induced SCC by 6 months. UV radiation and exogenous estrogen cooperated to promote carcinogenesis in MmuPV1-infected mice. This murine infection model represents the first instance of de novo papillomavirus-mediated carcinogenesis in the female reproductive tract of wild-type mice resulting from active virus infection and is also the first report of the female hormone estrogen contributing to this process. This model will provide an additional platform for fundamental studies on papillomavirus infection, cervicovaginal disease, and the role of cellular cofactors during papillomavirus-induced carcinogenesis. IMPORTANCE Tractable and efficient models of papillomavirus-induced pathogenesis are limited due to the strict species-specific and tissue-specific tropism of these viruses. Here, we report a novel preclinical murine model of papillomavirus-induced cervicovaginal disease in wild-type, immunocompetent mice using the recently discovered murine papillomavirus, MmuPV1. In this model, MmuPV1 establishes persistent viral infections in the mucosal epithelia of the female reproductive tract, a necessary component needed to accurately mimic HPV-mediated neoplastic disease in humans. Persistent MmuPV1 infections were able to induce progressive neoplastic disease and carcinogenesis, either alone or in combination with previously identified cofactors of papillomavirus-induced disease. This new model will provide a much-needed platform for basic and translational studies on both papillomavirus infection and associated disease in immunocompetent mice.

A Mouse Model of Oropharyngeal Papillomavirus-Induced Neoplasia Using Novel Tools for Infection and Nasal Anesthesia

“…This broad tropism contrasts with the HPV strains associated with neoplasia, which generally target mucosal or cutaneous tissues and rarely cross-infect [25]. Despite this difference in tropism, MmuPV1 appears to mimic many of the known features of neoplasia associated with more limited HPV strains: MmuPV1 cutaneous papillomas are classic warts, and MmuPV1-induced cervical cancer closely resembles human cervical cancer pathogenesis [5,9].…”

“…A papillomavirus capable of infecting laboratory mice, MmuPV1, was identified in immune-deficient mice in India in 2010 [5]. This virus has been shown to infect both cutaneous and mucosal tissues [5][6][7], where it can cause both skin and cervical cancer in immune-competent mice-particularly after immune-suppressive UVB irradiation [7][8][9]. In the mouse, deliberate primary infection with MmuPV1 elsewhere has been shown to lead to secondary infection in the oropharynx, at the base of the tongue [10].…”

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

“…These limitations have been overcome by the discovery of the mouse papillomavirus, MmuPV1 or MusPV1, in 2011 [14], the first papillomavirus discovered to infect laboratory mice (Mus musculus). We and others found that MmuPV1 can be used to model infection by high-risk HPVs: 1) MmuPV1 and HPVs encode a similar set of genes and express similar patterns of viral transcripts [15,16]; 2) like HPV, MmuPV1 E6 and E7 genes both play critical roles in pathogenesis [17,18] (manuscript in preparation); 3) MmuPV1 preferentially causes disease in immunocompromised hosts [19][20][21][22] as observed for HPVs in humans; and 4) persistent viral infections lead to cancer in both cutaneous and mucosal sites [20,[23][24][25]. Prior studies of MmuPV1 infection in immunocompetent FVB/N mice showed that persistence of cutaneous papillomas correlated with an immunosuppressive state [20].…”

An Infection-Based Murine Model for Papillomavirus-Associated Head and Neck Cancer

“…While initially found to cause cutaneous warts in immunodeficient mice, MmuPV1 also causes cutaneous warts in immunocompetent strains with or without alterations to their immune system (19,(22)(23)(24)(25)(26)(27). Importantly, MmuPV1 has a wide tissue tropism: it infects not only cutaneous epithelia but also sites typically implicated in the sexual transmission of HPV, including the mucosa of the female and male genitalia, the anus, and oropharyngeal sites (28)(29)(30)(31)(32)(33)(34). We have previously shown that immunocompetent mice experimentally infected with MmuPV1 in their female reproductive tract developed cervical and vaginal cancers (28), much like high-risk HPVs in humans.…”