Mouse papillomavirus infection persists in mucosal tissues of an immunocompetent mouse strain and progresses to cancer

Nancy M Cladel,Lynn R Budgeon,Karla K Balogh,Sarah A Brendle,Timothy K Cooper,Todd D Schell,Jiafen Hu,Neil D Christensen

doi:10.1038/s41598-017-17089-4

Abstract

Mouse papillomavirus has shown broad tissue tropism in nude mice. Previous studies have tested cutaneous infections in different immunocompromised and immunocompetent mouse strains. In the current study, we examined mucosal infection in several immunocompetent and immunocompromised mouse strains. Viral DNA was monitored periodically by Q-PCR of lavage samples. Immunohistochemistry and in situ hybridization were used to determine viral capsid protein and viral DNA respectively. All athymic nude mouse strains showed active infections at both cutaneous and mucosal sites. Interestingly, NOD/SCID mice, which have a deficiency in T, B, and NK cells, showed minimal disease at cutaneous sites but developed persistent infection at the mucosal sites including those of the anogenital region and the oral cavity. Three strains of immunocompetent mice supported mucosal infections. Infections of the lower genital tract in heterozygous (immunocompetent) mice of the NU/J strain progressed to high grade dysplasia and to carcinoma in situ. Anti-MmuPV1 neutralizing antibodies were detected in the sera of all immunocompetent animals. Our findings demonstrate that the mucosae may be the preferred sites for this virus in mice. The mouse model is expected to be a valuable model for the study of mucosal papillomavirus disease, progression, and host immune control.

Highlights

Human papillomaviruses (HPVs) are obligate factors for the development of cervical cancer, which is responsible for the deaths of 250,000 women worldwide each year[1]
The cottontail rabbit papillomavirus (CRPV) model was the system of choice for several laboratories including our own, in part because CRPV lesions progress to cancer over time[6,7,8,9,10]
We found and reported on the first mucosal infections with the MmuPV1 virus and have definitively shown that oral, vaginal, anal and penile tissues are all highly susceptible to the virus, putting to rest the idea that the virus is restricted to cutaneous sites[22,23,24,25]

Summary

Introduction

Human papillomaviruses (HPVs) are obligate factors for the development of cervical cancer, which is responsible for the deaths of 250,000 women worldwide each year[1]. We found and reported on the first mucosal infections with the MmuPV1 virus and have definitively shown that oral, vaginal, anal and penile tissues are all highly susceptible to the virus, putting to rest the idea that the virus is restricted to cutaneous sites[22,23,24,25] These observations were further confirmed by studies in another group[21,26]. In addition to the active anogenital infections and dysplasia in these animals, we have observed that the single circumvallate papilla of the mouse tongue is uniquely susceptible to infection by the virus This site is comparable to back of the tongue sites so commonly found in oral papillomavirus-associated cancers in humans, for which an increasing incidence is reported in younger male Caucasians[27]. We anticipate that this new mouse model will be of use in studying progression of oral papillomavirus disease

Methods

Results

Conclusion