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

Abstract

High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. We used a mouse papillomavirus infection model to characterize virus-host interactions. We found that mouse papillomavirus (MmuPV1) suppresses host immune responses via overexpression of stress keratins. In mice deficient for stress keratin K17 (K17KO), we observed rapid regression of papillomas dependent on T cells. Cellular genes involved in immune response were differentially expressed in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8 + T cells and upregulation of IFNγ-related genes, including CXCL9 and CXCL10, prior to complete regression. Blocking the receptor for CXCL9/CXCL10 prevented early regression. Our data provide a novel mechanism by which papillomavirus-infected cells evade host immunity and defines new therapeutic targets for treating persistent papillomavirus infections.

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

“…These carcinomas express markers of MmuPV1 infections and biomarkers commonly found in HPV-associated cancers. We also observed upregulated levels of cytokeratin 17 in MmuPV1-induced oral tumors, a host gene recently identified to mediate papillomavirus-induced immunosuppression (26). We extended our studies to genetically immunocompetent FVB mice and found that MmuPV1 also infects the tongue.…”

“…Our laboratory recently discovered that stress cytokeratin 17 is one of the most upregulated host genes upon cutaneous MmuPV1 infection and that K17 plays an important role in mediating the ability of the virus to evade immune clearance and establish persistent disease (26). We observed that K17 is also upregulated in the context of MmuPV1-infected tongue lesions ( Fig.…”

“…Immune marker profiling has demonstrated that the oral cavity has a significantly higher concentration of T cell-related immune markers than the cervix, including higher levels of interleukin-2 (IL-2), an important T cell response marker that is often reduced during cervical HPV infection (63). Because T cell responses play crucial roles in MmuPV1 infection and associated disease (23,24,26,65), the oral cavity may be better protected against viral infection and associated tumorigenesis than the female reproductive tract because of the increased immunological surveillance in the former. This would support the hypothesis that MmuPV1 causes less severe disease in the tongue than in the cervix/vagina because it is more difficult for the virus to establish, maintain, and mediate pathogenesis in the oral cavity.…”

“…However, the recent discovery of a mouse papillomavirus, MmuPV1, that infects laboratory mice (19)(20)(21) has opened the door to generating infection-based models for papillomavirus-associated pathogenesis in an animal that is highly tractable and can be genetically manipulated. 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).…”

The transcriptomic profiling of SARS-CoV-2 compared to SARS, MERS, EBOV, and H1N1

“…Keratin 6B ( KRT6B ) is a type II cytokeratin, which is an important biomarker for lung adenocarcinoma [ 40 ]. These genes are known as virus-induced host factors that control the recruitment of T-cells and correlate with chronic virus infections [ 41 ]. In addition, the tumor necrosis factor, alpha-induced protein 3 ( TNFAIP3 ), is a central regulator of immunopathology and is associated with the maintenance of immune homeostasis and severe viral infections [ 42 , 43 ].…”