HPV Infection of Human Epidermis: Single Cell Resolution & Metabolomic Consequences
Principal Investigator: Susanne Wells, PhD
Dry and moist skin (eg in the mouth or genital area) plays a critical role in maintaining a barrier against environmental insults, including infection. The outermost layer of skin is referred to as the epidermis. Keratinocytes represent the main cell type in epidermis, and are organized into basal stem/progenitor cells, and the more differentiated progeny. Tumors of the epidermis, referred to as squamous cell carcinoma (SCCs) represent the most common cancer type worldwide. A major cause of SCC is infection with high-risk human papillomavirus HPV16. Over half a million HPV-associated cancers are newly diagnosed each year, and particularly in vulnerable populations. Despite substantial knowledge about HPV positive tumor development, viral infection is very poorly understood and therefore, we do not have antivirals to combat infection to prevent cancer development. Viral replication, the amplification of genomes and transcripts, is particularly understudied, but this is precisely what puts an infected person at risk. We also do not have diagnostic tests to distinguish people with an active viral life cycle (and thus high cancer risk) from those with an inactive viral life cycle (and thus low cancer risk).
First, we will ask how HPV-replicating epidermis is different from uninfected epidermis and identify global transcripts and chemicals called metabolites which make it different. This will identify specific biomarkers of viral replication which will then be validated in HPV positive laboratory models and human populations. Second, we propose a radically new way to understand different stages of the viral life cycle which take place in geographically distinct epidermal cells. This will define the rare cells which harbor viral amplification, and we will then be able to localize and eliminate such cells. Taken together, we propose to develop highly specific and sensitive methodologies. The goal is to detect HPV replication to identify adolescent and young adult populations at-risk of cancer, and to design novel treatments to prevent cancer development by targeting the viral life cycle as a root cause.