Human genetic and immunological dissection of epidermodysplasia verruciformis and related infections by skin-tropic, oncogenic beta-papillomaviruses

• Applicant: Dr. Sarah Jill De Jong
• Subject Area: Human Genetics
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240820727

The genetic theory of infectious diseases proposes that human genetic factors largely determine the clinical features and outcome of infection. This study aims to define the molecular and cellular basis of Mendelian predisposition to persistent human beta-papillomavirus (EV-HPV) infections in otherwise healthy children and young adults, which leads to the development of epidermodysplasia verruciformis (EV). EV is a rare condition characterized by skin warts and non-melanoma skin cancer, which develop as a consequence of EV-HPV infection. Therefore, EV serves as a valuable model for the study of HPV-induced disease and oncogenesis. Previous studies of EV-causing mutations in the EVER1, EVER2, RHOH, and MST1 genes, suggest that keratinocytes as well as T cells contribute to the pathogenesis of EV. About 25% of EV patients, however, lack a defined genetic etiology and the cellular pathogenesis of EV remains largely elusive. To identify new genetic etiologies underlying EV, this study will utilize a combined genome-wide linkage (GWL) analysis and whole exome sequencing approach (WES) in a cohort of 15 EV patients from 6 kindreds. A candidate defect of the CIB1 gene identified in 6 patients of this cohort will be characterized at the molecular level. To this end, the functional consequences of the CIB1 mutation will be studied in patient-derived keratinocytes and T cells, in particular in relation to EV-HPV infection. These genetic and immunological studies will pave the way for a cellular and molecular dissection of EV pathogenesis. Findings from this study will define key human genes involved in host defense against oncogenic EV-HPVs in the setting of the natural ecosystem, a unique added value of human genetics.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jean-Laurent Casanova, Ph.D.