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Molecular and cellular basis of epidermodysplasia verruciformis

疣状表皮发育不良的分子和细胞基础

基本信息

批准号：
10352425
负责人：
Jean-Laurent Casanova
金额：
$ 39.31万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352425
关键词：
Affect Alleles Area Binding CRISPR/Cas technology Cell Line Cells Characteristics Clinical Communicable Diseases Complex Cutaneous Data Development Differentiation and Growth Disease Enrollment Epidermodysplasia Verruciformis Epithelial Cells Etiology Family General Population Genes Genetic Counseling Genetic Predisposition to Disease Genetic study Genotype Goals Growth Hematology Hematopoietic Stem Cell Transplantation Hereditary Disease Human Human Herpesvirus 8 Human Papillomavirus Human papilloma virus infection Human papillomavirus 6 IL2RG gene ITGAL gene ITGB2 gene Immunity Immunologics In Vitro Individual Infection Interferons JAK3 gene Kaposi Sarcoma Lesion Leukocyte Adhesion Deficiency Life Malignant Neoplasms Mendelian disorder Modeling Molecular Molecular Diagnosis Mucous Membrane Mus Mutate Mutation Neutropenia OX40 Oncogenic Oncogenic Viruses Papillomavirus Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physicians Predisposition Preventive Proteins Public Health RHOH gene Recurrence Reporting Research Severe Combined Immunodeficiency Skin Skin Cancer Skin Carcinoma Sun Exposure Syndrome T cell reconstitution T-Lymphocyte Therapeutic Ursidae Family Viral Viral Proteins Virulent Virus adaptive immunity base congenital immunodeficiency diagnostic strategy exome exome sequencing genome sequencing genome-wide genome-wide linkage human model improved innovation insight keratinocyte kindred member mutant notch protein novel novel diagnostics novel therapeutic intervention null mutation particle penis foreskin prevent recruit skin lesion tumor whole genome

项目摘要

Project Summary Epidermodysplasia verruciformis (EV) was the first described primary immunodeficiency (PID). By 1946, it was shown by Lutz to be an autosomal recessive (AR) predisposition to skin-tropic viruses, prior to the description of congenital neutropenia by Kostmann (1950). Its lack of associated immunological phenotypes long prevented its recognition as a PID. EV is characterized by disseminated and persistent flat warts, which often evolve into skin cancer. The lesions are caused by E5- and E8-deficient members of the β genus of human papillomaviruses (HPVs), which exclusively reside in keratinocytes and remain silent in the general population. EV typically strikes otherwise healthy individuals (“isolated EV”), or rarely occurs in the context of other infectious diseases (“syndromic EV”). In 2002, bi-allelic mutations in TMC6 and TMC8, encoding EVER1 and EVER2, were found in patients with isolated EV, whose T cells were normal. Bi-allelic mutations in CIB1 were reported in 2018 in other patients with isolated EV. Remarkably, CIB1, EVER1, and EVER2 form a complex that binds to E5 and E8. This complex operates as a restriction factor governing keratinocyte-intrinsic immunity to β-HPVs. From 2012 onward, mutations in RHOH, STK4, and other T cell genes were found in patients with syndromic EV. We hypothesize that other, related single-gene inborn errors of cutaneous immunity against β-HPVs, underlie EV in other patients. The goal of this application is thus to analyze in greater depth the molecular and cellular basis of isolated and syndromic EV. First, we will discover new genetic etiologies of EV thanks to the ongoing recruitment of unrelated EV families, by combining genome-wide linkage (GWL) and whole exome sequencing (WES). Second, we will functionally characterize the novel genotypes by studying the mutant proteins in isolation and in the patients’ cells, including their relationship with the products of the known EV-causing genes, such as the EVER-CIB1 complex in keratinocytes and RhoH or STK4 in T cells. Third, we will model HPV infection of keratinocytes in the presence of T cells in vitro, with viral proteins and particles, using keratinocyte cell lines, foreskin keratinocytes, the patients’ keratinocytes, or induced pluripotent step cell (iPSC)-derived keratinocytes, which will be edited by CRISPR/Cas9. Our project is highly innovative yet supported by strong preliminary data. Indeed, we have recruited 52 novel families, identified three novel genetic etiologies, underlying isolated (mutations in RBPJ) or syndromic EV (ITGAL and OX40), and began elucidating their mechanistic connection with keratinocytes and T cells, respectively. Our research provides novel insights into the mechanisms of cutaneous immunity to β-HPVs, highlighting the dual contribution of keratinocyte-intrinsic immunity and T-cell adaptive immunity. Our research benefits EV patients and families, with the development of novel diagnostic approaches, including genetic counseling, and facilitating the development of novel therapeutic approaches based on a rational understanding of the pathogenesis. Finally, the study of EV is a fruitful model to analyze other mucosal and cutaneous illnesses caused by other HPVs.

项目总结