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

感染性疾病的遗传理论认为，人类遗传因素在很大程度上决定了感染的临床特征和结果。本研究旨在确定孟德尔易感性的分子和细胞基础，以持续的人β-乳头瘤病毒（EV-HPV）感染，在其他健康的儿童和年轻人，导致疣状表皮发育不良（EV）的发展。EV是一种罕见的疾病，其特征是皮肤疣和非黑色素瘤皮肤癌，其发展是EV-HPV感染的结果。因此，EV是研究HPV引起的疾病和肿瘤发生的有价值的模型。先前对EVER1、EVER2、RHOH和MST 1基因中EV致突变的研究表明，角质形成细胞以及T细胞有助于EV的发病机制。然而，约25%的EV患者缺乏明确的遗传病因，EV的细胞发病机制在很大程度上仍然难以捉摸。为了确定EV潜在的新遗传病因，本研究将利用全基因组连锁（GWL）分析和全外显子组测序方法（WES），在来自6个国家的15名EV患者的队列中进行。将在分子水平上表征在该队列的6名患者中鉴定的CIB1基因的候选缺陷。为此，将在患者来源的角质形成细胞和T细胞中研究CIB1突变的功能后果，特别是与EV-HPV感染相关的功能后果。这些遗传学和免疫学研究将为EV发病机制的细胞和分子解剖铺平道路。这项研究的结果将定义在自然生态系统中参与宿主防御致癌EV-HPV的关键人类基因，这是人类遗传学的独特附加值。

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.