The role of CIB1 on cutaneous papillomavirus replication and transcription

项目摘要/摘要 皮肤乳头瘤病毒(PV)可导致严重的持续性感染和皮肤癌。 免疫缺陷患者。这些患者包括那些携带人类免疫缺陷病毒、器官移植和 原发免疫缺陷。针对粘膜疱疹开发的预防性光伏疫苗对 皮肤静脉曲张和治疗是有限的，而且往往无效。因此，迫切需要确定目标 治疗皮肤PV感染和PV相关皮肤癌。表皮型发育不良 疣状病毒(EV)是一种遗传性皮肤病，为研究细胞固有宿主防御机制提供了独特的机会。 防止皮肤中的PV，因为这些患者对皮肤PV感染非常敏感，但没有增加 易受其他感染。最近的一项研究发现，一组EV患者的钙基因零突变- 和整合素结合蛋白-1(CIB1)，以及EV患者中CIB1的表达降低，并有其他更多 常见的突变影响到约50%的EV患者。总体而言，这些发现表明CIB1在 对皮肤PV感染具有免疫力，并可能成为对抗皮肤PV的限制因素。然而，电动汽车是一种 因此，获取临床标本以供评估和未来的治疗试验是有问题的。我们 然而，他们在狗身上发现了一种自然发生的类似EV的疾病，这种疾病似乎与人类相似 几个关键方面的疾病：a)像人类感染EV一样，受影响的狗获得播散性皮肤PV 难以治疗并可能进展为癌症的感染；B)像人类一样，这些狗限制了 C)像人类一样，这种疾病是自发发生的。我们建议 狗作为研究免疫低下患者PV感染的模型。这可能是最有价值的动物 到目前为止，模型不仅研究EV的潜在致病机制，而且还识别EV的保守机制 角质形成细胞对PV感染的内在防御。重要的是，我们实验室的初步研究已经 在EV样犬的角质形成细胞中，CIB1的表达降低，这突出了一种保守的 人和狗之间对PV感染的易感性的潜在机制，与CIB1有关。我们假设 CIB1表达受损促进人和狗角质形成细胞中PV的复制和转录 和电动汽车。在目标1中，我们将确定在患有EV样疾病的狗和人类中CIB1的表达是否受损 以及携带由IL2RG突变引起的另一种形式EV的狗。在目标2中，我们将确定CIB1的表达 调节角质形成细胞内的PV复制和转录，如果这在狗和人之间是保守的。 使用人类光伏和角质形成细胞将解决人类疾病；使用犬光伏和角质形成细胞将 推广狗的模型。结果将直接通知下一阶段的实验，以及未来的R01建议， 旨在阐明EV患者PV易感性的分子机制。随着理解的提高 在这些感染的分子发病机制中，靶向治疗可能会进一步发展，这将 最终改善这些毁灭性感染患者的生活质量。

Project Summary/Abstract Cutaneous papillomaviruses (PVs) can cause severe, persistent infections and skin cancer in immunodeficient patients. These patients include those with human immunodeficiency virus, organ transplants, and primary immunodeficiencies. Prophylactic PV vaccines developed to target mucosal PVs are not effective against cutaneous PVs, and treatments are limited and often ineffective. Thus, there is a critical need to identify targeted therapeutics for treatment of cutaneous PV infections and PV-associated skin cancers. Epidermodysplasia verruciformis (EV), a genodermatosis, offers a unique opportunity to study mechanisms of cell intrinsic host defense against PV in the skin, as these patients are highly susceptible to cutaneous PV infections but have no increased susceptibility to other infections. A recent study identified a cohort of EV patients with null mutations within calcium- and integrin-binding protein-1 (CIB1), as well as decreased CIB1 expression in EV-patients with other, more common, mutations that affect ~50% of EV patients. Collectively, these findings suggest that CIB1 is a key player in immunity to cutaneous PV infections and may act as a restriction factor against cutaneous PVs. EV, though, is a rare disease and thus obtaining clinical specimens for evaluation and future therapeutic testing is problematic. We have, however, discovered a naturally occurring EV-like disease in dogs which appears to mimic the human disease in several critical aspects: A) Like humans with EV, affected dogs acquire disseminated cutaneous PV infections that are refractory to treatment and can progress to cancer; B) Like humans, these dogs have restricted susceptibility to cutaneous PV infection; and C) Like humans, the disease occurs spontaneously. We propose the dog as a model for studying PV infections in immunocompromised patients. This could be the most valuable animal model to date to study not only the underlying pathogenesis of EV, but also identify conserved mechanisms of intrinsic keratinocyte defense against PV infections. Importantly, preliminary studies from our laboratory have demonstrated decreased expression of CIB1 in keratinocytes from EV-like dogs, highlighting a conserved mechanism underlying susceptibility to PV infections between humans and dogs, linked to CIB1. We hypothesize that impaired CIB1 expression enhances PV replication and transcription in keratinocytes in both humans and dogs with EV. In Aim 1, we will determine if CIB1 expression in impaired in dogs with EV-like disease, and in humans and dogs with another form of EV caused by IL2RG mutations. In Aim 2, we will determine if CIB1 expression regulates PV replication and transcription within keratinocytes, and if this is conserved between the dog and human. Using human PV and keratinocytes will address the human disease; using canine PV and keratinocytes will advance the dog model. Results will directly inform the next phase of experiments, and future R01 proposal, designed to elucidate molecular mechanisms of PV susceptibility in EV patients. With improved understanding of the molecular pathogenesis of these infections, targeted therapeutics may be further developed, which would ultimately improve the quality of life for patients with these devastating infections.