Friday, March 24, 2023
3/24/2023
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.
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