The Polyomaviruses are a group of non-enveloped, double-stranded DNA viruses that establish persistent infections in otherwise immunocompetent individuals. The mode of transmission is not well defined, although clinically, JCPyV is known to infect kidney epithelial cells, peripheral blood, and tonsillar tissue. In immunocompromised patients, JCPyV targets the central nervous system (CNS), and causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). It is an increasingly common complication in AIDS patients as 5% develop PML. The mechanism by which JCPyV remains dormant and the role of innate immunity in JCPyV infection, latency, and reactivation are not completely understood. The goal of the proposed research is to better understand the role of defensins in JCPyV infection. Defensins are small, cationic peptides that are widely known to have anti-microbial properties. Defensins act on viruses at different stages of the infectious cycle, and their antiviral properties are cell and virus specific. Their effect on polyomaviruses is only beginning to be elucidated. Defensins have also shown promise as immunomodulatory molecules, and it is unclear if they have a role in controlling polyomavirus infection by initiatin innate signaling cascades. This work aims to accomplish the following: 1.) determine the mechanism of defensin-mediated neutralization of JCPyV infection using a multidisciplinary approach, and 2.) study the signaling events regulated by human alpha-defensins and JCPyV during infection. This will be accomplished using a variety of approaches including but not limited to molecular biological, biochemical, in vitro, and live cell microscopy techniques. By establishing a mechanism and elucidating the cellular response to defensins, this work will provide clues to how small molecules might effectively neutralize viral infections, and insight int how persistent infections manipulate innate immune signaling cascades.
This research will provide a platform for rational drug design for a persistent human pathogen with no current treatment or cure by elucidating the mechanism of a small molecule antiviral and its subsequent effects on the innate immune system. JC virus is a significant problem for immunosuppressed patients that includes individuals with conditions ranging from autoimmune diseases to organ transplants and AIDS. Immunosuppressed patients are significantly at risk for the fatal disease Progressive Multifocal Leukoencephalopathy (PML) caused by reactivation of JCPyV. Defensins are potent innate immune molecules with the potential to greatly improve treatment for this and other persistent viral infections. This work will be vital in contributing to the understanding of defensins'mechanism and immunomodulatory properties.
|Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60|