"Defensin-mediated antiviral immune modulation"
Defensins are small, cationic antimicrobial peptides that are one effector component of the innate immune system. There are two types produced by most mammals, α-defensins and β-defensins, which have broad anti-microbial activity against bacteria and enveloped viruses. The mechanism of inhibition is due at least in part to disruption of the lipid bi-layer leading to bacterial cell lysis or viral disassembly. Recently, our laboratory has shown that a-defensins inhibit infection by adenovirus (AdV). This inhibition is intriguing as AdV is a non-enveloped virus and, therefore, lacks a lipid component. AdV infects cells by binding to various host cell surface receptors followed by endocytic internalization. Subsequent exposure to cellular factors induces virus uncoating, which leads to escape of the virus from the endosomal compartment. AdV then migrates to the nuclear envelope where viral DNA passes through the nuclear pore. Recent work in the lab has shown that defensins bind AdV capsids and block virus uncoating. This block in uncoating not only prevents the endocytosed virus from escaping from the endosome and replicating but also prevents exposure of the virus genome outside of the capsid. Several studies have shown a large type I interferon (IFN) response to AdV upon detection of AdV DNA by the endosomal toll-like receptor-9 (TLR9) and by non-TLR9-mediated sensors, which is critical for initial antiviral defense and immune regulation. As the IFN response is largely dependent on exposure of viral DNA to cellular sensors, our studies will explore the hypothesis is that defensin binding to AdV will alter type I IFN production by AdV-infected cells. These studies will allow for a greater understanding of the initial sensing of virus infection leading to an immune response for DNA. As the induction of an inflammatory response correlates with the severity of AdV associated disease, defensin-mediated inhibition of the type I IFN response may be important to the pathology of virus infection.