Exploitation of skin innate immune defense by Herpes Simplex Virus Type 1 and Vaccinia Virus

Herpes Simplex Virus Type 1 (HSV-1) and Vaccinia Virus (VV) are two viruses that can infect the skin and occasionally cause severe disease, especially in patients with deficient cutaneous immunity. Chapter I of this dissertation discusses HSV-1 and VV infection and what is known about specific host-virus interactions that are critical to the pathogenesis of infection. One important determinant of pathogenesis is the presence of specialized innate immune receptors such as the scavenger receptor Macrophage Receptor with Collagenous Structure (MARCO), which facilitates the activation of Toll-Like Receptor (TLR)-3 by viral nucleic acids, promoting inflammatory responses to clear infections. We initially hypothesized that activation of TLR3 would inhibit HSV-1 and VV infection in keratinocytes. Testing this hypothesis led to the interesting finding that despite the role of MARCO in innate immune responses, this receptor is usurped by HSV-1 to enhance infection of keratinocytes. We establish this is Chapter II by specifically targeting the interaction of HSV-1 and MARCO. Pharmacological inhibitors of MARCO prevented HSV-1 adsorption and infection of keratinocytes and reduced the size of lesions in a murine model of severe HSV-1 skin infection. Furthermore, HSV-1 co- localized with MARCO on the surface of keratinocytes, and a specific glycoprotein from the viral membrane, HSV-1 glycoprotein C (gC), bound directly to MARCO with high affinity. Importantly, increasing the expression of MARCO enhanced infection, while cells lacking MARCO had reduced susceptibility to infection. We next hypothesized that MARCO could also serve as a receptor for VV infection of keratinocytes. This hypothesis is confirmed in Chapter III by demonstrating that pharmacological inhibitors of MARCO had potent antiviral activity, VV bound directly to MARCO, and MARCO expression also correlated with VV infection. Taken together, this work identifies that an important component of the innate immune system can be exploited by HSV-1 and VV to enhance cutaneous virulence. This increases our knowledge of the basic events guiding early steps of infection in the skin, enhances our understanding of host-pathogen interactions occurring at this epithelial surface, and identifies MARCO as a new therapeutic target for the treatment of HSV-1 and VV skin infection