The effect of local virus infection upon cutaneous wound healing: the impact of virus-induced Type III IFNs

SUMMARY The skin, with its surface area of approx 1.8m2, is one of the largest organs in the human body and is the most exposed to the environment. Maintenance of the skin barrier is of paramount importance to prevent infection by commensal or pathogenic bacteria, or other pathogens. However, study of the mechanisms of wound healing has been conducted primarily in the context of sterile wounding, and has never been conducted in the context of cutaneous virus infection, the focus of this proposal. A significant number of viral pathogens, such as papillomaviruses, some herpesviruses and some poxviruses, infect cutaneously and are responsible for infection of hundreds of millions of people worldwide. These viral infections can often induce a strong local immune response that differs from the response that is normally induced during sterile wounding. The paradigm of tissue renegeration is that wound healing only begins after clearance of a pathogenic infection. However, our preliminary data indicates that a wound healing response begins prior to the peak of cutaneous virus replication. Therefore, the antiviral response that aims to clear the virus can likely both enhance and oppose individual components of the highly regulated wound healing process that is occurring concurrently. Our preliminary data indicate that wound healing after cutaneous virus infection, which is crucial to prevent secondary bacterial infections, displays a number of crucial differences to sterile wounding. These differences include the composition of the cellular response, and the effects of antiviral molecules, such as interferons, upon wound healing. In Specific Aim 1 we will establish a new system to directly and systematically examine the effects of the local virus infection upon the molecular and cellular wound healing response. In this way we will identify key regulators of the antiviral response that also impact cutaneous healing. In Specific Aim 2 we will establish a pipeline to test these key regulators by investigating the role of Type III interferons (T3-IFN), which our preliminary data indicate are strongly induced only upon virus infection, as a candidate regulator of wound healing in our pipeline. T3-IFN are required for effective wound healing, but not control of virus replication. T3- IFN are a family of cytokines that are primarily produced at barrier surfaces, such as gut, lung and blood brain barrier. T3-IFNs can have a large number of downstream effects independent of control of virus growth, including control of the cell cycle as well as recruitment and modulation of the activation of innate and adaptive immune cells. The localized nature of T3-IFN production makes them a promising therapeutic target, as they can be administered, or their action modulated, without the need to account for systemic side effects. We will examine the role of previously identified T3-IFN-induced molecules, and identify additional T3-IFN-modulated regulators of cutaneous wound healing. We will then be poised to expand our studies, both to further understand how T3- IFN modulates wound healing at the molecular level, but also to investigate the role of other molecules and cell populations induced by cutaneous virus infection in the wound healing response, in a future RO1 proposal.