Investigating the dynamics of skin immune responses in arbovirus infection and disease

The skin is the first line of defence against most infections, including those by arthropod-borne viruses (arboviruses). The skin is a compartmentalised organ populated by a variety of immune cells that play a critical role in coordinating immune responses after skin infection. Arboviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) cause debilitating musculoskeletal and arthritic disease and are considered significant public health threats of major global concern due to the scale of outbreaks, and the limited treatment options available. To understand the dynamics of arthritogenic arbovirus dissemination following skin infection, we developed a pathogenic model of RRV infection to mimic a mosquito bite. We found that inflammatory monocytes, neutrophils and dermal macrophages dominated the early inflammatory response in the skin. In addition, we found that RRV-infected CD11b+ migratory cells translocate to the skin draining lymph nodes. Importantly, we unveiled a critical role for viral envelope glycosylation in driving viral dissemination kinetics and disease severity. Intradermal infection with RRV derived from mosquito cells resulted in more severe disease compared to RRV derived from mammalian cells. This difference in disease was accompanied by glycosylationspecific transcriptional response in the skin after intradermal infection. Interestingly we also show evidence indicating that viral envelope glycosylation dictates the dissemination of RRV to target tissues in muscle and joint. Using a new model of cutaneous arboviral infection, we show previously unappreciated mechanisms of immune response and viral dissemination that, in future, will help develop novel approaches to limit arboviral dissemination and ameliorate disease outcomes.