The role of pre-existing inflammation in the skin in modulating the outcome of arbovirus infection

As climate change expands mosquito habitats, the incidence of mosquito-borne virus infections is rising. Understanding of factors which underlie variability in susceptibility to arbovirus infections between individuals is limited. Identifying such factors would provide a better understanding of arbovirus pathogenesis to aid development of more effective vaccines and antivirals. This thesis identifies two factors which modulate host susceptibility to arbovirus infection in the skin: 1) UV exposure 2) the presence of pre-existing inflammation due to inflammatory disease. A unique in vivo model of natural arbovirus transmission, combining UV exposure, mosquito biting and virus infection at the same site, was used to investigate susceptibility to a model arbovirus, Semliki Forest virus (SFV), in UV-exposed skin. Prior erythemal UV exposure of skin, equivalent to sunburn, or repeated, sub-erythemal UV exposure of skin, mimicking daily tanning exposures, enhance subsequent arbovirus infection in vivo, causing an increase in virus replication at the inoculation site, the skin, and dissemination of virus. Susceptibility to infection is highest at 24h and 1-week post-UV exposure, although distinct mechanisms drive this at each timepoint. Virus-permissive leukocytes are recruited to UV-exposed skin by 24h post-UV exposure in response to elevated CCL2 expression. SFV utilises these infiltrating cells for replication. Contrastingly, by 1-week post-exposure, the damaged tissue is undergoing wound-healing, with an increase in actively proliferating cells, which SFV preferentially infects. Treatment of the UV burn with anti-inflammatory topical steroids offers partial protection against UV-mediated enhancement, by limiting viremia early post-infection but, crucially, does not prevent spread of virus to the brain, the main site of arbovirus pathology. Furthermore, we have found that PBMCs from patients with inflammatory skin conditions, either psoriasis or systemic sclerosis, are resistant to ZIKV infection in vitro. In psoriatic PBMCs, this is likely at least partly due to better induction of type I IFN responses compared to healthy PBMCs. This work identifies two novel factors which can alter host susceptibility to arbovirus infection.