Ebola virus' hidden target: virus transmission to and infection of skin.

Ebola virus (EBOV), the causative agent of Ebola virus disease, remains one of the World Health Organization's top 10 threats to global health. Infectious EBOV virions can be found on the surface of skin late in infection and may be transmitted to others through skin-to-skin contact. We investigate in vivo EBOV tropism and the kinetics of virus movement to and from the skin. Increasing viral loads were detected over time in the skin of EBOV-infected non-human primates and mice, with antigen detected in dermal stromal and immune cells. Epidermal cells within and surrounding hair follicles also harbored viral antigen, suggesting a novel mechanism of virus egress to the epidermal surface. During late infection, proinflammatory responses were elevated in infected visceral organs but minimal in the skin despite significant viral loads. We observed similar viral trafficking and cell tropism in the skin of mice intraperitoneally infected with a low containment EBOV model virus, rVSV/EBOV GP, allowing more detailed mechanistic studies. Sites of virus infection in the skin were patchy, with intense focal areas of infection surrounded by uninfected areas. To investigate virus entry into the body through skin, rVSV/EBOV GP was applied to the surface of gently abraded skin to remove the stratum corneum; epidermal keratinocytes were robustly infected with subsequent systemic viral dissemination observed in some mice. Optimal levels of infection within the skin required expression of the phosphatidylserine receptor, AXL. Collectively, our data demonstrate that skin serves as an important organ targeted by EBOV, facilitating virus entry into and egress from the body. IMPORTANCE Ebola virus (EBOV) remains one of the World Health Organization's top 10 threats to global health, despite the availability of a U.S. Food and Drug Administration-approved vaccine. EBOV spreads through human-to-human contact, yet the role of skin in viral transmission remains unclear. Here, we identify skin as a site of EBOV infection, serving as a potential portal for entry into and egress from the body. In vivo, infectious virions and viral RNA increased in the skin over time, localizing to dermal myeloid and stromal cells and to cells within and surrounding hair follicles, suggesting a novel mechanism for viral shedding. Skin infection was patchy and associated with minimal inflammation, despite significant viral loads. Using a surrogate EBOV model, we demonstrate that systemic infection can occur following topical administration through abraded skin and requires phosphatidylserine receptor, AXL, for optimal infection of skin. These findings redefine the role of skin in EBOV pathogenesis, with implications for barrier-targeted interventions.