349 S. aureus superantigens enhance viral pathogenesis of the skin epithelium

Abstract

Atopic dermatitis (AD) is characterized by skin barrier dysfunction, type 2 immunity, and an altered skin microbiota with high S. aureus abundance. Eczema vaccinatum (EV) is one of the most serious AD-associated viral infections and occurs following exposure to vaccinia virus (VV; smallpox vaccine). Previously we had observed that eczema herpeticum, another AD viral complication, was more commonly observed in S. aureus colonized patients. This led us to hypothesize that S. aureus virulence factors (e.g. superantigens [SAgs]) enhance epithelial cells susceptibility to viral infections. To test this, primary human foreskin keratinocytes (PHFK) were incubated with supernatants from multiple S. aureus strains that vary in secreted virulence factors (USA300, HG003, RN4220) and then infected with VV. Treatment of PHFK with USA300 supernatant, which contained the greatest number and quantity of SAgs, resulted in a significant increase in both plaque number and size. USA300 supernatant treatment also resulted in a significant reduction in transepithelial electrical resistance (e.g. barrier function). We have identified the S. aureus SAg, SElQ, as a virulence factor of interest as it is highly produced by USA300 and was detected on the skin of 100% of AD patients in a pilot study. Treatment of PHFK with purified SElQ decreased barrier function, enhanced viral permissiveness, and altered cellular integrity and metabolism. These changes were not observed in PHFK treated with the most homologous SAgs to SElQ, namely SElK and SElM. Our findings suggest that S. aureus SAgs, and uniquely SElQ, significantly alter PHFK and enhance their permissiveness to VV infection and spread. Based on these findings, S. aureus virulence factors are potentially key contributors to EV in AD patients, and this may extend to other viral infections afflicting this population.