943 Loss of both host-derived antimicrobial peptides and bacteriocin-producing commensals enables survival of Staphylococcus aureus on Th2-inflamed skin

Atopic dermatitis (AD) is susceptible to S. aureus colonization which exacerbates this disease. AD has reduced expression of cathelicidin (Camp) and b-defensin (Defb) antimicrobial peptides (AMPs) compared to other inflammatory disorders but the expression of these AMPs is still higher in AD than on normal skin. To understand why increased AMPs in AD compared to normal skin would enable increased S. aureus we analyzed the skin of Il4ra-/- or WT mice with or without MC903-induced Th2 inflammation. scRNA-Seq showed that topical application of S. aureus to WT skin increased frequency of Il17a+ Th17 subsets but enhanced frequency of Gata3+ Th2 subsets when pretreated with MC903. In contrast, Il4ra-/- skin shifted back toward Th17-predominant response to S. aureus despite MC903 pretreatment. In keratinocytes, scRNAseq identified diminished induction of multiple AMP genes such as S1008/9, Lnc2 and Camp from WT mice treated with MC903 and this was associated with an increase in S. aureus survival. Il4ra-/- mice exposed to MC903 had greatly increased AMP expression in keratinocytes relative to WT mice and a 3-log (P<.01) decrease in S. aureus survival, thus supporting a central role of IL-4Ra in suppressing the innate immune response to S. aureus but not explaining why S. aureus was increased relative to normal skin. We next asked if Th2 inflammation inhibited survival of coagulase-negative Staphylococcus (CoNS) strains producing bacteriocins (CoNS-Bac+) that kill S. aureus. CoNS-Bac+were 2-8 times more susceptible in vitro to human AMPs, LL-37, DEFB3 and DEFB2, than CoNS-Bac- (P<.001) and these protective bacteria were killed by low levels of AMPs that could still be produced by the Th2-inflamed skin. Notably, the selective killing of CoNS-Bac+ was rescued on the skin of Camp-/- mice with Th2 inflammation. These results show that the combination of both a partial loss of host AMPs and elimination of CoNS-Bac+during Th2 inflammation can explain why S. aureus expands on AD skin.