Mechanisms of skin commensal colonization resistance against opportunistic Staphylococci

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PROJECT SUMMARY Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including Staphylococcus aureus, in a variety of mechanisms collectively termed colonization resistance. The most frequently isolated and best characterized CoNS from human skin is Staphylococcus epidermidis. Given its relative abundance on the skin, it is unsurprising that S. epidermidis has historically been used for studies assumed to be representative of all CoNS. However, investigation of colonization resistance merits a wider dissection of other skin CoNS, especially given that S. epidermidis is an opportunistic pathogen and the leading cause of medical implant- associated infections. Of particular interest is the second most frequently isolated CoNS, Staphylococcus hominis. While relatively unstudied compared to S. epidermidis, current evidence suggests that S. hominis may be an underappreciated yet important player in maintaining cutaneous homeostasis and colonization resistance. S. hominis makes multiple anti-pathogen lantibiotics and our preliminary findings suggest S. hominis does not contain the same pathogenic genes that S. epidermidis can use to degrade the skin barrier. This proposal seeks to fill a significant gap in in our understanding of the multifaceted roles of specific CoNS in maintaining skin health by determining mechanisms of S. hominis skin colonization resistance. One potential colonization resistance mechanism is the Accessory Gene Regulator (agr) quorum sensing system, which is ubiquitous among staphylococci. This two component system responds to its cognate auto-inducing peptide (AIP) signal. In S. aureus, agr regulates the expression of a suite of virulence factors necessary for productive skin infection. Some, but not all CoNS make AIPs that inhibit S. aureus agr and importantly, not all S. epidermidis AIPs inhibit S. aureus agr signaling suggesting that other CoNS may also contribute to crosstalk and colonization resistance. Our collaborators showed that S. hominis makes at least one AIP inhibitor of S. aureus quorum sensing. Through analysis of spent media from healthy skin S. hominis strains, I determined that S. hominis makes at least six AIP variants that inhibit both S. aureus and S. epidermidis agr quorum sensing. With these preliminary data and clinical observations, I hypothesize that S. hominis and its agr-regulated factors protect host skin from challenge by opportunistic staphylococcal pathogens. To address this hypothesis, I propose two innovative specific aims to (1) characterize each S. hominis AIP type and function in inter- and intraspecies crosstalk, and (2) determine how S. hominis colonization and agr-regulated factors stimulate a protective anti-pathogen environment on human skin. Together, this proposal will be the first to provide mechanistic insight into the colonization resistance mechanisms of a ubiquitous, yet understudied member of the normal human flora with potential applications as a novel probiotic or therapeutic for skin diseases.