Chemerin-Derived Peptide Val66-Pro85 Is Effective in Limiting Methicillin-Resistant S. aureus Skin Infection.

Aneta Zegar,Brian A Zabel,Joanna Cichy,Urszula Godlewska,Dorota Kozłowska-Chmielewska,Pawel Majewski

doi:10.3389/fmicb.2021.742610

Abstract

Chemerin-derived peptide Val66-Pro85 (p4) restricts the growth of a variety of skin-associated bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). To better understand the antimicrobial potential of chemerin peptide, we compared p4 activity against MRSA in vitro to cathelicidin LL-37, one of the key endogenous peptides implicated in controlling the growth of S. aureus. The efficacy of p4 was also validated in relevant experimental models of skin pathology, such as topical skin infection with community-acquired MRSA, and in the context of skin inflammatory diseases commonly associated with colonization with S. aureus, such as atopic dermatitis (AD). We showed that p4 collaborates additively with LL-37 in inhibiting the growth of S. aureus, including MRSA, and that p4 was effective in vivo in reducing MRSA burden. p4 was also effective in reducing levels of skin-infiltrating leukocytes in S. aureus-infected AD-like skin. Taken together, our data suggest that p4 is effective in limiting S. aureus and, in particular, MRSA skin infection.

Highlights

Chemerin is a potent protein attractant for several leukocyte subsets, including dendritic cells, macrophages, and an adipokine implicated in metabolic regulation (Wittamer et al, 2003; Zabel et al, 2005b, 2014; Goralski et al, 2007).Chemerin bactericidal potential and expression by the skin suggest that chemerin plays a direct role in shaping resident cutaneous bacterial communities and can limit skin infection
These data suggest that p4 may be useful therapeutically against S. aureus strains resistant to common antibiotics and acts additively with endogenous LL-37 to suppress bacterial growth in infected skin
P4 is more effective than chemerin as an antimicrobial biologic against S. aureus (Banas et al, 2013; Godlewska et al, 2017, 2020), and due to its short length (20 amino acids), p4 can be chemically synthesized for low cost and as a homogenous product

Summary

Introduction

Chemerin is a potent protein attractant for several leukocyte subsets, including dendritic cells, macrophages, and an adipokine implicated in metabolic regulation (Wittamer et al, 2003; Zabel et al, 2005b, 2014; Goralski et al, 2007).Chemerin bactericidal potential and expression by the skin suggest that chemerin plays a direct role in shaping resident cutaneous bacterial communities and can limit skin infection. Recombinant chemerin exhibits antimicrobial activity in vitro against various bacterial strains of the commensal skin microbiome (Kulig et al, 2011; Banas et al, 2013; Godlewska et al, 2019, 2020). Human epidermal chemerin is largely responsible for the natural antimicrobial activity present in keratinocyte secretions (Banas et al, 2013). Genetic ablation of the chemerin gene RARRES2 can result in higher counts of viable epidermal bacteria in an experimental model of skin infection (Banas et al, 2015). Epidermal downregulation of chemerin in psoriasis correlates with some changes in the skin microbiome (Godlewska et al, 2020). Since chemerin is downregulated in psoriasis and is bactericidal against certain bacteria and not others, it is possible

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