SOCS-1 inhibition of type I interferon restrains Staphylococcus aureus skin host defense.

Nathan Klopfenstein,Amondrea Blackman,Matthias Gunzer,Stephanie L Brandt,Sydney Castellanos,C Henrique Serezani

doi:10.1371/journal.ppat.1009387

Abstract

The skin innate immune response to methicillin-resistant Staphylococcus aureus (MRSA) culminates in the formation of an abscess to prevent bacterial spread and tissue damage. Pathogen recognition receptors (PRRs) dictate the balance between microbial control and injury. Therefore, intracellular brakes are of fundamental importance to tune the appropriate host defense while inducing resolution. The intracellular inhibitor suppressor of cytokine signaling 1 (SOCS-1), a known JAK/STAT inhibitor, prevents the expression and actions of PRR adaptors and downstream effectors. Whether SOCS-1 is a molecular component of skin host defense remains to be determined. We hypothesized that SOCS-1 decreases type I interferon production and IFNAR-mediated antimicrobial effector functions, limiting the inflammatory response during skin infection. Our data show that MRSA skin infection enhances SOCS-1 expression, and both SOCS-1 inhibitor peptide-treated and myeloid-specific SOCS-1 deficient mice display decreased lesion size, bacterial loads, and increased abscess thickness when compared to wild-type mice treated with the scrambled peptide control. SOCS-1 deletion/inhibition increases phagocytosis and bacterial killing, dependent on nitric oxide release. SOCS-1 inhibition also increases the levels of type I and type II interferon levels in vivo. IFNAR deletion and antibody blockage abolished the beneficial effects of SOCS-1 inhibition in vivo. Notably, we unveiled that hyperglycemia triggers aberrant SOCS-1 expression that correlates with decreased overall IFN signatures in the infected skin. SOCS-1 inhibition restores skin host defense in the highly susceptible hyperglycemic mice. Overall, these data demonstrate a role for SOCS-1-mediated type I interferon actions in host defense and inflammation during MRSA skin infection.

Highlights

Staphylococcus aureus is the leading cause of skin and soft tissue infections in the United States, accounting for almost 500,000 hospital admissions a year [1]
The control of Staphylococcus aureus skin and soft tissue infections is dictated by the balance between pro- and anti-inflammatory actions in phagocytes and structural cells
Most studies have focused on the actions of inflammatory mediators, the role of intracellular effectors that shape innate immune response during skin infection is not well understood

Summary

Introduction

Staphylococcus aureus is the leading cause of skin and soft tissue infections in the United States, accounting for almost 500,000 hospital admissions a year [1]. The resistance of S. aureus to multiple antibiotics, methicillin-resistant Staphylococcus aureus (MRSA), has made treatment of these infections increasingly difficult [2]. With the rise in antimicrobial resistance, there is a compelling need for safe, inexpensive, and non-antibiotic approaches that do not directly attack the bacterial target (which can lead to resistance over time), but instead host-centered strategies to prevent and treat these bacterial infections. Along with recruited monocytes and neutrophils, are responsible for major events during S. aureus skin infection, including recognizing the infection, abscess formation, and resolution of the inflammatory response [3,4]. Since the abscess harbors viable and necrotic neutrophils plus bacteria at its core, it must be tightly organized to prevent deeper infection and bacterial dissemination [4,5]

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