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Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus.

ABSTRACT: Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1^-/- mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1^-/- mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1^-/- mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (M?), Langerin⁺ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-?) as well as the antimicrobial peptides CRAMP and m?D-3. Priming also protected rag1^-/- mice against recurring SSSI, with increased M? and LDC infiltration and induction of IL-22, CRAMP, and m?D-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

SUBMITTER: Chan LC

PROVIDER: S-EPMC5278165 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus.

Chan Liana C LC Chaili Siyang S Filler Scott G SG Miller Lloyd S LS Solis Norma V NV Wang Huiyuan H Johnson Colin W CW Lee Hong K HK Diaz Luis F LF Yeaman Michael R MR

Infection and immunity 20170126 2

Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was ind ...[more]

PMID: 27849182

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Project description:IntroductionTo promote judicious prescribing of methicillin-resistant Staphylococcus aureus (MRSA)-active therapy for skin and soft tissue infections (SSTI), we previously developed an MRSA risk assessment tool. The objective of this study was to validate this risk assessment tool internationally.MethodsA multicenter, prospective cohort study of adults with purulent SSTI was performed at seven international sites from July 2016 to March 2018. Patient MRSA risk scores were computed as follows: MRSA infection/colonization history (2 points); previous hospitalization, previous antibiotics, chronic kidney disease, intravenous drug use, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), diabetes with obesity (1 point each). Predictive performance of MRSA surveillance percentage, MRSA risk score, and estimated MRSA probability (surveillance percentage adjusted by risk score) were quantified using the area under the receiver operating characteristic curves (aROC) and compared. Performance characteristics of different risk score thresholds across varying baseline MRSA prevalence were examined.ResultsTwo hundred three patients were included. Common SSTI were wounds (28.6%), abscess (25.1%), and cellulitis with abscess (20.7%). Patients with higher risk scores were more likely to have MRSA (P < 0.001). The MRSA risk score aROC (95%CI) [0.748 (0.678-0.819)] was significantly greater than MRSA surveillance percentage [0.646 (0.569-0.722)] (P = 0.016). Estimated MRSA probability aROC [0.781 (0.716-0.845)] was significantly greater than surveillance percentage (P < 0.001) but not the risk score (P = 0.192). The estimated negative predictive value (NPV) of an MRSA score ≥ 1 (i.e., a score of 0) was greater than 90% when MRSA prevalence was 30% or less.ConclusionThe MRSA risk score and estimated MRSA probability were significantly more predictive of MRSA compared with surveillance percentage. An MRSA risk score of zero had high predictive value and could help avoid unnecessary empiric MRSA coverage in low-acuity patients. Further study, including impact of such risk assessment tools on prescribing patterns and outcomes are required before implementation.

Dataset Information

Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus.

Publications

Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus.

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