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 Ϫ/Ϫ mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1 Ϫ/Ϫ 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 Ϫ/Ϫ mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (M⌽), Langerin ϩ 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 Ϫ/Ϫ 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.

Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory

“…Priming resulted in localized protection, as evidenced by smaller skin lesions over the course of infection compared with naïve-infected controls, as reported previously ( Fig. 1A) (22)(23)(24). In primed mice, MRSA burden in skin lesions was similar to naïve mice at day 2, but was significantly reduced by day 7.…”

“…Animal studies were performed in accordance with approved animal use policies of the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles following NIH guidelines. Male C57BL/6 (WT) mice (20-25 g; Jackson Labs) were studied using a subcutaneous SSSI model as we have previously detailed (22)(23)(24). For primary infection, SSSI was established via inoculation with ∼1 × 10 7 CFU MRSA in 100 μL PBS by subcutaneous injection into the right flank.…”

“…Immune Cell Subset Profiles. iLNs and spleen of each mouse were mechanically dissociated and cell isolated (23). Skin abscesses were processed and cells isolated per protocol (55).…”

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

“…In contrast, 2° IL-1β -/-mice had restored neutrophil abscess formation with an increase in circulating neutrophils (Figure 2G). Neutrophils differentiate into distinct effector subsets after an S. aureus infection (22), suggesting they might mediate trained immunity against a subsequent S. aureus challenge as previously described (23). To evaluate this possibility, neutrophils from d28 IL-1β -/-mice were transferred to naive WT and IL-1β -/-mice 2 hours prior to 1° S. aureus skin infection.…”

Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model

“…Other studies using S. epidermidis foreign-body infection models show similar results, with BALB/c mice exhibiting larger CFU counts and/or bigger abscesses, compared to C57BL/6 equivalents (Broekhuizen et al, 2007;Sander et al, 2012). Nevertheless, the number of studies is limited and the topic remains controversial when considering studies using S. aureus, which show contradictory results (Chan et al, 2016;Nippe et al, 2011;Nishitani et al, 2015;Prabhakara et al, 2011;von Kockritz-Blickwede et al, 2008). It is known that the immune system of C57BL/6 and BALB/c mice differ from each other (Sellers et al, 2012), with C57BL/6 mice being more Th1 polarised and BALB/c mice being more Th2 polarised.…”