Resident macrophages acquire innate immune memory in staphylococcal skin infection

Abstract

<jats:p>Staphylococcus aureus (S. aureus) is a common colonizer of healthy skin and mucous membranes. At the same time, S. aureus is the most frequent cause of skin and soft tissue infections. Dermal macrophages (Mφ) are critical for the coordinated defense against invading S. aureus, yet they have a limited life span with replacement by bone marrow derived monocytes. It is currently poorly understood whether localized S. aureus skin infections persistently alter the resident Mφ subset composition and resistance to a subsequent infection. In a strictly dermal infection model we found that mice, which were previously infected with S. aureus, showed faster monocyte recruitment, increased bacterial killing and improved healing upon a secondary infection. However, skin infection decreased Mφ half-life, thereby limiting the duration of memory. In summary, resident dermal Mφ are programmed locally, independently of bone marrow-derived monocytes during staphylococcal skin infection leading to transiently increased resistance against a second infection.</jats:p>

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

“…Interestingly, E. coli derived OMVs containing no staphylococcal antigens also provided strong protection against S. aureus sepsis and kidney abscess models. Such a finding may be a result of the short time frame between final immunization and infection (10 -14 days) whereby residual immune potentiators induced through OMV immunization mediate antistaphylococcal defense or, suggest that OMVs themselves induce non-specific protective immunity, an effect known as innate immune memory or trained immunity that has previously shown to play a protective role during murine models of S. aureus infection (28)(29)(30)(31).…”

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“…Interestingly, trained immunity is not stimulus-specific and can induce widespread changes in how a leukocyte responds to a second insult. Several studies have shown that prior infection with S. aureus establishes trained immunity in macrophages that provides temporary protection from a second bacterial challenge (155)(156)(157). Trained immunity in response to S. aureus has been shown to occur via epigenetic changes induced by the metabolite fumarate.…”

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“…Recent studies now show that macrophages create a memory of a pathogenic attack by S. aureus, allowing macrophages to generate a more robust response to the pathogen on secondary exposure, with faster monocyte recruitment, bactericidal activity, and healing. 145 Similarly, secondary infection with MRSA in a mouse model demonstrates a memory mechanism, with an induced infiltration of neutrophils, macrophages, Langerin positive dendritic cells (LDC), and NK cells along with increased levels of IL-17, IL-22, IFNγ, and AMPs such as CRAMP and mβ3-D. 146 Moreover, this memory is widely observed in macrophages with activity against MRSA as well 147 and has been shown to be mediated by STAT1 and CXCL9 signalling. 145…”