Rapid pathogen-specific recruitment of immune effector cells in the skin by secreted toxins

Abstract

Swift recruitment of phagocytic leukocytes is critical to prevent infection when bacteria breach through the protective layers of the skin. According to canonical models, this occurs via an indirect process that is initiated by contact of bacteria with resident skin cells and which is independent of the pathogenic potential of the invader. Here, we describe a more rapid mechanism of leukocyte recruitment to the site of intrusion of the important skin pathogen Staphylococcus aureus that is based on direct recognition of specific bacterial toxins, the phenol-soluble modulins (PSMs), by circulating leukocytes. We used a combination of intravital imaging, ear infection and skin abscess models, and in-vitro gene expression studies to demonstrate that this early recruitment was dependent on the transcription factor EGR1 and significantly contributed to the prevention of infection. Our findings refine the classical notion of the non-specific and resident cell-dependent character of the innate immune response to bacterial infection by demonstrating a pathogen-specific high-alert mechanism involving direct recruitment of immune effector cells by secreted bacterial products.

Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus

“…As for the cytolytic capacities this is expected from the general absence of cytolysins other than PSMs in these species. Like in S. aureus , where PSMs are by far the most pro-inflammatory secreted components ( 36 ), pro-inflammatory capacity of S. xylosus was also mainly due to PSMs.…”

“…The isolation of neutrophils from mouse bone marrow was performed as described previously ( 36 ). Briefly, 8- to 10-week-old C57Bl/6NCrl female mice were sacrificed followed by the collection of the tibiae and femora.…”

“…Calcium flux in murine or human neutrophils was measured as previously described ( 36 ). Briefly, neutrophils were suspended at a concentration of 5 × 10 6 cells/ml in RPMI/H and incubated with ~ 2 mM Fluo3-AM (Invitrogen, F1242) for 20 minutes at 37°C.…”

Microbes and the fate of neutrophils

“…219 Studies in multiple animal infection models demonstrate that PSMs contribute significantly to CA-MRSA virulence. 217,219,220 More recently, PSM production has been associated significantly with human skin and soft tissue infections. 221 Inasmuch as PSMs cause neutrophil cytolysis, it is perhaps not unexpected that they cause rapid formation of NETs.…”

Photocatalytic Cu2WS4 Nanocrystals for Efficient Bacterial Killing and Biofilm Disruption

“…Bacteria usually exist as biofilms, and biofilm-associated infectious diseases, such as chronic wound infections, pulmonary infections, endocarditis osteomyelitis, musculoskeletal infections, dental periodontitis, peri-implantitis, or even nosocomial infections, are an increasingly serious problem in the global medical community. 19–22 During the process of biofilm formation, bacteria attach to inert or biological surfaces and become wrapped in self-produced EPSs. EPSs have many negative effects, such as facilitating bacterial aggregation and biofilm cohesion, allowing cell–cell communication among the biofilm population and providing a source of nutrients.…”