Rapid, Non-Classical Mechanism of Leukocyte Recruitment to Staphylococcus Aureus Skin Infection
Swift recruitment of phagocytic leukocytes is critical to prevent infections when bacteria breach through the protective layers of the skin. While this process is commonly believed to be dependent on the prior activation of resident skin cells by invariant bacterial surface structures, we show here that secreted Staphylococcus aureus toxins directly recruit leukocytes, resulting in an efficient and pathogen-specific response. In a mouse model of S. aureus cutaneous infection, we found that as early as 4 hours post infection, neutrophil influx was entirely dependent on a family of S. aureus secreted toxins called phenol-soluble modulins (PSMs). Transcriptional analysis of PSM-mediated stimulation of human neutrophils revealed EGR1 as the primary mediator of the response. Accordingly, EGR1-/- mice had significantly larger skin abscesses compared to wild-type (WT) mice. Lastly, adoptive transfer of equal numbers of labeled EGR1-/- and WT bone marrow derived leukocytes revealed that EGR1-/- leukocytes had significant defects in migration to the infection sites. Remarkably, this difference was abrogated in mice infected with a psm isogenic mutant. Taken together, this thesis reveals a mechanism that is critical for the early leukocyte response to invading S. aureus on the skin and attributes a previously unknown key role to secreted bacterial toxins and the transcription factor EGR1 in that process, providing a paradigmatic example of an innate host defense mechanism that is pathogen-specific in mode and extent.
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