α-Toxin Regulates Local Granulocyte Expansion from Hematopoietic Stem and Progenitor Cells in Staphylococcus aureus-Infected Wounds.
Patrick C FalaheeLeif S AndersonMack B ReynoldsMauricio PirirBridget E McLaughlinCarly A DillenAmbrose L CheungLloyd S MillerScott Irwin SimonPublished in: Journal of immunology (Baltimore, Md. : 1950) (2017)
The immune response to Staphylococcus aureus infection in skin involves the recruitment of polymorphonuclear neutrophils (PMNs) from the bone marrow via the circulation and local granulopoiesis from hematopoietic stem and progenitor cells (HSPCs) that also traffic to infected skin wounds. We focus on regulation of PMN number and function and the role of pore-forming α-toxin (AT), a virulence factor that causes host cell lysis and elicits inflammasome-mediated IL-1β secretion in wounds. Infection with wild-type S. aureus enriched in AT reduced PMN recruitment and resulted in sustained bacterial burden and delayed wound healing. In contrast, PMN recruitment to wounds infected with an isogenic AT-deficient S. aureus strain was unimpeded, exhibiting efficient bacterial clearance and hastened wound resolution. HSPCs recruited to infected wounds were unaffected by AT production and were activated to expand PMN numbers in proportion to S. aureus abundance in a manner regulated by TLR2 and IL-1R signaling. Immunodeficient MyD88-knockout mice infected with S. aureus experienced lethal sepsis that was reversed by PMN expansion mediated by injection of wild-type HSPCs directly into wounds. We conclude that AT-induced IL-1β promotes local granulopoiesis and effective resolution of S. aureus-infected wounds, revealing a potential antibiotic-free strategy for tuning the innate immune response to treat methicillin-resistant S. aureus infection in immunodeficient patients.
Keyphrases
- wound healing
- staphylococcus aureus
- immune response
- wild type
- escherichia coli
- bone marrow
- toll like receptor
- pseudomonas aeruginosa
- end stage renal disease
- inflammatory response
- newly diagnosed
- ejection fraction
- methicillin resistant staphylococcus aureus
- acute kidney injury
- air pollution
- dendritic cells
- intensive care unit
- prognostic factors
- oxidative stress
- diabetic rats
- patient reported
- antibiotic resistance genes
- microbial community
- peritoneal dialysis
- drug induced