α-Toxin Regulates Local Granulocyte Expansion from Hematopoietic Stem and Progenitor Cells in

The immune response to Staphylococcus aureus infection in skin involves the recruitment of neutrophils (PMN) from the bone marrow via the circulation and local granulopoiesis from hematopoietic stem and progenitor cells (HSPC) that also traffic to infected skin wounds. We focus on regulation of PMN number and function and the role of pore-forming alpha-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 mutant strain (ΔAT) was unimpeded, exhibiting efficient bacterial clearance and hastened wound resolution. HSPC recruited to infected wounds was 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-1 receptor signaling. Immunodeficient MyD88 knockout mice infected with S. aureus experienced lethal sepsis that was reversed by PMN expansion mediated by injection of wild type HSPC 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 MRSA infection in immunodeficient patients.