Introduction: Staphylococcus aureus (Sa) is the greatest bacterial cause of lost life-years. Frequently starting as skin colonization/infection, invasive Sa often requires critical care support. Reactive oxygen species (ROS) production by host NADPH-Oxidase (NOX) provides Sa defense as proven by recurrent infections in chronic granulomatous disease (total NOX dysfunction). NOX function has been largely attributed to neutrophils, however recent fungal studies suggest unique functions of NOX in macrophages. We hypothesized that similar phagocyte specific NOX functionality exists in Sa infections. Though NOX’s overall role in Sa defense is known, clarifying cell-specific contributions may reveal novel therapeutic targets in Sa infections. Methods: Critical NOX subunits were conditionally knocked out using the Cre-loxP system producing mice with dysfunctional NOX in either neutrophils or macrophages. These and NOX intact control mice were infected subcutaneously with Sa. Local tissue destruction (dermonecrosis) and signs of systemic disease were monitored for 7 days. Tissue was processed for flow cytometry, immunohistochemistry, cytokine array, and bacterial burden. Results: Neutrophil NOX dysfunction caused larger dermonecrosis and greater bacterial burden, despite similar cellular infiltration. In contrast, dysfunctional macrophage NOX resulted in smaller skin lesions with similar bacterial burden compared with control mice. Histology showed inflammatory lesions with increased neutrophil infiltration, abscess formation and tissue disruption in neutrophil NOX dysfunction. Lesions with dysfunctional macrophages showed preservation of tissue integrity with greater sequestration and phagocytosis of bacteria. Conclusions: Our findings show differential functions for NOX in macrophages and neutrophils in Sa skin infection. The hyperinflammatory destructive lesions in neutrophil NOX dysfunction align with previous models of neutrophil dominant ROS function. We demonstrated macrophage NOX dysfunction was protective against pathology suggesting a potentially pathogenic role for macrophage ROS. While innate host responses frequently cause collateral damage, our results implicate macrophage ROS as a key driver in Sa skin infection pathology. This maladaptive host process may represent a novel therapeutic target.
Francis et al. (Sun,) studied this question.