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Although the crucial role of professional phagocytes for the clearance of  S. aureus  infections is well-established, several studies indicate an adverse role of leukocytes in the dissemination of  S. aureus  during infection. Since only little is known about macrophages in this context, we analyzed the role of macrophages, and in particular reactive oxygen species deficiency, for the seeding of  S. aureus  metastases. Infection of bone marrow-derived macrophages (BMDM) with  S. aureus  revealed that NADPH oxidase 2 (NOX2-) deficient, but not NOX1- or NOX4-deficient, BMDM failed to clear intracellular  S. aureus . Despite of larger intracellular bacterial burden, NOX2-deficient BMDM showed significantly improved survival. Intravenous injection of mice with  in vitro -infected BMDMs carrying intracellular viable  S. aureus  led to higher bacterial loads in kidney and liver of mice compared to injection with plain  S. aureus . An even higher frequency of liver abscesses was observed in mice infected with  S. aureus -loaded  nox2  −/−  BMDM. Thus, the improved intracellular survival of  S. aureus  and improved viability of NOX2-deficient BMDM is associated with an aggravated metastatic dissemination of  S. aureus  infection. A combination of vancomycin and the intracellularly active antibiotic rifampicin led to complete elimination of  S. aureus  from liver within 48 h, which was not achieved with vancomycin treatment alone, underscoring the impact of intracellular  S. aureus  on the course of disease. The results of our study indicate that intracellular  S. aureus  carried by macrophages are sufficient to establish a systemic infection. This suggests the inclusion of intracellularly active antibiotics in the therapeutic regimen of invasive  S. aureus  infections, especially in patients with NADPH oxidase deficiencies such as chronic granulomatous disease.

NOX2 Deficiency Permits Sustained Survival of S. aureus in Macrophages and Contributes to Severity of Infection