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

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