AUTHOR=Tosetti Bettina , Ward Beate , Grumme Daniela , Herb Marc , Schramm Michael , Utermöhlen Olaf , Heukamp Lukas C. , Krönke Martin , Krut Oleg 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.633629

DOI=10.3389/fimmu.2021.633629

ISSN=1664-3224

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