Antibiotic-induced microbiota disruption impairs neutrophil-mediated immunity to respiratory Aspergillus fumigatus infection in mice.

Aspergillus fumigatus is an environmental mold that forms ubiquitous airborne conidia and can cause life-threatening infections in immunocompromised individuals. Invasive aspergillosis occurs in patients with quantitative or qualitative neutrophil defects, who often receive systemic antibiotics to prevent or manage bacterial infections. Antibiotic-induced bacterial dysbiosis has been linked to impaired neutrophil bactericidal activity and to intestinal commensal bacteria escape during systemic candidiasis, though it remains unclear whether receipt of antibacterial antibiotics impairs neutrophil-dependent defenses against inhaled mold pathogens in the lung. Herein, we measured the outcome of Aspergillus challenge in C57BL/6J mice that were treated with different antibiotics in the drinking water for three weeks prior to experimental infection. We found that ampicillin but not neomycin or vancomycin treatment significantly increased murine mortality and lung fungal burden. The heightened susceptibility was associated with impaired fungal killing by lung-infiltrating neutrophils and monocytes, as well as reduced neutrophil production of NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS). These findings demonstrate that systemic antibiotic treatment can compromise pulmonary anti-Aspergillus immunity and suggest that the host microbiota can enhance neutrophil fungicidal activity by promoting NOX2-mediated ROS production.