4.6 Article

Influenza Infection Suppresses NADPH Oxidase-Dependent Phagocytic Bacterial Clearance and Enhances Susceptibility to Secondary Methicillin-Resistant Staphylococcus aureus Infection

Journal

JOURNAL OF IMMUNOLOGY
Volume 192, Issue 7, Pages 3301-3307

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1303049

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Funding

  1. Pfizer
  2. National Institutes of Health/National Heart, Lung, and Blood Institute [R01 HL118408]
  3. National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01 AI41517, R01 AI75312]

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Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a leading contributor to mortality during recent influenza pandemics. The mechanism for this influenza-induced susceptibility to secondary S. aureus infection is poorly understood. In this study, we show that innate antibacterial immunity was significantly suppressed during the recovery stage of influenza infection, even though MRSA superinfection had no significant effect on viral burdens. Compared with mice infected with bacteria alone, postinfluenza MRSA-infected mice exhibited impaired bacterial clearance, which was not due to defective phagocyte recruitment, but rather coincided with reduced intracellular reactive oxygen species levels in alveolar macrophages and neutrophils. NADPH oxidase is responsible for reactive oxygen species production during phagocytic bacterial killing, a process also known as oxidative burst. We found that gp91(phox)-containing NADPH oxidase activity in macrophages and neutrophils was essential for optimal bacterial clearance during respiratory MRSA infections. In contrast to wild-type animals, gp91(phox-/-) mice exhibited similar defects in MRSA clearance before and after influenza infection. Using gp91(phox+/-) mosaic mice, we further demonstrate that influenza infection inhibits a cell-intrinsic contribution of NADPH oxidase to phagocyte bactericidal activity. Taken together, our results establish that influenza infection suppresses NADPH oxidase-dependent bacterial clearance and leads to susceptibility to secondary MRSA infection.

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