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

Abstract

Methicillin-resistant S. 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. Here we show that innate antibacterial immunity was significantly suppressed during the recovery stage of influenza infection, despite the fact that MRSA super-infection had no significant effect on viral burdens. Compared to mice infected with bacteria alone, post-influenza MRSA infected mice exhibited impaired bacterial clearance, which was not due to defective phagocyte recruitment, but rather coincided with reduced intracellular reactive oxygen species (ROS) levels in alveolar macrophages and neutrophils. NADPH oxidase is responsible for ROS production during phagocytic bacterial killing, a process also known as oxidative burst. We found that gp91phox-containing NADPH oxidase activity in macrophages and neutrophils was essential for optimal bacterial clearance during respiratory MRSA infections. In contrast to WT animals, gp91phox−/− mice exhibited similar defects in MRSA clearance before and after influenza infection. Using gp91phox+/− mosaic mice, we further demonstrate that influenza infection inhibits a cell-intrinsic contribution of NADPH oxidase to phagocyte bactericidal activity. Together, our results establish that influenza infection suppresses NADPH oxidase-dependent bacterial clearance and leads to susceptibility to secondary MRSA infection.

Novel protective mechanism for interleukin-33 at the mucosal barrier during influenza-associated bacterial superinfection

“…Neutrophils present during the window of increased susceptibility at 6–7 days post-influenza may be dysfunctional and lead to decreased bacterial killing. Influenza suppresses NAPDH oxidase-dependent bacterial clearance during post-influenza MRSA pneumonia, increasing susceptibility to super-infection 34 . Our laboratory has previously shown that influenza inhibits Type 17 immunity and Type 17-associated antimicrobial peptides, allowing for poor bacterial clearance during post-influenza staphylococcal pneumonia 17,22 .…”

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

“…Somewhat in contrast to those results, Sun and Metzger showed that type II interferon signaling induced by day 7 after influenza virus infection inhibited macrophage expression of the scavenger receptor MARCO, which the authors attributed to inhibition of S. pneumoniae uptake and killing during superinfection (34). In another study, influenza-altered production of reactive oxygen species (ROS) by an intracellular NADPH-dependent mechanism was shown to contribute to reduced bacterial killing by both monocytes and neutrophils in a model of S. aureus superinfection 7 days after influenza virus infection (32). Consistent with this report, overexpression of GM-CSF improved the resolution of secondary S. aureus pneumonia via stimulation of ROS production by AMs and enhancement of neutrophil functions (35).…”

“…Alveolar macrophages (AMs) constitute the predominant, highly phagocytic, CD11c integrin-expressing cell population and play a critical role in homeostasis and host defense against numerous pulmonary infections, including infections by influenza virus, S. aureus, and S. pneumoniae, as well as against superinfections (26)(27)(28)(29)(30)(31)(32). Insufficient numbers of AMs in influenza virus-infected mice due to either depletion of clodronate liposomes or the lack of granulocyte-macrophage colony-stimulating factor (GM-CSF) seen in Csf2 Ϫ/Ϫ mice resulted in impaired gas exchange, fatal hypoxia, and severe morbidity but affected viral clearance only moderately (29 lo-int cells), by day 7 after influenza virus infection severely impaired early pneumococcal clearance (up to 3 h after superinfection) (31).…”

The immunology of influenza virus-associated bacterial pneumonia

“…Recent work has demonstrated that influenza virus does not induce a defect in S. aureus uptake by alveolar macrophages ex vivo or in vivo 24 hours after challenge, suggesting a phagocyte-independent mechanism for pathogenesis [17]. Somewhat contrary to these findings, other investigators have demonstrated functional impairment of both macrophages and neutrophils associated with a decreased generation of intracellular reactive oxygen species (ROS) [18]. Oxidative burst is a process by which nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) produces ROS, toxic compounds used to kills bacteria within phagocytes.…”