title: Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia.
abstract: Clinical post-influenza Staphylococcus aureus pneumonia is characterized by extensive lung inflammation associated with severe morbidity and mortality even after appropriate antibiotic treatment. In this study, we show that antibiotics rescue nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2)-deficient mice but fail to fully protect WT animals from influenza and S. aureus coinfection. Further experiments indicate that the inefficacy of antibiotics against coinfection is attributable to oxidative stress-associated inflammatory lung injury. However, Nox2-induced lung damage during coinfection was not associated with aggravated inflammatory cytokine response or cell infiltration but rather caused by reduced survival of myeloid cells. Specifically, oxidative stress increased necrotic death of inflammatory cells, thereby resulting in lethal damage to surrounding tissue. Collectively, our results demonstrate that influenza infection disrupts the delicate balance between Nox2-dependent antibacterial immunity and inflammation. This disruption leads to not only increased susceptibility to S. aureus infection, but also extensive lung damage. Importantly, we show that combination treatment of antibiotic and NADPH oxidase inhibitor significantly improved animal survival from coinfection. These findings suggest that treatment strategies that target both bacteria and oxidative stress will significantly benefit patients with influenza-complicated S. aureus pneumonia.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198 Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208 Keer.sun@unmc.edu.
authors.forename: Keer
authors.identifier: 0000-0002-9702-9584
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Vijaya Kumar
authors.identifier: 0000-0001-6155-1138
authors.initials: VK
authors.lastname: Yajjala
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Christopher
authors.identifier: 0000-0002-5652-9582
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Geoffrey A
authors.identifier: 0000-0002-4841-286X
authors.initials: GA
authors.lastname: Talmon
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Karl J
authors.identifier: 0000-0001-7907-873X
authors.initials: KJ
authors.lastname: Fischer
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Tammy
authors.identifier: 0000-0001-7624-670X
authors.initials: T
authors.lastname: Kielian
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002470:Cell Survival; D005260:Female; D007249:Inflammation / Q000209:etiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000150:complications*; D018384:Oxidative Stress; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases