Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia

Keer Sun, Vijaya Kumar Yajjala, Christopher Bauer, Geoffrey A Talmon, Karl J. Fischer, Tammy L Kielian, Dennis W. Metzger

Research output: Contribution to journalArticle

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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 (NAD PH) 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 NAD PH 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.

Original languageEnglish (US)
Pages (from-to)1851-1864
Number of pages14
JournalJournal of Experimental Medicine
Volume213
Issue number9
DOIs
StatePublished - Jan 1 2016

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Coinfection
NAD
Human Influenza
Pneumonia
Oxidoreductases
Oxidative Stress
Staphylococcal Pneumonia
Anti-Bacterial Agents
NADP
Staphylococcus aureus
Lung
Lung Injury
Myeloid Cells
Infection
Immunity
Cell Death
Therapeutics
Cytokines
Inflammation
Morbidity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia. / Sun, Keer; Yajjala, Vijaya Kumar; Bauer, Christopher; Talmon, Geoffrey A; Fischer, Karl J.; Kielian, Tammy L; Metzger, Dennis W.

In: Journal of Experimental Medicine, Vol. 213, No. 9, 01.01.2016, p. 1851-1864.

Research output: Contribution to journalArticle

Sun, Keer ; Yajjala, Vijaya Kumar ; Bauer, Christopher ; Talmon, Geoffrey A ; Fischer, Karl J. ; Kielian, Tammy L ; Metzger, Dennis W. / Nox2-derived oxidative stress results in inefficacy of antibiotics against post-influenza S. aureus pneumonia. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 9. pp. 1851-1864.
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