NADPH Oxidase Inhibitor Treatment Protects Mice from Being Killed by Pneumonia

Influenza sufferers who develop methicillin-resistant Staphylococcus aureus (MRSA) pneumonia often die from damage caused to their lungs by reactive oxygen species released from necrotic inflammatory cells.

Clinical post-influenza Staphylococcus aureus pneumonia is characterized by extensive lung inflammation associated with severe morbidity and mortality even after appropriate antibiotic treatment. Investigators at the University of Nebraska Medical Center (Omaha, USA) had shown previously that mice infected with influenza were susceptible to MRSA because the ability of their macrophages and neutrophils to kill bacteria by releasing hydrogen peroxide and other reactive oxygen species was suppressed. However, it remained unclear why MRSA-infected influenza patients often died, even after receiving an appropriate antibiotic treatment.

In the current study, which was published in the August 15, 2016, online edition of The Journal of Experimental Medicine, the investigators found that antibiotics rescued nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2)-deficient mice but failed to fully protect wild type animals from influenza and S. aureus co-infection.

Results indicated that the inefficacy of antibiotics against co-infection was attributable to oxidative stress–associated inflammatory lung injury. However, Nox2-induced lung damage during co-infection was not associated with aggravated inflammatory cytokine response or cell infiltration but rather was caused by reduced survival of myeloid cells. Specifically, oxidative stress increased necrotic death of inflammatory cells, thereby resulting in lethal damage to surrounding tissue.

These results demonstrated that influenza infection disrupted the delicate balance between Nox2-dependent antibacterial immunity and inflammation. This disruption led to not only increased susceptibility to S. aureus infection, but also extensive lung damage. Combination treatment of antibiotic and NADPH oxidase inhibitor significantly improved animal survival from co-infection.

"Our results demonstrate that influenza infection disrupts the delicate balance between Nox2-dependent antibacterial immunity and inflammation," said first author Dr. Keer Sun, assistant professor of pathology and microbiology at the University of Nebraska Medical Center. "This not only leads to increased susceptibility to MRSA infection but also extensive lung damage. Treatment strategies that target both bacteria and reactive oxygen species may significantly benefit patients with influenza-complicated MRSA pneumonia."

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