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Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection

Abstract

Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-γ (IFN-γ) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-γ abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-γ neutralization after influenza infection. Direct inoculation of IFN-γ can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-γ, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.

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Figure 1: Influenza infection inhibits initial resistance of mice to pneumococcal infection.
Figure 2: Influenza infection impairs alveolar macrophage–mediated bacterial uptake.
Figure 3: IFN-γ expressed after influenza virus infection inhibits initial bacterial clearance in the lung.
Figure 4: Regulatory role of IFN-γ on alveolar macrophage function.
Figure 5: T cell activation after influenza virus infection inhibits initial bacterial clearance in the lung.
Figure 6: IFN-γ neutralization following viral infection restores innate immunity to pneumococci.

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Acknowledgements

This work was supported by US National Institutes of Health grant RO1 AI41715. We thank J. Zhang and G. Kirimanjeswara for critical reading of the manuscript. Pneumococcal strain A66.1 was provided by D. Briles, University of Alabama at Birmingham. Pneumococcal strain D39 is provided by J. Zhang, Albany Medical College. Clodronate was a gift from Roche Diagnostics. We also thank the Center for Immunology and Microbial Disease Immunology Core Laboratory for experimental assistance.

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K.S. performed the experimental work and D.W.M. supervised the project. The manuscript was written by K.S. and D.W.M.

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Correspondence to Dennis W Metzger.

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Sun, K., Metzger, D. Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection. Nat Med 14, 558–564 (2008). https://doi.org/10.1038/nm1765

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