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Klebsiella pneumoniae  is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating  K .  pneumoniae  clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with  K .  pneumoniae  by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 ( Ifnar1 )-deficient mice infected with  K .  pneumoniae  failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in  Ifnar1 -deficient hosts by  Ifnar1 -proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of  Ifnar1 -deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of  K .  pneumoniae  clearance, and reveal specific targets for future therapeutic exploitations.

Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection