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The strategies deployed by antibiotic‐resistant bacteria to counteract host defences are poorly understood. Here, we elucidate a novel host–pathogen interaction resulting in skewing lung macrophage polarisation by the human pathogen Klebsiella pneumoniae. We identify interstitial macrophages (IMs) as the main population of lung macrophages associated with Klebsiella. Single‐cell transcriptomics and trajectory analysis of cells reveal type I IFN and IL10 signalling, and macrophage polarisation are characteristic of infected IMs, whereas Toll‐like receptor (TLR) and Nod‐like receptor signalling are features of infected alveolar macrophages. Klebsiella‐induced macrophage polarisation is a singular M2‐type we termed M(Kp). To rewire macrophages, Klebsiella hijacks a TLR‐type I IFN‐IL10‐STAT6 axis. Absence of STAT6 limits Klebsiella intracellular survival and facilitates the clearance of the pathogen in vivo. Glycolysis characterises M(Kp) metabolism, and inhibition of glycolysis results in clearance of intracellular Klebsiella. Capsule polysaccharide governs M(Kp). Klebsiella also skews human macrophage polarisation towards M(Kp) in a type I IFN‐IL10‐STAT6‐dependent manner. Klebsiella induction of M(Kp) represents a novel strategy to overcome host restriction, and identifies STAT6 as target to boost defences against Klebsiella. Synopsis: Klebsiella pneumoniae exemplifies the threat of antibiotic resistant infections to public health. How Klebsiella adapts to the immune system to flourish in tissues such as the airways remains poorly understood. Here, Klebsiella skews lung macrophages to a new state to overcome host restriction. Lung interstitial macrophages are permissive for Klebsiella whereas alveolar macrophages are restrictive.Klebsiella polarizes lung macrophages to a singular M2‐type we termed M(Kp).Hypervirulent and multidrug resistant strains induce M(Kp).Klebsiella hijacks a TLR‐type I IFN‐IL10‐STAT6 axis to skew macrophages.Absence of STAT6 facilitates the clearance of Klebsiella in vivo. [ABSTRACT FROM AUTHOR]

Undoubtedly, vaccination is one of the health interventions showing major impact on humankind. Vaccines remain one of the most effective and safest ways to tackle infections. The current coronavirus pandemic is not an exception, and we all hope that ongoing international efforts will succeed in developing a vaccine soon. In this scenario, the present work published in this edition of EMBO Molecular Medicine by Demminger and colleagues (Demminger et al, 2020) is timeliness to exemplify the steps needed to develop effective vaccines. [ABSTRACT FROM AUTHOR]