LAUSR

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.