Salmonella Typhimurium hijacks a host glucose transporter for intravacuolar proliferation.

Salmonella is an intracellular pathogen that can reside within a vacuole, which protects it from cytosolic host defenses at the expense of limited nutrient access. Glucose serves as a critical carbon source supporting Salmonella's intracellular replication. However, the molecular mechanisms driving glucose uptake of host cells and the pathways by which cytosolic glucose becomes accessible to intravacuolar Salmonella remain poorly understood. Here, we elucidate a three-pronged strategy through which Salmonella Typhimurium (S. Typhimurium) exploits Glut1 to co-opt host glucose metabolism for pathogenic advantage. Firstly, S. Typhimurium infection upregulates the glucose transporter Glut1 by activating the MAPK signaling cascade, enhancing host glucose uptake, and accelerating glycolytic flux. Secondly, S. Typhimurium utilizes Glut1 to the bacterial vacuolar membrane to establish a glucose-import conduit that facilitates bacterial acquisition of cytosolic glucose. Thirdly, K29-linked ubiquitination on bacterial vacuolar membranes is a previously unrecognized regulatory mechanism that potentiates Glut1 transporter activity. Inhibition of Glut1 potentiates S. Typhimurium-triggered innate immune responses and attenuates bacterial virulence in vitro and in vivo. Collectively, these findings delineate a novel paradigm of metabolic hijacking, wherein S. Typhimurium systematically rewires host glucose metabolic networks to support intracellular proliferation, providing new insights into host-directed antimicrobial interventions.