Salmonellahijacks a host glucose transporter for intravacuolar proliferation

Salmonellais an intracellular pathogen that resides within a vacuole, which protects it from cytosolic host defenses at the expense of limited nutrient access. Glucose serves as a critical carbon source supportingSalmonella’s intracellular replication. However, the molecular mechanisms driving glucose enhancement and the pathways by which cytosolic glucose becomes accessible to intravacuolarSalmonellaremain poorly understood. Here, we elucidate a sophisticated three-pronged strategy through whichSalmonellahijacks GLUT1 to co-opt host glucose metabolism for pathogenic advantage. Firstly,Salmonellainfection upregulates the glucose transporter GLUT1 by activating the MAPK signaling cascade, enhancing host glucose uptake, and accelerating glycolytic flux. Secondly,Salmonellaredirects GLUT1 to the bacterial vacuolar membrane to establish a glucose-import conduit that facilitates bacterial acquisition of cytosolic glucose. Thirdly, K29-linked ubiquitination modifications on bacterial vacuolar membranes are a previously unrecognized regulatory mechanism that potentiates GLUT1 transporter activity. Inhibition of GLUT1 potentiatesSalmonella-triggered innate immune responses and attenuates bacterial virulencein vitro(RAW264.7 macrophages) andin vivo(murine infection model). Collectively, these findings delineate a novel paradigm of metabolic hijacking, whereinSalmonellasystematically rewires host glucose metabolic networks to support intracellular proliferation, providing new insights into host-directed antimicrobial interventions.