Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense

Author summaryMacrophages undergo metabolic adaptations when they respond to invading pathogens. On the other hand, pathogens are also known to disrupt metabolic pathways to evade immune defense. In this study, we have employed metabolomics and transcriptomics to unravel that S. Typhimurium abrogates glycolysis and the modulators of glycolysis such as insulin-signaling. Downregulation of glycolysis leads to reduced acidification of phagosomes resulting in impaired bacterial clearance and antigen presentation. Furthermore, we provide evidence that induction of glycolysis facilitates v-ATPase assembly and the acidification of phagosomes by mobilizing aldolase to the v-ATPase complex. Our results highlight a previously unknown molecular link between metabolism and phagolysosome, which is targeted by S. Typhimurium to evade cell-autonomous defense. Regulation of cellular metabolism is now recognized as a crucial mechanism for the activation of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. Despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages upon Salmonella enterica serovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggest that S. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolysis facilitates glycolytic enzyme aldolase A mediated v-ATPase assembly and the acidification of phagosomes which is critical for lysosomal degradation. Thus, impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in murine macrophages (BMDM). Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted by S. Typhimurium to evade cell-autonomous defense.