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

Saray Gutiérrez,Alberto Pessia,Raja Ganesan,Nina Judith Hos,Gökhan Cildir,Vidya Velagapudi,Julia Fischer,Vincenzo Desiderio,Peter Frommolt,Nirmal Robinson,Martina Wolke,Nina R Salama

doi:10.1371/journal.ppat.1009943

Abstract

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.

Highlights

Macrophages are sentinel immune cells playing pivotal roles in the host defense
Downregulation of glycolysis leads to reduced acidification of phagosomes resulting in impaired bacterial clearance and antigen presentation
We show that downregulation of glycolysis by direct chemical inhibition or by genetically disrupting insulin-signaling in myeloid cells leads to elevated bacterial burden and impaired antigen presentation as a result of reduced acidification of phagosomes

Summary

Introduction

Macrophages are sentinel immune cells playing pivotal roles in the host defense. They engulf and degrade the pathogens, and secrete cytokines and present antigens to T cells to mount an effective adaptive immune response [1]. Several pathogens such as Salmonella enterica serovar Typhimurium Transfer of IFN-I receptor (IFNAR)-deficient or RIP3 kinase-deficient macrophages (that are cell death resistant) to wild type (WT) mice promotes better control of the pathogen implying that metabolically stable macrophages are more efficient in the control of pathogens [2]

Results

Discussion

Conclusion