Universität zu Köln

Gutierrez, Saray, Fischer, Julia ORCID: 0000-0001-6138-7454, Ganesan, Raja, Hos, Nina Judith, Cildir, Goekhan, Wolke, Martina, Pessia, Alberto, Frommolt, Peter, Desiderio, Vincenzo, Velagapudi, Vidya and Robinson, Nirmal ORCID: 0000-0002-7361-9491 (2021). Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense. PLoS Pathog., 17 (9). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gutierrez, Saray UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Julia UNSPECIFIED orcid.org/0000-0001-6138-7454 UNSPECIFIED Ganesan, Raja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hos, Nina Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Cildir, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolke, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pessia, Alberto UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommolt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Desiderio, Vincenzo UNSPECIFIED UNSPECIFIED UNSPECIFIED Velagapudi, Vidya UNSPECIFIED UNSPECIFIED UNSPECIFIED Robinson, Nirmal UNSPECIFIED orcid.org/0000-0002-7361-9491 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-591179
DOI:	10.1371/journal.ppat.1009943
Journal or Publication Title:	PLoS Pathog.
Volume:	17
Number:	9
Date:	2021
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DENDRITIC CELL; GLUCOSE-METABOLISM; ACTIVATION; INFECTION; LYSOSOMES; MECHANISM; ALDOLASE; FUSION; GROWTH; DEATH Multiple languages Microbiology; Parasitology; Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59117