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Review
. 2022 Oct 13:13:923024.
doi: 10.3389/fimmu.2022.923024. eCollection 2022.

Biting the hand that feeds: Metabolic determinants of cell fate during infection

Affiliations
Review

Biting the hand that feeds: Metabolic determinants of cell fate during infection

Isabella Fraschilla et al. Front Immunol. .

Abstract

Metabolic shifts can occur in cells of the innate immune system in response to microbial infection. Whether these metabolic shifts benefit host defense and propagation of an immune response appears to be context dependent. In an arms race, host-adapted microbes and mammalian cells vie for control of biosynthetic machinery, organelles, and metabolites. Herein, we discuss the intersection of host metabolism and cell-intrinsic immunity with implications for cell fate during infection. Sensation of microbial ligands in isolation results in host metabolic shifts that imbues normal innate immune function, such as cytokine secretion. However, living microbes have an arsenal of effectors and strategies to subvert cell-intrinsic immune responses by manipulating host metabolism. Consequently, host metabolism is monitored as an indicator of invasion or manipulation by a pathogen, primarily through the actions of guard proteins and inflammasome pathways. In this review, we frame initiation of cell-intrinsic immunity in the context of host metabolism to include a physiologic "Goldilocks zone" of allowable shifts with guard circuits monitoring wide perturbations away from this zone for the initiation of innate immune responses. Through comparison of studies with purified microbial ligands, dead microbes, and live pathogens we may begin to understand how shifts in metabolism determine the outcome of host-pathogen interactions.

Keywords: cell fate decisions; cell-intrinsic immunity; guard theory; host-pathogen arms race; inflammasome; inflammation; metabolism; pathogenesis.

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Conflict of interest statement

The reviewers MG and XZ declared a shared parent affiliation with the authors to the handling editor at the time of review.

Figures

Figure 1
Figure 1
A Goldilocks zone of physiologic shifts in metabolic activity with guard circuits surveying wide perturbations. (A) Low concentration of a monitored metabolite or metabolic activity can lead to increased cell-intrinsic immunity through inflammasome activation in the case of low hexokinase (HK) activity or IFN production and ISG expression in low cholesterol biosynthesis. (B) Physiological range of host-adaptive changes in metabolite concentration and metabolic activity does not preclude cell-intrinsic immunity through orthogonal inflammasome activation such as monitoring for direct microbial ligands. (C) High concentration of a monitored metabolite or metabolic activity can lead to increased cell-intrinsic immunity through inflammasome activation in the case of high hexokinase (HK) activity or cholesterol accumulation. (D) A Goldilocks zone of allowed host-adaptive changes in metabolite concentration and metabolic activity without incurring cell-intrinsic immune responses such as inflammasome activation.
Figure 2
Figure 2
Guard circuits sense metabolic perturbations and activate inflammasome pathways. (A) Inhibition of glycolysis via hexokinase 2 (HK2) recognition of bacterial N-acetyl glucosamine (NAG) or activation of glycolysis via increased hexokinase 1 (HK1) activity result in NLRP3 inflammasome activation. (B) Increased production of reactive oxygen species (ROS) metabolites activates the NLRP3 inflammasome, such as through the generation of oxidized lipids, and directly promotes gasdermin D (GSDMD) pore formation. (C) Alterations to homeostatic cholesterol levels can result in lysosomal or mitochondrial dysfunction that results in inflammasome activation or type I interferon (IFN) production.
Figure 3
Figure 3
Host-adapted delivery of potentially toxic metabolites for control of intracellular pathogens. Sensation of PAMPs, cytokines, and IFNs can promote cell-intrinsic immune responses such as generation of antimicrobial metabolites. Upregulation of NOS2 can produce NO radicals from the amino acid Arginine. TLR driven mitochondrial ROS (mtROS) or phagocytosis- and BAI1-induced NADPH oxidase production of ROS. ROS can cooperate with low pH environment created by pumping H+ ions into the vesicle lumen via the action of v-ATPase to form hydrogen peroxide and hypochlorous acid. Accumulation of TCA intermediates based on break in the TCA cycle in activated macrophages allows for Irg1 production of anti-microbial itaconate that can be delivered to a pathogen-containing phagosome via RAB32.

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