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Immunometabolism at the interface between macrophages and pathogens

Nature Reviews Immunology volume 19, pages 291–304 (2019)Cite this article

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Abstract

It is generally regarded that the progression of an infection within host macrophages is the consequence of a failed immune response. However, recent appreciation of macrophage heterogeneity, with respect to both development and metabolism, indicates that the reality is more complex. Different lineages of tissue-resident macrophages respond divergently to microbial, environmental and immunological stimuli. The emerging picture that the developmental origin of macrophages determines their responses to immune stimulation and to infection stresses the importance of in vivo infection models. Recent investigations into the metabolism of infecting microorganisms and host macrophages indicate that their metabolic interface can be a major determinant of pathogen growth or containment. This Review focuses on the integration of data from existing studies, the identification of challenges in generating and interpreting data from ongoing studies and a discussion of the technologies and tools that are required to best address future questions in the field.

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Fig. 1: Phenotypic characteristics of the M1-like and M2-like macrophage polarization states.
Fig. 2: Modulation of macrophage metabolism by microbial mediators.
Fig. 3: The links between macrophage phenotype and S. Typhimurium physiology.
Fig. 4: The links between macrophage phenotype and the progression of Mycobacterium tuberculosis infection in non-human primates and mice.
Fig. 5: Technologies and tools for investigating the metabolic interplay between host and pathogen.

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Acknowledgements

D.G.R., L.H. and B.C.V. acknowledge the support of the National Institutes of Health, USA, and the Bill and Melinda Gates Foundation.

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Nature Reviews Immunology thanks K. Fitzgerald, C. Sassetti and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    David G. Russell, Lu Huang & Brian C. VanderVen

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  1. David G. Russell
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D.G.R. researched data for the article. All authors contributed to discussing content and writing and editing the manuscript.

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Glossary

Foamy macrophages

Macrophages with cytosolic lipid droplets containing cholesterol, cholesterol ester and triacylglycerol, which are frequently induced by chronic pro-inflammatory stimuli.

M1 and M2 macrophages

M1 and M2 are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with IFNγ and lipopolysaccharide) or as anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo, macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Dual RNA sequencing

(Dual RNA-seq). A transcriptional profiling technique that enables simultaneous acquisition of the expression levels of mRNA transcripts in both the host cell and the pathogen.

Tricarboxylic acid cycle

(TCA cycle). Also known as the citric acid cycle or Krebs cycle. This is a series of enzymatic reactions used in aerobic metabolism to release energy through the oxidation of acetyl-CoA to yield ATP and carbon dioxide.

Succinate dehydrogenase complex

(SDH complex). An enzyme complex found in bacterial cells and in the inner mitochondrial membrane of eukaryotic mitochondria that is active in both the tricarboxylic acid cycle and the electron transport chain.

Bipartite metabolism

A metabolic programme whereby one carbon source is used exclusively as an energy supply while another carbon source, or sources, is used for anabolic processes.

Auxotrophic

Bacteria that are unable to synthesize all of the compounds required for growth are auxotrophic, meaning that they are dependent on their hosts to supply those compounds they cannot synthesize.

Oxygen consumption rate

(OCR). The total oxygen utilization capacity of a biological system under examination against time.

Spare respiratory capacity

(SRC). The difference in the amount of ATP generated by oxidative phosphorylation at basal rate and at maximal respiratory capacity.

Aerobic glycolysis

The conversion of glucose to lactate under conditions where oxygen is present at non-limiting concentrations.

Type IV secretion system

An ATP-dependent bacterial transporter complex that is frequently used to inject bacterial effector proteins or bacterial DNA into eukaryotic and prokaryotic target cells.

Mitochondrial fusion and fission

The fusion or fragmentation of mitochondria in a highly controlled manner, which can regulate the oxidative phosphorylation capacity of eukaryotic cells.

Fitness reporter organisms

Bacterial reporter strains, usually encoding a fluorescent protein-based readout, that are used to assess bacterial fitness with respect to responsiveness to noxious stimuli and replicative capacity.

Ribosomal RNA correlates

Sequences encoding a destabilized or short-lived green fluorescent protein are inserted into ribosomal RNA loci to provide a correlate of ribosomal RNA activity and bacterial replication.

pH-sensitive green fluorescent protein

A green fluorescent protein derivative that exhibits a shift in fluorescence emission wavelength in a pH-dependent manner.

Fluorescence dilution reporter strain

A bacterial strain that can be induced to transiently express a fluorescent protein, which can then be quantified as it becomes diluted when the bacteria divide to infer bacterial replication rates.

TIMER

A re-engineered red fluorescent protein that undergoes a conformational shift, and hence a change in fluorescence emission wavelength, as it ages, thus providing a correlate of replication rates.

‘Clock’ plasmid

An episomal plasmid encoding an antibiotic-resistance marker that is lost from a bacterial population at a fixed rate directly proportional to the rate of replication.

Chromosomal replication complex reporter

A single-stranded DNA-binding protein–green fluorescent protein fusion complex that persists for the duration of chromosomal replication and can be used to assess the replication status of a bacterial population.

Environmentally responsive promoter reporter

A dual-fluorescent bacterial reporter strain that expresses one fluorescent protein constitutively and the other fluorescent protein under the control of promoters that are responsive to specific environmental stimuli.

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Russell, D.G., Huang, L. & VanderVen, B.C. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol 19, 291–304 (2019). https://doi.org/10.1038/s41577-019-0124-9

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