Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages

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Abstract

How Mycobacterium tuberculosis (Mtb) rewires macrophage energy metabolism to facilitate survival is poorly characterized. Here, we used extracellular flux analysis to simultaneously measure the rates of glycolysis and respiration in real-time. Mtb infection induced a quiescent energy phenotype in human monocyte-derived macrophages and decelerated flux through glycolysis and the TCA cycle. In contrast, infection with the vaccine strain, M. bovis BCG, or dead Mtb induced glycolytic phenotypes with greater flux. Furthermore, Mtb reduced the mitochondrial dependency on glucose and increased the mitochondrial dependency on fatty acids, shifting this dependency from endogenous fatty acids in uninfected cells to exogenous fatty acids in infected macrophages. We demonstrate how quantifiable bioenergetic parameters of the host can be used to accurately measure and track disease, which will enable rapid quantifiable assessment of drug and vaccine efficacy. Our findings uncovered new paradigms for understanding the bioenergetic basis of host metabolic reprogramming by Mtb.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

Bridgette M Cumming

Africa Health Research Institute, Durban, South Africa

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6977-765X
Kelvin W Addicott

Africa Health Research Institute, Durban, South Africa

Competing interests
The authors declare that no competing interests exist.
John H Adamson

Africa Health Research Institute, Durban, South Africa

Competing interests
The authors declare that no competing interests exist.
Adrie JC Steyn

Africa Health Research Institute, Durban, South Africa

For correspondence
adrie.steyn@ahri.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9177-8827

Funding

National Institutes of Health (R01AI111940)

Adrie JC Steyn

U.S. Department of Defense (PR121320)

Adrie JC Steyn

National Institutes of Health (R21127182)

Adrie JC Steyn

South African Medical Research Council

Adrie JC Steyn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human monocytes were isolated from buffy coats bought from the South African National Blood Service with approval from SANBS Human Research Ethics Committee (Clearance Certificate No. 2016/02)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.