Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion
Jason D. Simmons, … , W. Henry Boom, Thomas R. Hawn
Jason D. Simmons, … , W. Henry Boom, Thomas R. Hawn
Published June 10, 2021
Citation Information: J Clin Invest. 2021;131(14):e140073. https://doi.org/10.1172/JCI140073.
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Research Article Immunology Infectious disease

Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion

Abstract

After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion.

Authors

Jason D. Simmons, Phu T. Van, Catherine M. Stein, Violet Chihota, Thobani Ntshiqa, Pholo Maenetje, Glenna J. Peterson, Anthony Reynolds, Penelope Benchek, Kavindhran Velen, Katherine L. Fielding, Alison D. Grant, Andrew D. Graustein, Felicia K. Nguyen, Chetan Seshadri, Raphael Gottardo, Harriet Mayanja-Kizza, Robert S. Wallis, Gavin Churchyard, W. Henry Boom, Thomas R. Hawn

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Figure 1

Comparison of RSTR and LTBI gene expression in whole blood and monocytes from Ugandan household Mtb contacts and from gold miners in South Africa.

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Comparison of RSTR and LTBI gene expression in whole blood and monocytes...
RNA from whole blood of Ugandan and South African donors was analyzed by RNAseq. (A and B) Differential gene expression between RSTR and LTBI donors were compared after exclusion of the indicated samples. (C and D) CD14+ monocytes were purified from cryopreserved PBMCs and differentiated in M-CSF for 48 hours before RNA isolation and sequencing. In Uganda, 50 subjects were included in both analyses (26 RSTR, 24 LTBI), while additional unique subjects were included in the monocyte (12 RSTR and 16 LTBI) and whole blood (5 RSTR and 4 LTBI) analyses. In South Africa, 39 of 40 subjects included in the whole blood analysis were also included in the monocyte analysis. Volcano plots identify no single genes that were significantly (FDR < 0.2) differentially expressed between RSTR and LTBI subjects in either population in the whole blood (B) and monocyte (D) analyses.