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 3

Gene sets derived from FFA-stimulated macrophages are consistently enriched among RSTR donors across the Ugandan and South African cohorts.

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Gene sets derived from FFA-stimulated macrophages are consistently enric...
Gene sets related to a variety of macrophage stimuli were obtained from previously published weighted gene coexpression analysis (WGCNA) modules (33). Enrichment among RSTR vs. LTBI transcriptomes in any of these 49 WGCNA modules was analyzed using CAMERA gene set enrichment (30). (A) All modules with significant enrichment in South Africa were also enriched in Uganda (FDR < 0.001). (B) The correlation plot compares P values from CAMERA enrichment scores in Uganda (x axis) versus South Africa (y axis) and indicates the corresponding direction of enrichment with RSTR phenotype (red) or LTBI phenotype (blue). This enrichment direction among Ugandan monocyte donors (color of data point) and among South African monocyte donors (color of module number) is highly concordant. Gene sets that correlate to macrophage FFA stimulations (Set 27, Set 6, Set 24, Set 26) were enriched among RSTR donors in Uganda and South Africa.