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.
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
Title and authors | Publication | Year |
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Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli
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Journal of Clinical Investigation | 2025 |
Multi-omic latent variable data integration reveals multicellular structure pathways associated with resistance to tuberculin skin test (TST)/interferon gamma release assay (IGRA) conversion in Uganda
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BMC Genomics | 2025 |
Resistance to tuberculin skin test/interferon-gamma release assay conversion among highly TB exposed, HIV infected goldminers in South Africa
Ntshiqa T, Velen K, Ginindza S, Nhlangulela L, Charalambous S, Hawn TR, Churchyard G, Boom WH, Chihota V, Wallis R |
PLOS One | 2025 |
Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli.
Schurr E, Dallmann-Sauer M, Fava V, Malherbe S, McDonald C, Orlova M, Kroon E, Cobat A, Boisson-Dupuis S, Hoal E, Abel L, Möller M, Casanova JL, Walzl G, du Plessis N |
Research square | 2024 |
Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis.
Dill-McFarland KA, Simmons JD, Peterson GJ, Nguyen FK, Campo M, Benchek P, Stein CM, Vaisar T, Mayanja-Kizza H, Boom WH, Hawn TR |
bioRxiv : the preprint server for biology | 2024 |
Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis
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Frontiers in immunology | 2024 |
Specific CD4(+) T cell phenotypes associate with bacterial control in people who 'resist' infection with Mycobacterium tuberculosis.
Sun M, Phan JM, Kieswetter NS, Huang H, Yu KKQ, Smith MT, Liu YE, Wang C, Gupta S, Obermoser G, Maecker HT, Krishnan A, Suresh S, Gupta N, Rieck M, Acs P, Ghanizada M, Chiou SH, Khatri P, Boom WH, Hawn TR, Stein CM, Mayanja-Kizza H, Davis MM, Seshadri C |
Nature Immunology | 2024 |
Epigenetic programming of host lipid metabolism associated with resistance to TST/IGRA conversion after exposure to Mycobacterium tuberculosis
Dill-McFarland KA, Simmons JD, Peterson GJ, Nguyen FK, Campo M, Benchek P, Stein CM, Vaisar T, Mayanja-Kizza H, Boom WH, Hawn TR |
mSystems | 2024 |
Immune correlates of protection as a game changer in tuberculosis vaccine development.
Wang J, Fan XY, Hu Z |
NPJ vaccines | 2024 |
Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis
Luo Y, Huang CC, Howard NC, Wang X, Liu Q, Li X, Zhu J, Amariuta T, Asgari S, Ishigaki K, Calderon R, Raman S, Ramnarine AK, Mayfield JA, Moody DB, Lecca L, Fortune SM, Murray MB, Raychaudhuri S |
Nature Communications | 2024 |
Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation.
McHenry ML, Simmons J, Hong H, Malone LL, Mayanja-Kizza H, Bush WS, Boom WH, Hawn TR, Williams SM, Stein CM |
PLoS genetics | 2023 |
Differentially expressed transcript isoforms associate with resistance to tuberculin skin test and interferon gamma release assay conversion.
Simmons JD, Segnitz RM, Dill-McFarland KA, Stein CM, Peterson GJ, Mayanja-Kizza H, Boom WH, Hawn TR |
PloS one | 2023 |
Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
Hong H, Dill-McFarland KA, Simmons JD, Peterson GJ, Benchek P, Mayanja-Kizza H, Boom WH, Stein CM, Hawn TR |
2023 | |
Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk
Nakken O, Vaage AM, Stigum H, Heldal E, Meyer HE, Holmøy T |
2023 | |
Mycobacterium tuberculosis-induced monocyte transcriptional responses associated with resistance to tuberculin skin test/interferon-gamma release assay conversion in people with HIV
HONG H, DILL-MCFARLAND KA, BENSON B, SIMMONS JD, PETERSON GJ, BENCHEK P, STEIN CM, BOOM WH, MAYANJA-KIZZA H, HAWN TR |
AIDS | 2023 |
Resistance to Mycobacterium tuberculosis infection among highly TB exposed South African gold miners
V Chihota, T Ntshiqa, P Maenetje, R Mansukhani, K Velen, T Hawn, R Wallis, A Grant, G Churchyard, K Fielding, F Quinn |
PloS one | 2022 |
Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion
Simmons JD, Dill-McFarland KA, Stein CM, Van PT, Chihota V, Ntshiqa T, Maenetje P, Peterson GJ, Benchek P, Nsereko M, Velen K, Fielding KL, Grant AD, Gottardo R, Mayanja-Kizza H, Wallis RS, Churchyard G, Boom WH, Hawn TR |
mSphere | 2022 |
Immune evasion and provocation by Mycobacterium tuberculosis
Chandra P, Grigsby SJ, Philips JA |
Nature reviews. Microbiology | 2022 |