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

• Published in: The Journal of clinical investigation 2021-07, Vol.131 (14)
• Main Authors: Simmons, Jason D, Van, Phu T, Stein, Catherine M, Chihota, Violet, Ntshiqa, Thobani, Maenetje, Pholo, Peterson, Glenna J, Reynolds, Anthony, Benchek, Penelope, Velen, Kavindhran, Fielding, Katherine L, Grant, Alison D, Graustein, Andrew D, Nguyen, Felicia K, Seshadri, Chetan, Gottardo, Raphael, Mayanja-Kizza, Harriet, Wallis, Robert S, Churchyard, Gavin, Boom, W Henry, Hawn, Thomas R
• Format: Article
• Language: English
• Subjects: Adult; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Humans; Interferon-gamma Release Tests; Latent Tuberculosis - diagnosis; Latent Tuberculosis - metabolism; Male; Middle Aged; Monocytes - metabolism; Mycobacterium tuberculosis - metabolism; Polymorphism, Single Nucleotide; Transcription, Genetic; Tuberculin Test; U937 Cells
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI140073

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.