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

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

doi:10.1172/jci140073

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.

Highlights

Tuberculosis (TB) was the leading cause of death from a single infectious agent worldwide in 2019, accounting for 1.5 million deaths [1]
We found no difference in the frequency of CD14+ cells, T cell subsets, NK cells, or B cells in PBMCs isolated from Ugandan donors when measured by flow cytometry (23 RSTR versus 23 Latent Mtb infection (LTBI) subjects, Supplemental Figure 3)
Our study suggests that RSTR and LTBI populations have distinct monocyte transcriptional profiles that relate to differences in metabolic pathways and the cellular response to free fatty acid (FFA)

Summary

Introduction

Tuberculosis (TB) was the leading cause of death from a single infectious agent worldwide in 2019, accounting for 1.5 million deaths [1]. One contributor to this burden of disease is the large reservoir of asymptomatic Mycobacterium tuberculosis (Mtb) infections that affects approximately a quarter of the world’s population [2]. Despite this prevalence, some individuals show no evidence of Mtb infection even after heavy and prolonged exposures and may be considered relatively resistant to infection [3]. Individuals who are resistant to LTBI (resisters [RSTRs]) have persistently

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