Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection
Deepak Tripathi, … , Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
Deepak Tripathi, … , Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e152357. https://doi.org/10.1172/jci.insight.152357.
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Research Article Immunology

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Abstract

To determine the mechanisms that mediate resistance to Mycobacterium tuberculosis (M. tuberculosis) infection in household contacts (HHCs) of patients with tuberculosis (TB), we followed 452 latent TB infection–negative (LTBI–) HHCs for 2 years. Those who remained LTBI– throughout the study were identified as nonconverters. At baseline, nonconverters had a higher percentage of CD14+ and CD3–CD56+CD27+CCR7+ memory-like natural killer (NK) cells. Using a whole-transcriptome and metabolomic approach, we identified deoxycorticosterone acetate as a metabolite with elevated concentrations in the plasma of nonconverters, and further studies showed that this metabolite enhanced glycolytic ATP flux in macrophages and restricted M. tuberculosis growth by enhancing antimicrobial peptide production through the expression of the surface receptor sialic acid binding Ig-like lectin–14. Another metabolite, 4-hydroxypyridine, from the plasma of nonconverters significantly enhanced the expansion of memory-like NK cells. Our findings demonstrate that increased levels of specific metabolites can regulate innate resistance against M. tuberculosis infection in HHCs of patients with TB who never develop LTBI or active TB.

Authors

Deepak Tripathi, Kamakshi Prudhula Devalraju, Venkata Sanjeev Kumar Neela, Tanmoy Mukherjee, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Igor Dozmorov, Abhinav Vankayalapati, Mohammad Soheb Ansari, Varalakshmi Mallidi, Anvesh Kumar Bogam, Karan P. Singh, Buka Samten, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati

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Figure 1

Study design and conversion of LTBI– individuals to LTBI+ individuals in a cohort of HHCs of patients with TB.

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Study design and conversion of LTBI– individuals to LTBI+ individuals in...
(A) Schematic representation of the experimental design and conversion of LTBI– HHCs (n = 452) of patients with TB into LTBI+ (converters) and remaining LTBI– (nonconverters) at 24 months of follow-up. (B) Immune cell populations in the peripheral blood mononuclear cells (PBMCs) of M. tuberculosis–exposed HHCs of patients with TB. PBMCs were isolated from age-matched, epidemiological risk–matched, healthy (no comorbid conditions and not on any immunosuppressive drugs) converters (n = 96) and nonconverters (n = 293) at baseline (during the enrollment of the study, when all participants were healthy and LTBI–, and after 24 months), and the percentages of CD4+, CD4+CD25+FoxP3+, CD56+CD16+, CD3–CD56+CD27+, CD3–CD56+CD27+CCR7+, CD14+CD16+, and CD16+ cells were determined by flow cytometry. The P values were determined by repeated measures mixed effects ANOVA followed by post hoc Tukey’s multiple comparisons test. Mean values, SDs, and P values are shown. Baseline, 0 months: at the time of recruitment; follow-up: 24 months after enrollment in the study.