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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

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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 6

Deoxycorticosterone acetate treatment promotes Siglec-14–dependent antibacterial activity in macrophages.

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Deoxycorticosterone acetate treatment promotes Siglec-14–dependent antib...
(A) Freshly prepared MDMs from healthy donors (n = 4) cultured in the presence or absence of γ-M. tuberculosis (10 μg/mL). Some γ-M. tuberculosis–cultured wells supplemented with metabolites were enriched in the plasma of nonconverters (4-hydroxypyridine, dl-methionine sulfoxide, l-kynurenine, l-α-glycerophosphocholine, d-sedoheptulose 7-phosphate, deoxycorticosterone acetate). After 72 hours, the expression (MFI) of Siglec-14 was determined by flow cytometry. (B) MDMs from healthy donors (n = 8) were infected at an MOI of 2.5. Some of the infected MDMs were cultured in the presence of the metabolites 4-hydroxypyridine, dl-methionine sulfoxide, l-kynurenine, l-α-glycerophosphocholine, d-sedoheptulose 7-phosphate, and deoxycorticosterone acetate (each 100 μM). Intracellular CFUs were determined at 5 days postinfection. P values were determined by unpaired 2-tailed t test. The mean ± SD is shown. (C) In the above panel, the supernatant was aspirated, and the level of HBD2 and S100A12 was determined by ELISA. P values were determined by unpaired 2-tailed t test. The mean ± SD is shown. (D) MDMs from healthy donors (n = 5) were isolated and transfected with siRNA targeting Siglec-14 or control siRNA and infected with M. tuberculosis H37Rv at an MOI of 2.5. In some M. tuberculosis–infected wells, deoxycorticosterone acetate (100 μM) was added. After 5 days, CFUs were counted. P values were determined by 1-way ANOVA with Tukey’s multiple comparisons test. Data are representative of 4 independent experiments. The mean ± SD is shown. (E) The concentrations of HBD2 and S100A12 were determined by ELISA. The P values were determined by unpaired t test. The mean ± SD is shown.

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