Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection
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
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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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 8

Metabolites enhance the expansion of memory-like NK cells and cytokine production.

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Metabolites enhance the expansion of memory-like NK cells and cytokine p...
PBMCs from LTBI+ donors (n = 6) were labeled with CFSE and cultured with or without γ-M. tuberculosis. Some wells were supplemented with metabolites that were highly enriched in the plasma of nonconverters (4-hydroxypyridine, deoxycorticosterone acetate, dl-methionine sulfoxide, l-kynurenine, l-α-glycerophosphocholine, and d-sedoheptulose 7-phosphate, each 100 μM). After 5 days, the proliferation of memory NK cells was measured by flow cytometry. (A) A representative flow cytometry plot is shown. NK cells were identified by sequential gating on the lymphocytic singlet population and then on CD3−CD56+ NK cells. The events within the gated CD3–CD56+ NK cells were analyzed for CFSE+ cells and plotted in dot plots. (B) The total absolute number of CFSE+CD3–CD56+CD27+ cells is shown. (C) Absolute number of proliferating CD3–CD56+CD27+ cells. (D) Absolute number of proliferating CD3–CD56+CD27+CCR7+ cells. (E) Absolute number of proliferating CD3–CD56+CD27+CCR7– cells. (F) Absolute number of proliferating CD3+ T cells. (G) In the above panels, after 5 days, the supernatants were aspirated, and cytokine and chemokine production was measured by multiplex ELISA. The P values were derived using an unpaired 2-tailed independent t test. The mean values, SDs, and P values are shown.