Tryptophan catabolism reflects disease activity in human tuberculosis
Jeffrey M. Collins, … , Henry M. Blumberg, Thomas R. Ziegler
Jeffrey M. Collins, … , Henry M. Blumberg, Thomas R. Ziegler
Published May 5, 2020
Citation Information: JCI Insight. 2020;5(10):e137131. https://doi.org/10.1172/jci.insight.137131.
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Research Article Infectious disease Metabolism

Tryptophan catabolism reflects disease activity in human tuberculosis

Abstract

There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1–mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.

Authors

Jeffrey M. Collins, Amnah Siddiqa, Dean P. Jones, Ken Liu, Russell R. Kempker, Azhar Nizam, N. Sarita Shah, Nazir Ismail, Samuel G. Ouma, Nestani Tukvadze, Shuzhao Li, Cheryl L. Day, Jyothi Rengarajan, James C.M. Brust, Neel R. Gandhi, Joel D. Ernst, Henry M. Blumberg, Thomas R. Ziegler

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Figure 3

Tryptophan catabolism in persons with multidrug-resistant pulmonary TB disease in South Africa.

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Tryptophan catabolism in persons with multidrug-resistant pulmonary TB d...
(A) The plasma K/T ratio was significantly higher in South African multidrug-resistant TB (MDR-TB) patients with (n = 64) and without (n = 21) HIV coinfection versus controls (n = 57). (B) In MDR-TB patients with plasma samples available for the duration of the 2-year treatment period (12 HIV positive, 5 HIV negative), the plasma K/T ratio significantly declined at both 12- to 15-month and 21- to 27-month time points relative to baseline. The red line indicates the trend of the mean over time. (C) The ROC curve for the plasma K/T ratio demonstrated excellent classification accuracy for identification of pulmonary TB in South Africa. The plasma K/T ratio in active TB cases was compared with controls using a Wilcoxon rank-sum test, and changes relative to baseline were compared using a Wilcoxon signed-rank test (*P ≤ 0.05, and ***P < 0.001). The AUC for the ROC curve was calculated using logistic regression with 2-fold crossvalidation. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range.