Tryptophan catabolism reflects disease activity in human tuberculosis
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
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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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 5

The plasma K/T ratio is increased in persons with LTBI and normalizes with latent TB treatment.

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The plasma K/T ratio is increased in persons with LTBI and normalizes wi...
(A) Kenyan household contacts (n = 30) and US refugees (n = 28) with LTBI had a significantly higher plasma K/T ratio compared with Kenyan household contacts testing negative for latent TB (n = 39). (B) In persons treated for latent TB with 3 months of weekly isoniazid and rifapentine (3HP; n = 28), the plasma K/T ratio decreased in a stepwise fashion 3 and 6 months after treatment start and remained significantly lower after 9 and 12 months compared with baseline. The red line indicates the trend of the mean over time. (C) Although the plasma K/T ratio was similar at baseline for Kenyan contacts and US refugees with LTBI, it was significantly lower 6 and 12 months after starting 3HP treatment in the US refugee cohort. Cohorts with LTBI were compared with each other and to uninfected controls using a Wilcoxon rank-sum test. For the latent TB treatment cohort, each treatment time point was compared with baseline using a Wilcoxon signed-rank test (*P ≤ 0.05, and **P < 0.01). 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.