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Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy
Bindu Singh, … , Xavier Alvarez, Smriti Mehra
Bindu Singh, … , Xavier Alvarez, Smriti Mehra
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e163101. https://doi.org/10.1172/jci.insight.163101.
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Research Article Immunology Infectious disease

Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy

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Abstract

The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.

Authors

Bindu Singh, Chivonne Moodley, Dhiraj K. Singh, Ruby A. Escobedo, Riti Sharan, Garima Arora, Shashank R. Ganatra, Vinay Shivanna, Olga Gonzalez, Shannan Hall-Ursone, Edward J. Dick Jr., Deepak Kaushal, Xavier Alvarez, Smriti Mehra

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Figure 3

Inclusion of D1MT adjunctive to ME treatment results in better control of M. tuberculosis infection with complete clearance of bacilli.

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Inclusion of D1MT adjunctive to ME treatment results in better control o...
(A–E) M. tuberculosis burdens were assessed in BAL collected at various time points during the study timeline and at the endpoint. (A) Graph shows log M. tuberculosis CFU/mL of BAL in the 3 study groups at time points ranging from preinfection to the end of treatment. Gray area represents whole treatment period, whereas black dotted line shows end of D1MT treatment time point. Graphical representations of log CFU/mL of BAL (B), log CFU/g of lung (C), log CFU/g of granulomas (D), and log CFU/g of bronchial lymph nodes (E) obtained at endpoint/necropsy from macaques belonging to the 3 study groups. D1MT treatment led to complete clearance of M. tuberculosis from tissues. Further, lung tissues and granulomas obtained were assessed for sterility by using Fischer’s sterility test, to determine the sterile and nonsterile (in terms of M. tuberculosis presence) lung lobes and granulomas in ME and ME/D1MT groups. The graphs (F and G) depict the number of sterile (samples recording 0 CFUs) lung lobes and granulomas, respectively, among the 2 selected groups. H&E staining was performed on lung tissues obtained from all RMs at the endpoint. (H) Shown are representative images of H&E staining of lung from each group. Scale bars, 1 mm. H&E-stained lung sections were then scanned using Zeiss Axio Scan Z1 slide scanner and were used to quantify the lung area involved in inflammation or granulomatous lesions using HALO analysis software. (I) The graph depicts differences in the percentage lung involvement among the groups. For accurate depiction of 0 on log scale, a numeric value of 1 CFU was added to all CFU values before transforming them into log values, so that we have a value for 0 CFU or nondetectable CFU. P values are indicated above the plots as obtained from 1-way ANOVA (B–E) with Tukey’s multiple-comparison test, contingency χ2 (and Fisher’s exact) test (F and G) to compare number of sterile (samples recording 0 CFUs) lung lobes (F) and granulomas (G) between the groups using 2×2 contingency tables, and Kruskal-Wallis test (I). Data are represented as mean ± SEM.

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