Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection
Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra
Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra
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Research Article Immunology Infectious disease

Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection

Abstract

Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis–specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.

Authors

Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra

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Figure 2

IDO activity/expression in D1MT+cART-treated relative to cART-treated M. tuberculosis/SIV–coinfected untreated and SIV monoinfected RMs.

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IDO activity/expression in D1MT+cART-treated relative to cART-treated M....
(A–F) Lung sections were stained for IDO1 and DAPI. The representative confocal images of the lung granulomas of the D1MT+cART-treated (A and B), cART-treated (C and D), and untreated (E and F) macaques showing IDO1 (green) and nuclei (gray) captured at ×10 (A, C, and E) and ×20 (B, D, and F) magnification. The whole tissue images were subsequently quantified using HALO software for IDO expression. Graph shows IDO1 expression in granulomas of D1MT+cART-treated, cART-treated, and untreated macaques (G). Immunofluorescence was also performed on BAL single-cell suspension collected on a slide surface using cytospin at wk11 (before D1MT treatment) and wk15 after infection (at the end of D1MT treatment) with Kyn antibody and DAPI. Representative confocal images (×20 magnification) showing kynurenine (red) and nucleus (blue) in BAL cells at pretreatment time point — i.e., wk11 (H and I) — and at the end of D1MT treatment — i.e., wk15 (J and K) — in the untreated and D1MT+cART groups. Twelve random fields/animal in each group were and quantified using ImageJ (Fiji) software. (L) Graph depicting the percentages of Kyn+ cells present in BAL pre- and post-D1MT treatment. (M) K/T ratios for D1MT+cART-treated, cART-treated, untreated, and SIV-only infected RMs at pretreatment, post-D1MT treatment, and endpoint. Scale bars: 200 μm (×10 magnification; A, C, and E), 100 μm (×20 magnification; B, D, F, and H–K). P values are indicated above the plots as obtained from 1-way ANOVA (G) and 2-way ANOVA (L and M). Data are represented as mean ± SEM.