In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis

Uma S. Gautam, Taylor W. Foreman, Allison N. Bucsan, Ashley V. Veatch, Xavier Alvarez, Toidi Adekambi, Nadia A. Golden, Kaylee M. Gentry, Lara A. Doyle-Meyers, Kasi E. Russell-Lodrigue, Peter J. Didier, James L. Blanchard, K. Gus Kousoulas, Andrew A. Lackner, Daniel Kalman, Jyothi Rengarajan, Shabaana A. Khader, Deepak Kaushal, Smriti Mehra

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4+ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4+ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.

Original languageEnglish
Pages (from-to)E62-E71
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number1
DOIs
StatePublished - Jan 2 2018

Keywords

  • Granuloma
  • IDO
  • Macaque
  • T cell
  • Tuberculosis

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    Gautam, U. S., Foreman, T. W., Bucsan, A. N., Veatch, A. V., Alvarez, X., Adekambi, T., Golden, N. A., Gentry, K. M., Doyle-Meyers, L. A., Russell-Lodrigue, K. E., Didier, P. J., Blanchard, J. L., Gus Kousoulas, K., Lackner, A. A., Kalman, D., Rengarajan, J., Khader, S. A., Kaushal, D., & Mehra, S. (2018). In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 115(1), E62-E71. https://doi.org/10.1073/pnas.1711373114