In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of
| العنوان: | In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of |
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| المؤلفون: | 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 |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Granuloma, Macrophages, macaque, Tryptophan, T cell, Mycobacterium tuberculosis, Biological Sciences, Macaca mulatta, IDO, Immunology and Inflammation, PNAS Plus, tuberculosis, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Tuberculoma, Lung, Tuberculosis, Pulmonary, Cell Proliferation |
| الوصف: | Significance Mycobacterium tuberculosis induces the expression of the indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes tryptophan. Tryptophan metabolites potently suppress host immunity. The present study demonstrates that blockade of IDO activity reduces both clinical manifestations of tuberculosis (TB) as well as microbial and pathological correlates of the human TB syndrome in macaques. In granulomas, T cells localize in the periphery, and are unable to access the core, where bacilli persist. Inhibiting IDO activity altered granuloma organization such that more T cells translocated to the lesion core and exhibited highly proliferative signatures. Our results identify a highly efficient immunosuppressive mechanism at play in the granuloma environment that aids in M. tuberculosis persistence. The ability to modulate this pathway with safe and approved compounds could, however, facilitate chemotherapy-adjunctive host-directed therapy approaches for the control of TB. 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. |
| تدمد: | 1091-6490 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid________::f451c952bcf5daccdf1ae867ac7f80c5 https://pubmed.ncbi.nlm.nih.gov/29255022 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.pmid..........f451c952bcf5daccdf1ae867ac7f80c5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 |
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