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

被引:135
作者
Gautam, Uma S. [1 ]
Foreman, Taylor W. [1 ,2 ,7 ]
Bucsan, Allison N. [1 ,2 ]
Veatch, Ashley V. [1 ]
Alvarez, Xavier [1 ]
Adekambi, Toidi [3 ]
Golden, Nadia A. [1 ]
Gentry, Kaylee M. [1 ]
Doyle-Meyers, Lara A. [1 ]
Russell-Lodrigue, Kasi E. [1 ]
Didier, Peter J. [1 ]
Blanchard, James L. [1 ]
Kousoulas, K. Gus [4 ,5 ]
Lackner, Andrew A. [1 ,2 ]
Kalman, Daniel [4 ,5 ]
Rengarajan, Jyothi [3 ]
Khader, Shabaana A. [6 ]
Kaushal, Deepak [1 ,2 ]
Mehra, Smriti [1 ,4 ,5 ]
机构
[1] Tulane Univ, Sch Med, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA
[2] Tulane Univ, Sch Med, Dept Microbiol & Immunol, New Orleans, LA 70112 USA
[3] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA
[4] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Baton Rouge, LA 70803 USA
[5] Louisiana State Univ, Sch Vet Med, Ctr Expt Infect Dis Res, Baton Rouge, LA 70803 USA
[6] Washington Univ, Dept Mol Microbiol, St Louis, MO 63130 USA
[7] NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA
关键词
macaque; tuberculosis; granuloma; IDO; T cell; T-CELL PROLIFERATION; 2,3-DIOXYGENASE-EXPRESSING DENDRITIC CELLS; HOST-DIRECTED THERAPY; INDOLEAMINE 2,3-DIOXYGENASE; RHESUS MACAQUES; SUPPRESSION; EXPRESSION; LYMPHOCYTES; ACTIVATION; RESPONSES;
D O I
10.1073/pnas.1711373114
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:E62 / E71
页数:10
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