Mycobacterium tuberculosis (Mtb) infection can lead to tuberculosis (TB) disease, causing ~ 9 million new infections and ~ 1.5 million deaths globally, every year. The resurgence of TB in the last two decades can be attributed to the failure of the anti-TB vaccine, Bacille Calmette-Guerin (BCG) in containing adult, pulmonary TB as well, the emergence of drug-resistance and the AIDS pandemic. The failure to control TB stems from the lack of complete understanding of the virulence and pathogenesis programs utilized by this highly specialized and successful pathogen to persist in the lungs of its hosts. A large volume of data points to the fact that as part of its virulence cycle, Mtb modulates host immunity. However, the true scope of these processes may yet not have been uncovered. This failure is directly related to the inability of the often-used experimental models of TB to accurately recapitulate human TB. In-vitro and classical rodent models fail to generate the true breadth of in-vivo stresses encountered by Mtb within human lungs as part of its life cycle, fail to model latency characterized by paucibacillary infection, or various progression to pathology and disease. We have developed a robust macaque model of TB and TB/AIDS co-infection, by using natural routes of Mtb infection and by using Simian Immunodeficiency Virus (SIV) as a surrogate for HIV. This model can be leveraged to study the physiology of Mtb in a true in-vivo setting. Furthermore, correlates of reactivation due to HIV co-infection as well as protection due to BCG vaccination could be studied using our model. Our preliminary data indicates that the expression of INDO (IDO1) is dramatically enhanced in classical granuloma lesions present in the lungs of two faithful models of human TB lesions, namely the rhesus macaques as well as the Krasnik mice. Furthermore, at least in NHP lesions, the expression of IDO1 is confined to the macrophage rich inner and not the lymphocyte rich outer-region of the lesion. IDO1 encodes for indoleamine 2,3, dioxygenase, a tryptophan catabolic enzyme. IDO1 is a powerful immunosuppressant of activated CD4+ T cells. Thus, based on the available data and literature, we hypothesize that IDO1 is responsible for keeping activated CD4+ T cells away from the center of the granuloma, where Mtb infected macrophages as well as extracellular Mtb are present. These T cells can eliminate infection, and thus we further hypothesize that their special demarcation away from the lesion-center allows Mtb to persist and survive within host lungs. This specialized inner ring distribution of IDO1 expression indicates that active Mtb infection programs infected and bystander macrophages to prevent activated CD4+ T cells from accessing the pathogen infected regions of the granuloma. We will utilize macrophage culture model and banked samples to study the role of IDO1 in immunosuppressing Th1 responses to Mtb infection and in the persistence of the pathogen. Unraveling this potential mechanism of latency may pave the way for the development of host directed immunotherapies adjunctive to anted TB chemotherapy.
The expression of INDO (IDO1), a powerful immunosuppressant of activated CD4+ T cells is dramaticallyenhancedinclassicalTBgranulomalesions.WehypothesizethatIDO1isresponsibleformaintainingactivatedCD4+Tcells,whicharecapableofeliminatinginfection,andhencebyextension,allowingMtbtopersistandsurvivewithinhostlungs.
|Gautam, Uma S; Foreman, Taylor W; Bucsan, Allison N et al. (2018) In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 115:E62-E71|