Small molecule-directed immunotherapy against recurrent infection by Mycobacterium tuberculosis.
Tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. Current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. Therefore, alternate methods to treat tuberculosis are urgently needed. Mycobacterium tuberculosis evades host immune responses by inducing T helper (Th)2 and regulatory T (Treg) cell responses, which diminish protective Th1 responses. Here, we show that animals (Stat-6(-/-)CD4-TGFβRIIDN mice) that are unable to generate both Th2 cells and Tregs are highly resistant to M. tuberculosis infection. Furthermore, simultaneous inhibition of these two subsets of Th cells by therapeutic compounds dramatically reduced bacterial burden in different organs. This treatment was associated with the generation of protective Th1 immune responses. As these therapeutic agents are not directed to the harbored organisms, they should avoid the risk of promoting the development of drug-resistant M. tuberculosis variants.
From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
Debapriya
D
Bhattacharya
From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
Ved Prakash
VP
Dwivedi
the Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21231-1001, and.
Mamoudou
M
Maiga
the Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21231-1001, and.
Mariama
M
Maiga
the Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Luc
L
Van Kaer
the Center for Tuberculosis Research, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21231-1001, and.
William R
WR
Bishai
From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa, gobardhan.das07@gmail.com.
Gobardhan
G
Das
D000818:Animals; D005434:Flow Cytometry; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
Immunology; Immunotherapy; Interleukin; Mycobacterium tuberculosis; T Cell