Abstract
Tuberculosis (TB) remains a pervasive global health threat. A significant proportion of the world’s population that is affected by latent tuberculosis infection (LTBI) is at risk for reactivation and subsequent transmission to close contacts. Despite sustained efforts in eradication, the rise of multidrug-resistant strains of Mycobacterium tuberculosis (M. tb) has rendered traditional antibiotic therapy less effective at mitigating the morbidity and mortality of the disease. Management of TB is further complicated by medications with various off-target effects and poor compliance. Immunocompromised patients are the most at-risk in reactivation of a LTBI, due to impairment in effector immune responses. Our laboratory has previously reported that individuals suffering from Type 2 Diabetes Mellitus (T2DM) and HIV exhibited compromised levels of the antioxidant glutathione (GSH). Restoring the levels of GSH resulted in improved control of M. tb infection. The goal of this review is to provide insights on the diverse roles of TGF- β and vitamin D in altering the levels of GSH, granuloma formation, and clearance of M. tb infection. We propose that these pathways represent a potential avenue for future investigation and development of new TB treatment modalities.
Highlights
Mycobacterium tuberculosis (M. tb), the causative agent for tuberculosis (TB), is an intracellular bacterial pathogen that typically colonizes the lower respiratory tract in humans
Increased concentration of GSH has been demonstrated to promote Th1 cell differentiation via IL-12 and/or IL-27 [43]. While these cytokine responses are blunted in immunocompromised patients, Transforming growth factor β (TGF-β) and other pro-inflammatory cytokines have been found to be overexpressed in individuals with Type 2 Diabetes Mellitus (T2DM) [17]
Decreased concentrations of GSH were observed in macrophages, natural killer (NK) cells, and T cells isolated from the peripheral blood of HIV-positive patients, as compared to controls
Summary
Mycobacterium tuberculosis (M. tb), the causative agent for tuberculosis (TB), is an intracellular bacterial pathogen that typically colonizes the lower respiratory tract in humans. The transition to an interdigitated epithelioid phenotype creates a physical barrier which sequesters the pathogen at the site of infection, allowing selective monocyte infiltration of the lesion under the regulation of CD4+ lymphocytes [6] This results in the inhibition of bacterial growth and localization of the inflammatory response to the site of infection by providing a microenvironment for continuous T-cell activation of infected macrophages [6,7]. It has been shown that, in these individuals, GSH decrease is likely due to increased levels of TGF-β which has been previously demonstrated to inhibit the rate-limiting enzyme, catalytic subunit of GCL (GCLC) that is responsible for GSH synthesis [24] Another mechanism proposed to regulate GSH synthesis involves vitamin D. The immune-enhancing effects of vitamin D against M. tb infection, its interaction with TGF-β, and its modulatory effects on the levels of GSH are of great interest for investigation as an adjunct to current therapy
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