Challenges of Multidrug-Resistant Tuberculosis Meningitis: Current Treatments and the Role of Glutathione as an Adjunct Therapy

Abstract

Multidrug-resistant tuberculosis (MDR-TB) poses a significant global health threat, especially when it involves the central nervous system (CNS). Tuberculous meningitis (TBM), a severe manifestation of TB, is linked to high mortality rates and long-term neurological complications, further exacerbated by drug resistance and immune evasion mechanisms employed by Mycobacterium tuberculosis (Mtb). Although pulmonary TB remains the primary focus of research, MDR-TBM introduces unique challenges in diagnosis, treatment, and patient outcomes. The effectiveness of current treatments is frequently compromised by poor CNS penetration of anti-TB drugs and the necessity for prolonged therapy, which often involves considerable toxicity. This review explores the potential of cytokine-based adjunct immunotherapies for MDR-TBM, addressing the challenges of balancing pro-inflammatory and anti-inflammatory signals within the CNS. A central focus is the prospective role of glutathione, not only in reducing oxidative stress but also in enhancing host immune defenses against Mtb's immune evasion strategies. Furthermore, the development of vaccines aimed at upregulating glutathione synthesis in macrophages represents a promising strategy to bolster the immune response and improve treatment outcomes. By integrating glutathione and innovative vaccine approaches into MDR-TBM management, this review proposes a comprehensive strategy that targets Mtb directly while supporting immune modulation, with the potential to enhance patient outcomes and reduce treatment related adverse effects. We underscore the urgent need for further research into adjunctive therapies and immunomodulatory strategies to more effectively combat MDR-TBM.

Keywords: adjunct therapy; antioxidants; central nervous system; cytokines; glutathione; immune modulation; immune response; multidrug-resistant tuberculosis; mycobacterium tuberculosis; oxidative stress; therapeutic strategies; tuberculosis; tuberculosis meningitis; vaccines.

Figure 1

The role of cytokines in modulating immune response and Mtb susceptibility. Macrophages, which can differentiate into pro-inflammatory (M1) or anti-inflammatory (M2) subtypes, play a critical role in TBM by interacting with T cell subsets, including Th1, Th2, and regulatory T (Treg) cells. M1 macrophages are key for eliminating Mtb in the central nervous system, while M2 macrophages support tissue repair and regulate inflammation. Th1 cells, through cytokines such as IFN-γ, activate M1 macrophages to enhance the clearance of Mtb. In contrast, Th2 cells secrete cytokines like IL-4 and IL-13, promoting M2 macrophage polarization to facilitate tissue repair. Treg cells, by producing cytokines like IL-10 and TGF-β, help control excessive inflammation and maintain immune homeostasis.

Figure 2

The Protective Role of Glutathione in TBM. This figure illustrates the mechanisms by which antioxidants contribute to host defense against Mtb infection. Antioxidants protect against oxidative stress, enhance phagocytic activity, and balance cytokine levels, all of which are crucial for effective immune responses.