Thursday, November 21, 2024
11/21/2024
Project Summary: Tuberculous Meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB) and is associated with significant morbidity and mortality in humans worldwide. Individuals with TBM show a marked deficiency in the levels of glutathione (GSH), the principal non-protein thiol responsible for cellular homeostasis and maintaining the intracellular redox balance. Since the current anti-TB regimen is formulated for pulmonary TB, they are not optimal for treating TBM. Thus, adjunctive immunotherapy is a promising approach to improving the clinical outcome of refractory mycobacterial infections in these cases. We have reported that GSH has direct antimycobacterial activity in vitro and at physiological concentrations. In combination with cytokines such as IL-2 and IL-12, GSH enhances the functional activity of natural killer (NK) cells to inhibit the growth of Mycobacterium tuberculosis (Mtb) inside human monocytes. Similarly, GSH activates the functions of T lymphocytes to control Mtb infection inside human monocytes. In our previous R15 award, we demonstrated that GSH deficiency in the lungs resulted in increased Mtb burden in the lungs and spleen. Furthermore, GSH restoration resulted in favorable immune responses in the lungs leading to improved control of Mtb infection. Importantly, we reported that GSH has additive effects in improving the ability of rifampicin (RIF) to control Mtb infection. Put together, our findings 1) unfold a novel and potentially important innate defense mechanism adopted by human macrophages to control Mtb infection and 2) indicate that GSH controls Mtb infection by functioning as an antimycobacterial agent as well as by enhancing the effector functions of immune cells. However, the underlying mechanisms by which GSH deficiency alters the immune responses leading to increased susceptibility to TBM remains unknown, and the potential use of GSH as a possible therapeutic agent for TBM remains untapped. The translational aspect of the studies proposed in this grant application may lay the foundation for the development of adjunctive pharmacotherapy to improve TBM treatment. Our long-term goals are to acquire a detailed understanding of the pathogenesis of TBM in various settings such as in pediatric subjects and in those with HIV infection and develop novel therapies to combat TBM.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
