Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects’ blood was drawn pre- and post- L-GSH/ or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.
Highlights
Mycobacterium tuberculosis (M. tb), the etiological agent for tuberculosis (TB) caused 1.5 million deaths and 10 million active cases of disease in the year 2018 [1].This work is licensed under the Creative Commons AttributionKimberly To et al: The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering The Immune ... 17According to the World Health Organization (WHO), 1.2 million deaths from the 1.5 million total were from HIVnegative people, and about 251,000 deaths were from HIVpositive people [1]
When compared to untreated Peripheral Blood Mononuclear Cells (PBMCs), in vitro everolimus treatment resulted in a 50% reduction in the viability of BCG (Figure 2)
PBMCs isolated from individuals with type 2 diabetes at pre- and post- L-GSH/or placebo supplementation were infected in vitro with BCG and treated in vitro with everolimus (1nM) and terminated at 8 days (Figure 3A, C, E, G) or 15 days (Figure 3B, D, F, H) post-infection
Summary
Mycobacterium tuberculosis (M. tb), the etiological agent for tuberculosis (TB) caused 1.5 million deaths and 10 million active cases of disease in the year 2018 [1].This work is licensed under the Creative Commons AttributionKimberly To et al: The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering The Immune ... 17According to the World Health Organization (WHO), 1.2 million deaths from the 1.5 million total were from HIVnegative people, and about 251,000 deaths were from HIVpositive people [1]. Despite the availability of anti-TB drugs and the attenuated BCG vaccine, there is no significant drop in the number of TB cases [1]. Immunocompromised individuals such as HIV patients, diabetics, those in the condition of undernutrition, smokers, and individuals with heavy alcohol consumption are more susceptible to an active TB infection [1]. HIV patients and individuals with type 2 diabetes (T2DM) are at 19 times and 3 times higher risk for developing active TB than healthy individuals, respectively [2]. T2DM is characterized by hyperglycemia caused by insulin resistance and accounts for 90-95% of the total prevalence of diabetes [3]
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