The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes

• Published in: Biomolecular concepts Vol. 12; no. 1; pp. 16 - 26
• Main Authors: To, Kimberly, Cao, Ruoqiong, Yegiazaryan, Aram, Owens, James, Sasaninia, Kayvan, Vaughn, Charles, Singh, Mohkam, Truong, Edward, Sathananthan, Airani, Venketaraman, Vishwanath
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 09.05.2021; Walter de Gruyter GmbH
• Subjects: Administration, Oral; Adolescent; Adult; Aged; BCG Vaccine - administration & dosage; Cytokines; Cytokines - metabolism; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - immunology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - microbiology; Dietary Supplements; Double-Blind Method; Drug resistance; everolimus; Everolimus - pharmacology; Female; Glutathione; Glutathione - administration & dosage; Granuloma - immunology; Granulomas; host-directed therapies; Humans; Immune response; immune responses; Immunity; Immunosuppressive Agents - pharmacology; In Vitro Techniques; Infections; Infectious diseases; Interleukin 2; Interleukin 6; Intracellular; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - microbiology; Lymphocytes T; Male; Middle Aged; mycobacteria; Mycobacterium bovis; Mycobacterium bovis - drug effects; Mycobacterium bovis - immunology; Mycobacterium bovis - metabolism; Peripheral blood mononuclear cells; Placebos; Public health; Rapamycin; TOR protein; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - immunology; Tuberculosis - metabolism; Tuberculosis - microbiology; Tumor necrosis factor-α; Young Adult; γ-Interferon; everolimus; host-directed therapies; cytokines; diabetes; mycobacteria; Glutathione; immune responses
• ISSN: 1868-5021; 1868-5021; 1868-503X
• DOI: 10.1515/bmc-2021-0003

Tuberculosis (TB) caused by ( ) 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 infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, 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 have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within 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 glutathione (GSH) supplementation in individuals with T2DM along with 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 studies with everolimus. We found that treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with everolimus treatment produced a greater effect in inhibiting the growth of intracellular BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with 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, 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.