RLG in Virus and COVID: Restoring GSH and Immune Function

A block in the function of GSH-producing enzymes occurs during viral infections and diabetes. ReadiSorb® Liposomal Glutathione (RLG) can bypass these blocks, restoring GSH levels in both serum and cells.

Key observations:

1. Viruses deplete glutathione (GSH) to facilitate replication.
2. Respiratory viruses block NRF2, a key regulator of GSH production. Examples include:
   1. SARS-CoV-2, Influenza, RSV
   1. HIV also blocks NRF2 function
3. Maintaining GSH with RLG in macrophages (PBMC) supports immune defense against bacteria and viruses.
4. Diabetes depletes GSH by impairing GSH-forming enzymes. RLG restores GSH in such conditions.

These observations are detailed in the studies cited below.

I. Viral Respiratory Disease

Beginning in 2020, three articles examined the loss of GSH in COVID-19 and observed that viruses deplete glutathione to facilitate replication (1-3): (1) Guloyan 2020, (2) Yegiazaryan 2022, (3) Glassman 2023

These articles identified various mechanisms of GSH loss during viral infections, including the loss of function of GSH-forming enzymes. A 2023 study further showed that GSH depletion in COVID-19 is caused by the loss of NRF2 function, an intracellular regulator of GSH production (4) Qu 2023. NRF2 dysfunction has also been observed in Influenza (5) Rashid 2022, Respiratory Syncytial Virus (RSV) (6) Komaravelli 2017, and HIV (7) Fan 2021. The loss of NRF2 function results in the reduced production of enzymes necessary for GSH synthesis. The role of the loss of NRF2 function in the Pathogenesis of Viral Respiratory Infections is summarized in an article (1) Daskou 2023.

Loss of NRF2 function or deficiency increases reactive oxygen species (ROS) and causes redox imbalance due to lower GSH levels (14) Reddy 2007. NRF2 function is also discussed in Guloyan 2020 (1)- search "NRF2".

When NRF2 function is blocked, RLG is able to bypass this block in GSH production, restoring glutathione levels and immune cell function. This has been demonstrated in two clinical studies involving individuals with HIV, which blocks NRF2 (8) Ly 2015, (9) Valivia 2017. Additionally, a 2024 animal study showed that RLG bypassed the NRF2 block caused by RSV, significantly reducing lung damage (10) Gauthier 2024.

The studies conducted in individuals with HIV demonstrated that their immune cells (PBMC, which are precursors to macrophages in tissues) do not function normally. This was evidenced by their inability to defend against the bacteria Mycobacterium tuberculosis when introduced to the PBMC ex vivo during the study (8) Ly 2015, (9) Valivia 2017.

During infection with SARS-CoV-2, the virus that causes COVID-19, there is an elevation of immune hormones called cytokines and an increase in thrombosis (clotting), resulting in a condition known as immunothrombosis (3) Glassman 2023. A cell study demonstrated that RLG can prevent immune inflammation and clotting (immunothrombosis) caused by the introduction of the SARS-CoV-2 spike protein to normal immune cells (PBMC) (11) Norris 2024.

II. Diabetes

When glucose levels rise enough to push HbA1c above 6.5%, a threshold associated with diabetes, the function of GSH-forming enzymes becomes blocked (12) Lagman 2015.

A study conducted on individuals with Type 2 Diabetes Mellitus (T2DM) demonstrated that RLG can bypass these enzyme blocks (13) To 2021. RLG restores GSH levels in both cells and serum under these conditions and also reestablishes macrophage defense against bacterial infections (13) To 2021.

References

1. Guloyan V, Oganesian B, Baghdasaryan N, Yeh C, Singh M, Guilford F, et al. Glutathione Supplementation as an Adjunctive Therapy in COVID-19. Antioxidants (Basel). 2020;9(10). PMCID: PMC7601802. https://www.ncbi.nlm.nih.gov/pubmed/32992775
2. Yegiazaryan A, Abnousian A, Alexander LJ, Badaoui A, Flaig B, Sheren N, et al. Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19. Int J Mol Sci. 2022;23(16). PMCID: PMC9409103. https://www.ncbi.nlm.nih.gov/pubmed/36012562
3. Glassman I, Le N, Mirhosseini M, Alcantara CA, Asif A, Goulding A, et al. The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review. Front Biosci (Landmark Ed). 2023;28(3):59. PMCID: PMC10406467. https://www.ncbi.nlm.nih.gov/pubmed/37005767
4. Qu Y, Haas de Mello A, Morris DR, Jones-Hall YL, Ivanciuc T, Sattler RA, et al. SARS-CoV-2 Inhibits NRF2-Mediated Antioxidant Responses in Airway Epithelial Cells and in the Lung of a Murine Model of Infection. Microbiol Spectr. 2023;11(3):e0037823. PMCID: PMC10269779. https://www.ncbi.nlm.nih.gov/pubmed/37022178
5. Rashid MU, Gao A, Coombs KM. Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response. J Virol. 2022;96(5):e0199021. PMCID: PMC8906419. https://www.ncbi.nlm.nih.gov/pubmed/35019712
6. Komaravelli N, Ansar M, Garofalo RP, Casola A. Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway. Free Radic Biol Med. 2017;113:494-504. PMCID: PMC5699968. https://www.ncbi.nlm.nih.gov/pubmed/29107745
7. Fan X, Murray SC, Staitieh BS, Spearman P, Guidot DM. HIV Impairs Alveolar Macrophage Function via MicroRNA-144-Induced Suppression of Nrf2. Am J Med Sci. 2021;361(1):90-7. PMCID: PMC7854972. https://www.ncbi.nlm.nih.gov/pubmed/32773107
8. Ly J, Lagman M, Saing T, Singh MK, Tudela EV, Morris D, et al. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals. J Interferon Cytokine Res. 2015;35(11):875-87. PMCID: PMC4642835. https://www.ncbi.nlm.nih.gov/pubmed/26133750
9. Valdivia A, Ly J, Gonzalez L, Hussain P, Saing T, Islamoglu H, et al. Restoring Cytokine Balance in HIV-Positive Individuals with Low CD4 T Cell Counts. AIDS Res Hum Retroviruses. 2017;33(9):905-18. PMCID: PMC5576219. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576219/
10. Gauthier TW, Ping X-D, Harris FL, Brown LAS. Liposomal Glutathione Augments Immune Defenses against Respiratory Syncytial Virus in Neonatal Mice Exposed in Utero to Ethanol. Antioxidants. 2024;13(2):137. https://www.mdpi.com/2076-3921/13/2/137
11. Norris B, Chorbajian A, Dawi J, Mohan AS, Glassman I, Ochsner J, et al. Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation. Antioxidants. 2024;13(3):271. https://www.mdpi.com/2076-3921/13/3/271
12. Lagman M, Ly J, Saing T, Kaur Singh M, Vera Tudela E, Morris D, et al. Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One. 2015;10(3):e0118436. PMCID: PMC4366217. https://www.ncbi.nlm.nih.gov/pubmed/25790445
13. To K, Cao R, Yegiazaryan A, Owens J, Nguyen T, Sasaninia K, et al. Effects of Oral Liposomal Glutathione in Altering the Immune Responses Against Mycobacterium tuberculosis and the Mycobacterium bovis BCG Strain in Individuals With Type 2 Diabetes. Front Cell Infect Microbiol. 2021;11:657775. PMCID: PMC8211104. https://www.ncbi.nlm.nih.gov/pubmed/34150674
14. Reddy N, kleeberger S, Cho H, Yamamoto M. Deficiency in Nrf2-GSH Signaling Impairs Type II Cell Growth and Enhances Sensitivity to Oxidants. Am J Respir Cell Mol Biol. 2007 Apr 5;37(1):3–8. PMCID: https://pmc.ncbi.nlm.nih.gov/articles/PMC1899352/#abstract1