Cysteamine-mediated blockade of the glycine cleavage system modulates epithelial cell inflammatory and innate immune responses to viral infection

Fraser-Pitt, Douglas; Mercer, Derry K.; Francis, Marie-Louise; Toledo-Aparicio, David; Smith, Daniel W.; O'Neil, Deborah A.

Abstract

Transient blockade of glycine decarboxylase (GLDC) can restrict de novo pyrimidine synthesis, which is a well-described strategy for enhancing the host interferon response to viral infection and a target pathway for some licenced anti-inflammatory therapies. The aminothiol, cysteamine, is produced endogenously during the metabolism of coenzyme A, and is currently being investigated in a clinical trial as an intervention in community acquired pneumonia resulting from viral (influenza and SARS-CoV-2) and bacterial respiratory infection. Cysteamine is known to inhibit both bacterial and the eukaryotic host glycine cleavage systems via competitive inhibition of GLDC at concentrations, lower than those required for direct antimicrobial or antiviral activity. Here, we demonstrate for the first time that therapeutically achievable concentrations of cysteamine can inhibit glycine utilisation by epithelial cells and improve cell-mediated responses to infection with respiratory viruses, including human coronavirus 229E and Influenza A. Cysteamine reduces interleukin-6 (IL-6) and increases the interferon-λ (IFN-λ) response to viral challenge and in response to liposomal polyinosinic:polycytidylic acid (poly I:C) simulant of RNA viral infection.

Citation

Fraser-Pitt, D., Mercer, D. K., Francis, M., Toledo-Aparicio, D., Smith, D. W., & O'Neil, D. A. (2023). Cysteamine-mediated blockade of the glycine cleavage system modulates epithelial cell inflammatory and innate immune responses to viral infection. Biochemical and Biophysical Research Communications, 677, 168-181. https://doi.org/10.1016/j.bbrc.2023.08.021

• Journal Article Type: Article
• Acceptance Date: Aug 9, 2023
• Online Publication Date: Aug 15, 2023
• Publication Date: Oct 15, 2023
• Deposit Date: May 10, 2024
• Journal: Biochemical and Biophysical Research Communications
• Print ISSN: 0006-291X
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 677
• Pages: 168-181
• DOI: https://doi.org/10.1016/j.bbrc.2023.08.021
• Public URL: https://keele-repository.worktribe.com/output/825199
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0006291X23009592?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Cysteamine-mediated blockade of the glycine cleavage system modulates epithelial cell inflammatory and innate immune responses to viral infection; Journal Title: Biochemical and Biophysical Research Communications; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bbrc.2023.08.021; Content Type: article; Copyright: © 2023 NovaBiotics Ltd. Published by Elsevier Inc.