July 1, 2021
Given the mitcochondrial dysfunction obeserved in COVID-19, I have turned my attention towards liver kinase B1 (LKB1). This kinase is intimately involved with both ATP production, T-cell development, peripheral T-cell homeostasis, and T-cell effector function.
I believe SARS-CoV-2 is epigenetically impairing LKB1. LKB1-deficient T cells exhibited defects in cell proliferation and viability and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4+ and CD8+ T cells.
LKB1 was recently found to have prominent roles in hematopoietic stem cell viability and renewal, suggesting a prominent function for LKB1 in hematopoietic cells. These features are also observed in COVID-19. Inhibition of mTOR induces immunosuppression in transplant rejections and autoimmune disorders. Furthermore, diminished LKB1 reduced t-cell survival and TCR-induced proliferation; increased metabolism and cytokine production.
Sphingosine-1-phosphate receptor 1 (S1PR1) — a G protein-coupled receptor for the bioactive lipid sphingosine-1-phosphate (S1P) — is a crucial regulator of T cell egress from the thymus and secondary lymphoid organs. G -protein coupled receptors have been implicated in COVID-19.
Upon examination of the above evidence, I believe SARS-CoV-2 is metabolically inducing immune deficiency – both against pathogens and self-tolerance.
SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport
LKB1 and AMPK: central regulators of lymphocyte metabolism and function
The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism
Regulation and function of mTOR signalling in T cell fate decisions