METABOLICALLY INDUCED IMMUNE DEFICIENCY

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.

Referenced/Related Papers

SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport

https://journals.physiology.org/doi/full/10.1152/ajplung.00499.2020

LKB1 and AMPK: central regulators of lymphocyte metabolism and function

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-065X.2012.01157.x

The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism

https://jimmunol.org/content/187/8/4187

Regulation and function of mTOR signalling in T cell fate decisions

https://www.nature.com/articles/nri3198