In COVID-19, the serine/threonine kinase mTOR (mechanisticTarget Of Rapamycin) pathways may offer valuable targets to controlcell injury, oxidative stress, and the onset of hyperinflammation.mTOR is a central regulator of inflammation within the immune system and a sensor of oxidative stress. mTOR forms two complexes:mTORC1 mediates TH1 and TH17 differentiation at the time of viralantigenic presentation by dendritic cells (DC); mTORC2 mediatesTH2 differentiation; while both complexes restrict regulatory T-cell(Treg) differentiation . With regards to T cells, mTORC1 activation isconsequence of oxidative stress, which can be blocked byN-acet-ylcysteine in Systemic Lupus Erythematosus (SLE) patients . Con-sistent with its role in pro-inflammatory T-cell differentiation, mTORC1activation is involved in SLE patients which can be blocked by rapa-mycin. In addition, mTORC1 is thus known as the rapamycin-sen-sitive complex
Cytokine storm, a hyper-inflammatory reaction in which cytokinesare produced rapidly and extensively by immune cells in reaction toendogenous or exogenous stress, is a major contributor to acuterespiratory distress syndrome and multiple organ dysfunction syndrome.In severe COVID-19 patients, IL-2, IL-6, IL-7, IL-10, TNF-α, G-CSF,IP-10, MCP-1, and MIP-1α levels increase significantly. Amongthese, several cytokines are involved in TH17 type responses. IL-1β andTNF-α (TH17 and TH1 cells highly express TNF-α), both promote TH17responses and vascular permeability and leakage. COVID-19 ex-pands TH17 cells further supporting a TH17 type cytokine storm in thisdisease. Cytokine storm may promote T-cell apoptosis, necrosis orpyroptosis, causing reduced T-cell counts.T-cell senescence is a state of T-cell dysfunction that occurs inchronic infections and cancer. In COVID-19, patients over60 years, and patients in ICU care have a decrease in CD4+, CD8+,and total T-cell numbers, and this is inversely correlated with pa-tients' survival .T cells play a vital role in viral clearance, particularly through se-cretion of cytotoxicity molecules such as perforin, granzyme and IFN-γ. However, patients with severe form of COVID-19 have less multi-functional and more non-functional CD4+ T cells, as well as highersenescent CD8+ T cells, that are unable to secrete the cytotoxicitymolecules, than patients with mild COVID-19. Also, reduced T-cellnumbers are negatively correlated with serum IL-6, IL-10 and TNF-α with higher levels of senescence markers PD-1 and Tim-3 , CTLA-4 and TIGIT . These constitute a hallmark of severe forms of COVID-19. In addition, senescent cells are known to secrete a broadspectrum of molecules such as cytokines (IL-1β, IL-6, IL-8, IL-10, IL-17,TNF-α...), chemokines, proteases and growth factors, which distinguishthem from healthy cells present within tissues . These factors re-present a typical hallmark of senescence and therefore they have beendefined as senescence-associated secretory phenotype (SASP).Taken together, T-cell senescence might be theprimum movens of cy-tokine storm in severe COVID-19.
Reference & source information: https://www.sciencedirect.com/
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