Toll\like receptors (TLRs) are by viral RNA (TLR3) and viral unmethylated CpG\DNA (TLR9) leading to substantial cellular signaling pathways and activation of MSCs

Toll\like receptors (TLRs) are by viral RNA (TLR3) and viral unmethylated CpG\DNA (TLR9) leading to substantial cellular signaling pathways and activation of MSCs.50 MSCs can play an important role in Immunomodulation by downregulating expression of anti\inflammatory factors such as prostaglandin E2 (PGE\2) and programmed death\ligand 1(PD\L1).25 Their paracrine activity can restore the metabolic capacity of alveolar macrophages through direct transfer of their functional mitochondria and switch of inflammatory phenotype (M1) to anti\inflammatory (M2).51, 52 They also have a protective effect against oxidative stress associated with lung inflammation by releasing antioxidant enzymes such as; catalase, superoxide dismutase, and glutathione peroxidase.20 MSCs treatment has shown a significant inhibition in virus\induced proinflammatory cytokines.53 The immune system homeostasis and immunosuppression activities of MSCs are depend on (1) regulating metabolism; (2) expression of CD73, an ATPase with ectonucleotidase property which involves in cell proliferation; (3) induction of mature Dendritic cells (DCs) into novel Jagged\2 dependent regulatory DCs; (4) regulation of immune cell function.10, 25, 45, 54 Moreover, MSCs have anti\virus activity by expressing Interferon\stimulated genes such as interferon induced transmembrane family (IFITM), spermine N1\acetyltransferase 1(SAT1), and interferon alpha inducible protein 6 (IFI6).50 MSCs repair and regenerate damaged lung tissue by increasing the expression of IL\10 and vascular endothelial growth factor (VEGF) which benefits for ARDS patients as an inflammatory disease.55 MSCs also have therapeutic effects on other organs. of Covid\19. of 40\150 nm that are produced by cells in their interior, more precisely in the endosomal compartments of most eukaryotic cells.13 It was found that MSCs produce exosomes with significant immunomodulatory capacity for tissue restoration. These properties of MSC\ES have been considered the basis for current on\going clinical trials.14 Many of these MSC\Es contains Dryocrassin ABBA microRNAs (miRNAs) that regulate crucial cellular functions including cell growth, apoptosis, Dryocrassin ABBA and host immune responses.15, 16 It has been proposed that MSC\Es represent an ideal vector for the delivery of targeted anti\viral drugs for the treatment of Covid\19.17 2.?PATHOGENICITY OF SARS\CoV\2 The cell entry mechanism of SARS\CoV\2 is a subject of interest of recent studies. Angiotensin\converting enzyme 2 (ACE\2) and C\type 209 lecithin (CD209L) act as Dryocrassin ABBA the main host receptors for binding the S protein of the virus, becoming the first stage of the pathogenesis of Covid\19. The virus enters the host cell either via infusion with the host plasma membrane or via clathrin\dependent and independent endocytosis.18, 19 It has also been reported that transmembrane protease serine 2 (TMPRSS2) facilitates virus entry into the host cell.20 The RNA virus itself, after entering into the cell, promotes disruption in host cell immunity.21 It has been shown that all three types of viral proteins (structural, non\structural, and accessory) have various regulatory impacts on the host cell,22 Structural and functional proteins of SARS\CoV\2 independently reduce the synthesis of host cell proteins and subsequently decrease the production of interferons (IFN) which GATA3 significantly impairs the host cell adaptive immune response. Current evidence suggests this is via three mechanisms; (1) Non\structural protein 16 (NSP16) suppresses mRNA splicing and diminishes recognition of viral RNA by intracellular helicase receptors, (2) NSP1 acts as a ribosome gatekeeper to impair cellular translation and specifically promotes viral translation, (3) NSP8, and NSP9 interfere with protein trafficking to the cell membrane.23, 24 ACE\2, the SARS\CoV\2 receptor, is widely expressed in human organs such as the heart, kidney, gut, liver, and brain which can become involved in systemic infection.25, 26, 27 The lungs are one of the most commonly affected organ in Covid\19 infection and this is partly explained by the high level of expression of ACE\2, in alveolar type II and capillary endothelial cells. Proposed mechanisms for viral\induced lung injury include \ direct injury to the vascular bed and in particular, the capillary endothelial cells that also involves disruption to the renin\angiotensin system (RAS) and a fulminant inflammatory response that results in the breakdown of capillary integrity in targeted organs and the progression to the acute respiratory distress syndrome (ARDS), acute lung injury (ALI), fibrosis, and multiple organ failure.20, 28, 29, 30 In addition to the lung, other organs involved include the heart and presentations with Kawasaki syndrome, acute coronary syndrome, coagulopathies, myocarditis, the brain and cerebrovascular accidents (CVAs) and focused areas of neuro\inflammation and acute kidney and renal failure, the gut and gastrointestinal alterations, the liver and acute liver injury and hepatic dysfunction.31, 32, 33, 34, 35 During infection, neutrophils, monocytes, and T cells are recruited to the site of infection by following the chemoattractant gradient of inflammatory chemokines and chemokines produced by infected cells.36 Under severe conditions, lymphocyte and leukocyte counts decrease, whereas inflammation marker (C\reactive protein), lactic dehydrogenase, proinflammatory cytokines and chemokines (interleukin (IL) 1, IL\6, IL\7, IL\2, tumor necrosis factor (TNF), granulocyte\colony stimulating factor (GCSF), interferon gamma\induced protein\10 (CXCL10), and monocyte chemoattractant protein\1) are elevated dramatically.37, 38, 39 The production of large amounts of proinflammatory cytokines by inflammatory cells leads to cytokine storm resulting in hyperinflammation and subsequently serious lung damage.37, 40 3.?COMBATING COVID\19 Currently, a small number of therapeutics such as remdesivir, dexamethasone and bamlanivimab plus etesevimab have already been authorized based on the results of randomised controlled trials (RTCs). Further RCTs of therapeutic candidates, including inhaled interferon\beta, baricitinib, tocilizumab, sarilumab, casirivimab plus imdevimab, and tofacitinib all report clinical benefit.41, 42 It is now well recognised that patients recovering from acute Covid\19 infection are susceptible to develop what is termed long\Covid syndrome. It is estimated that 1:10 individuals are at\risk of persistent disabling symptoms, particularly related to the brain and the lungs, long after the acute infective episode has subsided.43 It has been postulated that in response to.