Activated monocyte-derived macrophages (MDM) contribute to the COVID-19 cytokine storm by releasing massive amounts of pro-inflammatory cytokines. CCL , CC- chemokine ligand; CXCL10, CXC- chemokine ligand 10; ISG, interferon- stimulated gene; ITAM, immunoreceptor tyrosine- based activation motif; TRAM, TRIF- related adaptor molecule. Monocytes differentiate into pro-inflammatory macrophages though activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways. Activated natural killer (NK) cells and T cells further promote the recruitment and activation of monocyte-derived macrophages through the production of granulocyte–macrophage colony- stimulating factor (GM- CSF), tumor necrosis factor (TNF) and interferon-γ (IFNγ). Oxidized phospholipids (OxPLs) accumulate in infected lungs and activate MDMs through the Toll- like receptor 4 (TLR4)–TRAF6–NF-κB pathway. Virus sensing can trigger TLR7 activation through viral single-stranded RNA recognition. Type-I INF might induce the expression of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) entry receptors (ACE2, CD147), enabling the virus to access the macrophage cytoplasm and activate the NLRP3 inflammasome, leading to the secretion of IL-1β and/or IL-18. The engagement of Fcγ receptors (FcγRs) by anti-spike protein IgG immune complexes can contribute to increased inflammatory activation of MDMs
Coronavirus Vaccines Pathway
Unprecedented efforts are being made to develop a safe and effective vaccine against SARS-CoV-2.More than 90 vaccines are being developed against SARS-CoV-2 by research teams in companies and universities across the world. All vaccines aim to expose the body to an antigen that won’t cause disease, but will provoke an immune response that can block or kill the virus if a person becomes infected. There are at least eight types being tried against the coronavirus, and they rely on different viruses or viral parts (colored bars). These include 1) virus-based, live attenuated (weakened) or inactivated, 2) viral-vector based, replication and non-replicating (e.g. S protein expressing), 3) Protein-based (e.g. S protein and subunits) and virus-like particles (VLPs), 4) Nucleic acid based, DNA-based, and RNA-based vaccines.
Toll-like receptors (TLRs) play a pivotal role in the initiation of anti-infectious immune responses. Distinct pathogen-associated molecular patterns (PAMPs) are recognized by different TLRs, at the cell surface or in endosomes. TLR7 and TLR8 are endosomal receptors that share structural homology and sense viral single stranded (ss) RNA. The endosomal distribution of TLR7 and TLR8 allows them to scan for the presence of viral RNA in the phagocytic cargo. Their activation leads to NF-κB-, AP1- and IRF-mediated production of type-I IFNs (IFN-α/β) and pro-inflammatory cytokines. After cellular detection of the viral entry into a host cell, interferon (IFN) induction of interferon stimulated genes (ISGs) is essential for host antiviral defense. Recently it was found that ISGs are upregulated in ACE2 expressing cells, and in particular that IFN-alpha drives ACE2 expression. As SARS-CoV-S leads to ACE2-receptor-mediated internalization, the host IFN response could thus promote the ability for SARS-CoV and SARS-CoV-2 to maintain cellular targets in neighboring human upper airway epithelial cells.
Interactive HER_ErbB Pathway
Her/ErbB receptor tyrosine kinases are activated upon ligand binding and dimerization. They signal through Akt, MAPK, and other pathways to regulate proliferation, differentiation, apoptosis, migration, and motility. Reduced ErbB signaling is linked to neurodegenerative diseases such as multiple sclerosis and Alzheimer's. Cancers associated with mutation or increased expression of Her/ErbBs include lung, breast, stomach, colorectal, head and neck, and pancreatic cancers
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