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. 2021 Jan 23;149:112007. doi: 10.1016/j.fct.2021.112007

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Fig. 1 — Putative immunotoxic mechanism of SARS-CoV-2 and OPs at sub-cellular moiety.

Exposure to SARS-CoV-2 (left panel): SARS-CoV-2 invades host cell via S1/ACE-2 interaction and replicates using replication transcription complex (RCT) within the cytosolic moiety. S1 of spike protein or viral ds/sRNA binds with respective cell surface or endosomal Toll-like receptor (TLR) to fuel downstream signaling cascades involved in activation of NF-kB and synthesis of proinflammatory cytokines. Pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) are recognized by NLRP3 to induce pyroptosis of infected cells. Several viral proteins viz. NSP1, NSP3, ORF3b, ORF6 and PL-pro target JAK/STAT and RIG-1 pathways to dwarf interferon (IFN)-mediated anti-viral immune response. M protein blocks mitochondrial antiviral signaling protein (MAVS)-dependent activation of kinases to down-regulate IFN production. NSP1 also degrades various host mRNAs, some of them may be crucial for immune reaction against SARS-CoV-2.

Exposure to OP (right panel): Being lipophilic in nature, OP crosses cell membrane and passes through phase-I detoxification machinery to generate massive reactive oxygen species (ROS). Excess ROS and subsequent oxidative stress is the major driver of immunotoxicity. ROS inhibits phosphatases to enhance production of pro-inflammatory cytokines. ROS also stabilizes hypoxia-inducible factor 1-alpha (HIF-1α) by oxidizing prolyl-hydroxylase (PHD) to transcribe vascular endothelial growth factor (VEGF) involved in airway inflammation, airway hyper-responsiveness and lymphocyte dysfunction. ROS induced lipid peroxidation, protein degradation and DNA damage simultaneously trigger necroinflammation. OP activates suppressor of cytokine signaling-3 (SOCS3) to disrupt JAK/STAT mediated anti-viral immune response. Disruption of mitochondrial boundary is promoted by apoptosis signal regulating kinase 1 (ASK-1) which remains inactive as long as it is bound to thioredoxin. ROS oxidizes thioredoxin to encourage apoptosome or inflammasome mediated cellular demise.