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. 2020 Nov 20;891:173748. doi: 10.1016/j.ejphar.2020.173748

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Fig. 5 — Evasion of host innate immune responses by SARS-CoV-2 and stimulation of host antiviral immune responses by tizoxanide (TIZ). SARS-CoV-2 entry via ACE2 is hampered by TIZ which regulates renin-angiotensin system by blocking angiotensin II binding to its receptors (AT1R and AT2R), to provide protective responses. ADAM-17 mediated ACE2 shedding is prevented by TIZ due to PDI inhibition, thus curbing lung inflammation and consequently ARDS. Upon entry, SARS-CoV-2 pathogen-associated molecular patterns (PAMPs) evades recognition by host cells pattern-recognition-receptors (PRRs), like RLRs, TLRs and NLRs, which is opposed by TIZ. These PRRs cause downstream activation of NF-κB, IRF3/7 signalling, which leads to the secretion of proinflammatory cytokines and type I-IFN respectively. Secreted IFN binds to IFN receptor activating JAK/STAT signalling, which forms a complex with IRF9 and produces interferon stimulated genes (ISGs) promoted under IFN-stimulated response element (ISRE), boosting antiviral innate immune responses, enabling virus clearance. TIZ activates Type-I IFN secretion and curb proinflammatory responses. ACE2, Angiotensin converting enzyme 2; ADAM-17, A disintegrin and metallopeptidase domain 17; ARDS, Acute respiratory distress syndrome; AT1R, Angiotensin II receptor type 1; AT2R, Angiotensin II receptor type 2; cGAS, cyclic GMP-AMP synthase; IFN, Interferon; IFNR, IFNα/β receptor; IRF3/7, Interferon regulatory factor 3/7; JAK, Janus kinase; MAVS, Mitochondrial antiviral-signalling protein; MDA5, Melanoma differentiation-associated gene 5; NF-κB, Nuclear factor-κB; NLRs, Nucleotide-binding oligomerization domain-(NOD)-like receptors; PDI, Protein disulfide isomerase; PPKRA, Phopsphorylated protein kinase receptor; RLRs, Retinoic acid-inducible gene I protein (RIG-I) like receptors; ROS, Reactive oxygen species; STAT, Signal transducer and activator of transcription; STING, stimulator of interferon genes protein; TLRs, Toll-like receptors; TRIF, TIR-domain-containing adaptor protein including IFN-β; TYK2, Tyrosine kinase 2.