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Coronavirus Epidemics and the Current COVID-19 Pandemic
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Aparna Bhardwaj, Prateek Kumar, Shivani Krishna Kapuganti, Vladimir N. Uversky, Rajanish Giri
ORF8 is an immune evasion protein that has evolved very rapidly. The ORF8 of SARS-CoV-2 is very distinct from ORF8 of SARS-CoV, with a sequence similarity of less than 20%. ORF8 of SARS-CoV-2 interrupts IFN-I signaling and decreases the level of MHC-I cells [51]. Figure 1.3C presents structures of structural proteins, and Figures 1.3D, 1.3E, and 1.3F show three of the accessory proteins of SARS-CoV and SARS-CoV-2. Two of the accessory proteins of SARS-CoV, ORF3b, and ORF6, have been reported to act as interferon antagonists and inhibit the expression downstream, i.e., signaling for innate immunity in host cells [52]. As interferon antagonists, they block the movement of STAT1 to the nucleus. STAT1 is a signal mediator of both IFN-α and IFN-β and acts as a transactivator. Thus because of viral interference, the IFN pathway is downregulated [53]. ORF7a is a type I transmembrane protein, which induces apoptosis of host cells by inhibition of translation and suppression of the cell cycle [54]. ORF9b is translated from the bicistronic mRNA via leaky ribosome scanning and plays an important role in viral particle packaging [55].
Human Coronavirus Respiratory Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Thomas Edward Cecere, Stephanie Michelle Todd, Owen Benjamin Richmond
An overactive host immune response has been associated with many of the diseases associated with coronavirus infections.40 A similar phenotype was observed in human patients infected with SARS-CoV, namely, that clinical disease worsened 1–2 weeks following initial infection. This was due to bystander destruction of the respiratory system following the host immune response to viral infection. An inadequate T cell response, resulting in delayed viral clearance, contributes in part to this phenomenon. However, the relative success or failure of the initial innate immune response determines the extent of initial virus replication.3 The host interferon response is critical in limiting viral replication, and coronaviruses have developed multiple strategies to subvert interferon induction. SARS-CoV replicates in double-membrane vesicles, and it has been suggested that these serve to shield viral double-stranded RNA (a potent interferon stimulator) from infected cells, thus preventing signaling through RIG-I, MDA-5, and TLR3.41,42 Multiple viral proteins have been shown to directly inhibit induction of interferons, including nsp1, nsp3, N protein, and the accessory proteins ORF6 and ORF3b.3,43,44 Specifically, the N protein of SARS-CoV inhibits NF-κB. In addition to acting on interferons, SARS-CoV induces multiple proinflammatory chemokines and cytokines, including IL-1, IL-6, IL-12, IL-8 CCL2, and CXCL10.3
The chimera of S1 and N proteins of SARS-CoV-2: can it be a potential vaccine candidate for COVID-19?
Published in Expert Review of Vaccines, 2022
Amresh Kumar, Amit Ladha, Ankita Choudhury, Abu Md Ashif Ikbal, Bedanta Bhattacharjee, Tanmay Das, Gaurav Gupta, Chhavi Sharma, Adity Sarbajna, Subhash C Mandal, Manabendra Dutta Choudhury, Nahid Ali, Petr Slama, Nima Rezaei, Partha Palit, Onkar Nath Tiwari
After processing of the PP by main protease, 16 NSPs are produced, all of which perform vital functions by participating in the formation of different types of proteins involved in virus replication and transcription. Among these, NSP9 (dimeric form) is responsible for RNA-binding, a critical step during viral infection. Strategies for blocking the dimerization of NSP9 may be critical for preventing SARS-CoV-2 infection [31,32]. Pathogenesis of COVID-19 can also be triggered by the expression of novel proteins encoded by ORF3b and ORF8. Unlike ORF8, which does not have any known function, ORF3b is capable of inhibiting the expression of interferon (IFN)-β [33]. According to a structure modeling study, the endosome-associated-protein-like domain of NSP2 harbors a stabilizing mutation, which may explain why SARS-CoV-2 is more contagious than SARS-CoV-1. Additionally, the destabilizing mutation near the phosphatase domain of NSP3 may be indicative of an alternative pathogenic mechanism for SARS-CoV-2 [34].
An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies
Published in Expert Review of Anti-infective Therapy, 2021
Hin Fung Tsang, Lawrence Wing Chi Chan, William Chi Shing Cho, Allen Chi Shing Yu, Aldrin Kay Yuen Yim, Amanda Kit Ching Chan, Lawrence Po Wah Ng, Yin Kwan Evelyn Wong, Xiao Meng Pei, Marco Jing Woei Li, Sze-Chuen Cesar Wong
SARS-CoV-2 is a new strain of β-coronavirus from group 2B classified by phylogenetic analysis. SARS-CoV-2 is enveloped, positive-sense, single-stranded RNA virus [7]. The genome of SARS-CoV-2 comprises 29,891 nucleotides that encode 9,860 amino acids. Non-structural proteins (NSPS) are encoded by 5ʹ-untranslated region (5ʹ-UTR) and open reading frame (orf1/ab) for replication-transcription complex (RTC) formation in double membrane vesicles (DMVs). Accessory proteins and 3ʹ-untranslated region (3ʹ-UTR) are also involved. Structural proteins include spike (S), envelop (E), membrane (M) and nucleocapsid (N) proteins [2,31]. Receptor-binding domain (RBD) in S1 subunit of S protein showed important role for direct host entry [2]. M protein helps to shape the virions and bind nucleocapsid. E protein involves in viral pathogenesis through virus assembly and release. N protein packs the encapsidated genome into virions [31]. Orf3b, which is one of the N proteins, shown as IFN-β activities antagonist in synthesis and signaling, which is beneficial for viral replication [2,31].
Insights into the modulation of the interferon response and NAD+ in the context of COVID-19
Published in International Reviews of Immunology, 2022
Nada J. Habeichi, Cynthia Tannous, Andriy Yabluchanskiy, Raffaele Altara, Mathias Mericskay, George W. Booz, Fouad A. Zouein
Lastly, SARS-CoV Nsp1 has been shown to block phosphorylation of the transcription factor of ISGs, STAT6 [48]. Additionally, SARS-CoV accessory protein ORF3b inhibits transcription of ISGs, resulting in decreased IFN-I and IFN-III levels [45]. A cell culture experiment showed that the open reading frame 6 (ORF6), ORF8, and nucleocapsid (N) proteins of SARS-CoV-2 are able to inhibit expression of IFN-β and activation of ISGs [21]. These proteins exhibited strong inhibition of the type I IFN (IFN-β) promoter and NF-κB element. All three were able to inhibit the ISRE after infection of cells with Sendai virus, while ORF6 and ORF8 could inhibit the ISRE after treatment with IFN-β. SARS-CoV-2 ORF6 was found to block STAT1 and STAT2 nuclear translocation so as to impair transcriptional induction of ISGs [49]. Of note, however, SARS-CoV-2 ORF6 was reported to interfere less efficiently than SARS-CoV ORF6 with human IFN induction and IFN signaling [50]. Xia et al. identified multiple SARS-CoV-2 proteins that antagonize the IFN-I response [51]. Three proteins antagonize IFN-I production: ORF6 binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation; Nsp6 suppresses IRF3 phosphorylation by binding TANK binding kinase 1 (TBK1); and Nsp13 binds and blocks TBK1 phosphorylation. Two groups of proteins were found to antagonize IFN-I signaling by blocking STAT1/STAT2 phosphorylation or nuclear translocation. In this case, Nsp1 and Nsp6 of SARS-CoV-2 more efficiently suppressed IFN-I signaling than their counterparts from SARS-CoV or MERS-CoV [51]. Collectively, SARS-CoV-2 proteins interfere with the innate immune system leading to delayed anti-viral response mediated by IFNs secretion and thus facilitate virus replication [2]. These findings would be helpful to unveil the molecular pathways that may be targeted in the setting of SARS-CoV-2.