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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
The structural and accessory proteins are translation products of ~10 kb from the 3′ end one-third of the genome. The genes of these proteins are interspersed along the genome. As mentioned earlier, the structural proteins of SARS-CoV-2 are the S, E, M, and N proteins, and the ORFs code for accessory proteins ORF3a, ORF6, ORF7a, ORF8, ORF9, and ORF10, which are involved in the pathogenesis of the virus [40]. The structural proteins play crucial roles in pathogenesis, replication, viral packaging, and assembly [26]. Docking studies have shown that all four structural proteins interact with each other during their arrangement in the lipid bilayer [41]. The crystal structures of proteins from SARS-CoV and SARS-CoV-2 are presented in Figure 1.3.
Adenoviruses
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Anthony P. Malanoski, Baochuan Lin
E4 is predicted to encode seven different polypeptides that are required for lytic growth, and all but one are expressed. Both ORF3 and ORF6 are involved in viral DNA replication by interacting with E1B-55-kDa protein, as described earlier (see section above).83 Both ORF3 and ORF6 promote viral gene expression by facilitating the accumulation of relevant mRNAs at a posttranscriptional level in the cytoplasm and stabilizing the unprocessed late RNA in the nucleus. Evidence suggests that the E1B-55-kDa–E4ORF6 complex causes the redistribution of cellular factors necessary for RNA biogenesis and that ORF3 directly affects the distribution of essential transcription/replication factors in the nucleus. In addition, ORF6 interacts with p53 to inactivate its function, which is crucial for successful infection by AdV.43 Besides ORF3 and ORF6, studies suggested that ORF1 is a transforming protein and may stimulate quiescent cells to promote lytic infection and oncogenesis. E4ORF6/7 forms dimers to interact and modulate the activity of the cellular transcription factor E2F and subsequently activate cellular factors that are important for the S phase of cell cycle.43,95 The function of E4ORF4 is to negatively regulate E1A and E4 transcription via protein phosphorylation by interacting with protein phosphatase (PP)2A, which creates a regulatory loop limiting cytotoxicity in the early stages of infection. The functional information for E4ORF2 and E4ORF3/4 still awaits discovery.43
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
Considerations of the effects of commonly investigated drugs for COVID-19 in the cholesterol synthesis pathway
Published in Expert Opinion on Pharmacotherapy, 2021
Juan Luis Gomez Marti, Adam M. Brufsky
Antiparasitic agents have well-defined antiviral properties. During SARS-CoV-2 infection, Orf6 binds to the nuclear membrane importin IMPα/β1, which then translocates to the nuclei, antagonizing the antiviral activity of the transcription factor STAT1. Ivermectin efficiently blocks this transport through the nuclear pore complex; no cellular toxicity was identified in vitro [42]. In a retrospective cohort study (ICON study), use of 200 μg/kg ivermectin on admission was associated with approximately 50% reduction in an all-cause in-hospital mortality rate among patients with severe COVID-19 disease. No signs of toxicity were associated with ivermectin use [43]. A recent trial that evaluated ivermectin+doxycycline vs placebo+standard care, found clinical improvement on day 7 in 60.7% of patients compared to 44.4% in the control. By day 12, only 23% of ivermectin-users had not shown clinical improvement, compared to 37.2% in the control group. A trial has been registered to further investigate the utility of this drug (NCT04523831) [44].
Dendritic cell vaccine as a potential strategy to end the COVID-19 pandemic. Why should it be Ex Vivo?
Published in Expert Review of Vaccines, 2022
Jonny Jonny, Terawan Agus Putranto, Enda Cindylosa Sitepu, Raoulian Irfon
Delayed IFN-1 response might be due to SARS-CoV-2 infected pDC. Protein in SARS-CoV-2 such as ORF9b, Nsp14, Nsp10, M, and Nsp1 may inhibit IFN-1 production. At the same time, other proteins such as ORF3a and ORF6 can inhibit the IFN-1 signaling pathway [72]. Furthermore, congenital abnormalities (inborn errors) of the IFN-1 related genes, namely inborn error in TLR-3 and IFN regulatory factor 7 (IRF-7), are found in critical patients [75]. In line with these findings, pDC as the primary source IFN-1 expresses much IRF-7 [24,76]. Furthermore, the presence of autoantibodies against IFN-1 is also found in life-threatening COVID-19 [77]. So that, people with the IFN-1 genetic disorder become more susceptible to clinical worsening [75].
The vital role of animal, marine, and microbial natural products against COVID-19
Published in Pharmaceutical Biology, 2022
Aljawharah A. Alqathama, Rizwan Ahmad, Ruba B. Alsaedi, Raghad A. Alghamdi, Ekram H. Abkar, Rola H. Alrehaly, Ashraf N. Abdalla
The accessory proteins belong to another class of proteins encoded in SARS-CoV-2 and are less well-known compared to the rest. There are two major reasons for this; first, they are not essential or part of viral structure/replication, however, they play a role in viral spread and pathogenicity. Second, predicting protein complexity by bioinformatics is challenging due to their complex nature as short and overlapping ORFs (Michel et al. 2020). Five ORFs encoding accessory genes (ORF3a, ORF6, ORF7a, ORF7b, and ORF8) encode nine accessory proteins including ORF3a, 3d, 6, 7a, 7b, 8, 9b, 14, and 10 and N gene (ORF9b and 14) encodes novel overlapping ORF3d (earlier known as 3b) (Yadav et al. 2021).