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1.
J Med Virol ; 2022 Jul 11.
Article in English | MEDLINE | ID: covidwho-1929925

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since its outbreak in December 2019, has been capable of continuing the pandemic by mutating itself into different variants. Mass vaccinations, antibiotic treatment therapy, herd immunity, and preventive measures have reduced the disease's severity from the emerging variants. However, the virus is undergoing recombination among the current two variants: Delta and Omicron, resulting in a new variant, informally known as "Deltacron," which was controversial as it might be a product of lab contamination between Omicron and Delta samples. However, the proclamation was proved wrong, and the experts are putting more effort into better understanding the variant's epidemiological characteristics to control potential outbreaks. This review has discussed the potential mutations in the novel variant and prospective risk factors and therapeutic options in the context of this new variant. This study could be used as a guide for implementing appropriate controls in a sudden outbreak of this new variant.

3.
J Med Virol ; 94(5): 1825-1832, 2022 05.
Article in English | MEDLINE | ID: covidwho-1777580

ABSTRACT

Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as an Omicron variant. This variant is a heavily mutated virus and designated as a variant of concern by the World Health Organization (WHO). WHO cautioned that the Omicron variant of SARS-CoV-2 held a very high risk of infection, reigniting anxieties about the economy's recovery from the 2-year pandemic. The extensively mutated Omicron variant is likely to spread internationally, posing a high risk of infection surges with serious repercussions in some areas. According to preliminary data, the Omicron variant of SARS-CoV-2 has a higher risk of reinfection. On the other hand, whether the current COVID-19 vaccines could effectively resist the new strain is still under investigation. However, there is very limited information on the current situation of the Omicron variant, such as genomics, transmissibility, efficacy of vaccines, treatment, and management. This review focused on the genomics, transmission, and effectiveness of vaccines against the Omicron variant, which will be helpful for further investigation of a new variant of SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , COVID-19 Vaccines , Genomics , Humans , SARS-CoV-2/genetics
4.
J Med Virol ; 94(5): 1815-1820, 2022 05.
Article in English | MEDLINE | ID: covidwho-1777571

ABSTRACT

The polybasic furin cleavage site insertion with four amino acid motifs (PRRA) in spike protein's S1/S2 junction site is important in determining viral infectivity, transmission, and host range. However, there is no review so far explaining the effect of the furin cleavage site of the spike protein on SARS-CoV-2 replication and pathogenesis in the host and immune responses and vaccination. Therefore, here we specifically focused on genomic evolution and properties of the cleavage site of spike protein in the context of SARS-CoV-2 followed by its effect on viral entry, replication, and pathogenesis. We also explored whether the spike protein furin cleavage site affected the host immune responses and SARS-CoV-2 vaccination. This review will help to provide novel insights into the effects of polybasic furin cleavage site on the current COVID-19 pandemic.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , COVID-19 Vaccines , Furin/metabolism , Humans , Immunity , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccination
5.
J Virol ; 96(7): e0013622, 2022 04 13.
Article in English | MEDLINE | ID: covidwho-1745828

ABSTRACT

Viruses have evolved diverse strategies to hijack the cellular gene expression system for their replication. The poly(A) binding proteins (PABPs), a family of critical gene expression factors, are viruses' common targets. PABPs act not only as a translation factor but also as a key factor of mRNA metabolism. During viral infections, the activities of PABPs are manipulated by various viruses, subverting the host translation machinery or evading the cellular antiviral defense mechanism. Viruses harness PABPs by modifying their stability, complex formation with other translation initiation factors, or subcellular localization to promote viral mRNAs translation while shutting off or competing with host protein synthesis. For the past decade, many studies have demonstrated the PABPs' roles during viral infection. This review summarizes a comprehensive perspective of PABPs' roles during viral infection and how viruses evade host antiviral defense through the manipulations of PABPs.


Subject(s)
COVID-19 , Host Microbial Interactions , Immune Evasion , SARS-CoV-2 , Antiviral Agents , Humans , Poly(A)-Binding Proteins/genetics , Poly(A)-Binding Proteins/immunology , Protein Biosynthesis , RNA, Messenger/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism
6.
J Med Virol ; 94(7): 2962-2968, 2022 07.
Article in English | MEDLINE | ID: covidwho-1739192

ABSTRACT

Cyclin-dependent kinases (CDKs) are protein kinases that play a key role in cell division and transcriptional regulation. Recent studies have demonstrated the critical roles of CDKs in various viral infections. However, the molecular processes underpinning CDKs' roles in viral infection and host antiviral defense are unknown. This minireview briefly overviews CDKs' functions and highlights the most recent discoveries of CDKs' emerging roles during viral infections, thereby providing a scientific and theoretical foundation for antiviral regulation and shedding light on developing novel drug targets and therapeutic strategies against viral infection.


Subject(s)
COVID-19 , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cyclin-Dependent Kinases/metabolism , Cyclin-Dependent Kinases/therapeutic use , Humans , SARS-CoV-2 , Virus Diseases/drug therapy
7.
J Med Virol ; 94(7): 2977-2985, 2022 07.
Article in English | MEDLINE | ID: covidwho-1729157

ABSTRACT

The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently the most formidable challenge to humankind. Understanding the complicated virus-host interplay is crucial for fighting against viral infection. A growing number of studies point to the critical roles of RING (really interesting new gene) finger (RNF) proteins during SARS-CoV-2 infection. RNF proteins exert direct antiviral activity by targeting genome and envelope glycoproteins of SARS-CoV-2. Additionally, some RNF members serve as potent regulators for antiviral innate immunity and antibody-dependent neutralization of SARS-CoV-2. Notably, SARS-CoV-2 also hijacks the RNF proteins-mediated ubiquitination process to evade host antiviral innate immunity and enhance viral replication. In this mini-review, we discuss the diverse antiviral mechanisms of RNF proteins and viral immune evasion in an RNF proteins-dependent manner. Understanding the crosstalk between RNF proteins and SARS-CoV-2 infection would help design potential novel targets for COVID-19 treatment.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Immunity, Innate , Pandemics
8.
Cell Mol Life Sci ; 78(23): 7427-7434, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1491059

ABSTRACT

Viral infections pose a severe threat to humans by causing many infectious, even fatal, diseases, such as the current pandemic disease (COVID-19) since 2019, and understanding how the host innate immune system recognizes viruses has become more important. Endosomal and cytosolic sensors can detect viral nucleic acids to induce type I interferon and proinflammatory cytokines, subsequently inducing interferon-stimulated genes for restricting viral infection. Although viral RNA and DNA sensing generally rely on diverse receptors and adaptors, the crosstalk between DNA and RNA sensing is gradually appreciated. This minireview highlights the overlap between the RNA- and DNA-sensing mechanisms in antiviral innate immunity, which significantly amplifies the antiviral innate responses to restrict viral infection and might be a potential novel target for preventing and treating viral diseases.


Subject(s)
COVID-19/immunology , DNA, Viral/immunology , Immunity, Innate/immunology , RNA, Viral/immunology , SARS-CoV-2/immunology , COVID-19/prevention & control , Cytokines/metabolism , Endosomes/immunology , Humans , Interferon Type I/metabolism , Membrane Proteins/immunology , Nuclear Proteins/immunology , Phosphoproteins/immunology
10.
Nature ; 593(7859): 418-423, 2021 05.
Article in English | MEDLINE | ID: covidwho-1137788

ABSTRACT

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.


Subject(s)
Antiviral Agents/pharmacology , Clofazimine/pharmacology , Coronavirus/classification , Coronavirus/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Biological Availability , Cell Fusion , Cell Line , Clofazimine/pharmacokinetics , Clofazimine/therapeutic use , Coronavirus/growth & development , Coronavirus/pathogenicity , Cricetinae , DNA Helicases/antagonists & inhibitors , Drug Synergism , Female , Humans , Life Cycle Stages/drug effects , Male , Mesocricetus , Pre-Exposure Prophylaxis , SARS-CoV-2/growth & development , Species Specificity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Transcription, Genetic/drug effects , Transcription, Genetic/genetics
11.
J Biol Chem ; 296: 100435, 2021.
Article in English | MEDLINE | ID: covidwho-1087033

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/transmission , Pandemics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/diagnosis , COVID-19/immunology , Cats , Chickens/virology , Chiroptera/virology , Dogs , Elapidae/virology , Eutheria/virology , Gene Expression , Goats/virology , HEK293 Cells , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Macaca mulatta/virology , Mice , Models, Molecular , Mutation , Protein Binding , Protein Structure, Secondary , Recombinant Proteins/genetics , Recombinant Proteins/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Swine/virology , Virus Internalization
12.
Emerg Microbes Infect ; 9(1): 457-468, 2020.
Article in English | MEDLINE | ID: covidwho-124862

ABSTRACT

Porcine deltacoronavirus (PDCoV) is a newly emerging threat to the global porcine industry. PDCoV has been successfully isolated using various medium additives including trypsin, and although we know it is important for viral replication, the mechanism has not been fully elucidated. Here, we systematically investigated the role of trypsin in PDCoV replication including cell entry, cell-to-cell membrane fusion and virus release. Using pseudovirus entry assays, we demonstrated that PDCoV entry is not trypsin dependent. Furthermore, unlike porcine epidemic diarrhea virus (PEDV), in which trypsin is important for the release of virus from infected cells, PDCoV release was not affected by trypsin. We also demonstrated that trypsin promotes PDCoV replication by enhancing cell-to-cell membrane fusion. Most importantly, our study illustrates two distinct spreading patterns from infected cells to uninfected cells during PDCoV transmission, and the role of trypsin in PDCoV replication in cells with different virus spreading types. Overall, these results clarify that trypsin promotes PDCoV replication by mediating cell-to-cell fusion transmission but is not crucial for viral entry. This knowledge can potentially contribute to improvement of virus production efficiency in culture, not only for vaccine preparation but also to develop antiviral treatments.


Subject(s)
Cell Fusion , Coronavirus/physiology , Membrane Fusion , Trypsin/metabolism , Animals , Cell Line , Humans , Swine , Virus Internalization , Virus Replication
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