Virological characteristics of the SARS‐CoV‐2 Omicron EG.5.1 variant

Microbiology and Immunology, Год журнала: 2024, Номер 68(9), С. 305 - 330

Опубликована: Июль 4, 2024

Abstract In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron XBB, EG.5.1 (a progeny XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures experimental animals, use human sera antiviral compounds, reveal virological features newly emerging variant. Our analysis modeling suggested that two hallmark substitutions EG.5.1, S:F456L ORF9b:I5T are critical its increased viral fitness. Experimental investigations on growth kinetics, sensitivity clinically available antivirals, fusogenicity, pathogenicity comparable those XBB.1.5. However, cryo‐electron microscopy revealed structural differences between spike proteins further assessed impact features, but it was almost negligible our setup. provide knowledge for understanding evolutionary traits pathogenic viruses, population.

Язык: Английский

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Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic

Nature Microbiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract SARS-CoV-2 variants are mainly defined by mutations in their spike. It is therefore critical to understand how the evolutionary trajectories of spike affect virus phenotypes. So far, it has been challenging comprehensively compare many spikes that emerged during pandemic a single experimental platform. Here we generated panel recombinant viruses carrying different proteins from 27 circulating between 2020 and 2024 same genomic background. We then assessed several phenotypic traits both vitro vivo. found distinct among before after emergence Omicron variants. Spike post-Omicron maintained enhanced tropism for nasal epithelium large airways but displayed, over time, typical pre-Omicron Hence, with features pre- may continue emerge future.

Язык: Английский

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Unveiling the antiviral inhibitory activity of ebselen and ebsulfur derivatives on SARS-CoV-2 using machine learning-based QSAR, LB-PaCS-MD, and experimental assay

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 26, 2025

Ebsulfur and ebselen derivatives that were proven to be potent inhibitors against the main protease (MPro) of SARS-CoV-2 which is an essential enzyme for viral replication chosen study quantitative structure–activity relationship (QSAR) analysis using a classical multiple linear regression (MLR) machine learning approach random forest (RF) artificial neural network (ANN) in order find between molecular structural properties biological inhibitory activities. With statistical criteria, R2 values MLR, RF, ANN models training set 0.83, 0.82, 0.92, respectively. The RMSE test considered model evaluation, results 0.27, 0.18, 0.09 models, Therefore, was best-obtained predicting MPro activity thirteen new synthetic analogs haven't tested assay before. Notably, our predicted activities then examined enzyme-based assays cytotoxicity tests, found compound P8 resulted good potential candidate activity. Furthermore, dynamics simulations performed dynamic interaction ligand binding site; showed pathway mechanism with key residues surrounding active site MPro, useful further development derivatives.

Язык: Английский

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Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

mBio, Год журнала: 2024, Номер 15(8)

Опубликована: Июль 2, 2024

The continued evolution of severe acute respiratory syndrome 2 (SARS-CoV-2) requires persistent monitoring its subvariants. Omicron subvariants are responsible for the vast majority SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% circulating strains as January 2024. To better understand parameters involved in viral transmission, we characterized functional properties Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3, JN.1. We tested their capacity to evade plasma-mediated recognition neutralization, binding angiotensin-converting enzyme (ACE2), susceptibility cold inactivation, processing, well impact temperature on Spike-ACE2 interaction. found that compared early wild-type (D614G) strain, most subvariants' evolved escape neutralization by plasma individuals who received a fifth dose bivalent (BA.1 or BA.4/5) mRNA vaccine improve ACE2 binding, particularly at low temperatures. Moreover, had best affinity all temperatures tested. processing is associated inactivation. Intriguingly, was significantly growth rates humans. Overall, report Spikes newly emerged relatively stable resistant present improved which associated, temperatures, rates.IMPORTANCEThe gave rise wide range variants harboring new mutations glycoproteins. Several factors have been transmission fitness such plasma-neutralization whether additional could be importance variants' characterize several glycoprotein presents an further temperature. interaction strongly rate, such, represent another parameter affecting transmission.

Язык: Английский

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The ACE2 Receptor from Common Vampire Bat (Desmodus rotundus) and Pallid Bat (Antrozous pallidus) Support Attachment and Limited Infection of SARS-CoV-2 Viruses in Cell Culture

Viruses, Год журнала: 2025, Номер 17(4), С. 507 - 507

Опубликована: Март 31, 2025

During the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SC2) infection was confirmed in various animal species demonstrating a wide host range of virus. Prior studies have shown that ACE2 protein is primary receptor used by virus to gain cellular entry and begin replication cycle. In previous studies, we demonstrated human bat proteins can be utilized SC2 viruses for entry. Bats are suspected natural because genetic homology with other coronaviruses. this work, demonstrate expression genes from common vampire (CVB) (Desmodus rotundus) pallid (PB) (Antrozous pallidus), supports some cell culture. Two lines were produced, CVB-ACE2 PB-ACE2, expressing these along TMPRSS2, model previously established using non-permissive chicken DF-1 line. Results original Wuhan lineage (WA1) Delta variant able infect replicate either lines. contrast, Lambda Omicron infected both lines, but viral titers did not increase following infection. Viral detection immunofluorescence abundant spike (S) staining WA1 variants little signal variants. These while CVB PB infection, later (Lambda Omicron) poorly observations suggest more efficient adaption become less fit species.

Язык: Английский

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Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236

EBioMedicine, Год журнала: 2024, Номер 104, С. 105181 - 105181

Опубликована: Июнь 1, 2024

BackgroundAlthough several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences virological characteristics between SARS-CoV-2 SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat found to lack furin cleavage site (FCS) spike (S) protein. The comparison its with FCS-deleted (SC2ΔFCS) has not been conducted yet.MethodsWe prepared human induced pluripotent stem cell (iPSC)-derived airway lung epithelial cells colon organoids as organ-relevant models. B236, SARS-CoV-2, artificially generated SC2ΔFCS used for viral experiments. To investigate pathogenicity B236 vivo, we intranasal infection experiments hamsters.FindingsIn iPSC-derived cells, growth significantly lower than that SC2ΔFCS. A fusion assay showed S proteins less fusogenic experiment hamsters pathogenic even Interestingly, organoids, greater SARS-CoV-2.InterpretationCompared demonstrated exhibited tropism toward intestinal rather respiratory cells. Our results are consistent previous report showing is enterotropic macaques. Altogether, our strengthens assumption replicate primarily tissues tissues.FundingThis study supported part by AMED ASPIRE (JP23jf0126002, Keita Matsuno, Kazuo Takayama, Kei Sato); SCARDA Japan Initiative World-leading Vaccine Research Development Centers "UTOPIA" (JP223fa627001, Sato), Program on R&D new generation vaccine including modality application (JP223fa727002, Hokkaido University Institute (HU-IVReD) (JP223fa627005h0001, Takasuke Fukuhara, Matsuno); Emerging Re-emerging Infectious Diseases (JP21fk0108574, Hesham Nasser; JP21fk0108493, Fukuhara; JP22fk0108617 JP22fk0108146, Sato; JP21fk0108494 G2P-Japan Consortium, Shinya Tanaka, Terumasa Ikeda, JP21fk0108425, Takayama JP21fk0108432, Fukuhara JP22fk0108534, JP22fk0108511, Yuki Yamamoto, JP22fk0108506, HIV/AIDS (JP22fk0410055, Ikeda; JP22fk0410039, Infrastructure (JP22wm0125008 CREST (JP21gm1610005, Takayama; JP22gm1610008, JST PRESTO (JPMJPR22R1, Jumpei Ito); (JPMJCR20H4, JSPS KAKENHI Fund Promotion Joint International (International Leading Research) (JP23K20041, SPRING (JPMJSP2108 Shigeru Fujita); Grant-in-Aid Scientific C (22K07103, Ikeda); B (21H02736, Fukuhara); Early-Career Scientists (22K16375, 20K15767, Core-to-Core (A. Advanced Networks) (JPJSCCA20190008, Fellow DC2 (22J11578, Keiya Uriu); DC1 (23KJ0710, Yusuke Kosugi); Excellent Young Researchers (LEADER) (to Innovative Smart Education (WISE) 1801 Ministry Education, Culture, Sports, Science Technology (MEXT) Naganori Nao); Health, Labour Welfare (MHLW) under grant 23HA2010 Nao Cooperative (Joint Usage/Research Center program) Life Medical Sciences, Kyoto Project Science, Tokyo Ikeda Biochemical Foundation Takeda Mochida Memorial Pharmaceutical Naito Hokuto Bioscience Tomokazu Tamura); Hirose Mitsubishi Sato).

Язык: Английский

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Potential Role of APOBEC3 Family Proteins in SARS-CoV-2 Replication

Опубликована: Июнь 18, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has acquired multiple mutations since its emergence. Analyses of the SARS-CoV-2 genomes from infected patients exhibit a bias toward C-to-U mutations, which are suggested to be caused by apolipoprotein B mRNA editing enzyme polypeptide-like 3 (APOBEC3, A3) cytosine deaminase proteins. However, role A3 enzymes in replication remains unclear. To address this question, we investigated effect family proteins on THP-1 cells lacking A3A A3G genes. The Wuhan, BA.1, and BA.5 variants had comparable viral parent A3A-to-A3G-null THP-1-ACE2 cells. On other hand, infectivity these were abolished series passage experiments over 20 days. In contrast previous reports, observed no evidence for A3-induced mutagenesis experiments. Furthermore, our analysis large number publicly available did not reveal conclusive mutagenesis. Taken together, studies suggest that can positively contribute replication, however is deaminase-independent.

Язык: Английский

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Unique RNA replication characteristics and nucleocapsid protein expression may explain differences in the replication capacity of SARS-COV-2 lineages.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 14, 2024

Summary COVID-19 pandemic in Brazil was characterized by the sequential circulation of SARS-CoV-2 lineages B.1.1.33, and variants Zeta (P.2), Gamma (P.1/P.1.*), Delta (B.1.617.2/AY.*), Omicron (BA.*). Our research aimed to compare biological traits these analyzing aspects viral replication including binding, entry, RNA replication, protein production. We demonstrated that capacity varies depending on cell type, with BA.1 exhibiting lowest human pulmonary cells. Additionally, nucleocapsid proteoforms generated during infection exhibit distinct patterns across variants. findings suggest factors beyond initial stages virus entry influence efficiency among different Thus, our study underscores significance role proteins shaping replicative characteristics Author summary The emergence presents specific properties such as response antibodies, pathogenicity detection diagnostic tests. presented a particular pattern global geographic regions. Despite cessation pandemic, officially declared World Health Organization 2023, new continue emerge while virus-cell interaction contribute have not yet been completely understood. In study, we compared circulated verifying production proteins. results indicate variant has reduced lung also observed vary according variant. These differences could help explain

Язык: Английский

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A heterocyclic compound inhibits viral release by inducing cell surface BST2/Tetherin/CD317/HM1.24

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 5, 2024

Abstract The introduction of combined antiretroviral therapy (cART) has greatly improved the quality life human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, ever-present desire to seek out a full remedy for HIV-1 infections makes discovery novel antiviral medication compelling. Owing this, new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting proteins or processes, newer therapeutics targeting host restriction factors hold promise curative care infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is appealing therapeutic candidate. In this study, drug screening system established, using Jurkat/Vpr-HiBiT T cells, identify drugs that could obstruct release; candidate compounds were selected from Ono Pharmaceutical compound library. Jurkat cells expressing Vpr-HiBiT infected with NL4-3, and amount release quantified indirectly by incorporated into virions. Subsequently, suppressed viral used synthesize heterocyclic compound, HT-7, reduces less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled reduction but not Jurkat/KO-BST2 cells. Seemingly, impeded simian (SIV) severe acute respiratory syndrome coronavirus (SARS-CoV-2) release. Concisely, these results suggest release, following treatment, resulted modulation expression HT-7. Importance A collection scientific strategies been revealed find long-term cure infection. One techniques, approach, involves harnessing late events are targeted current medication. regulator assembly Gag protein, emerged as prospective inhibitor. We set up high-efficiency, economically viable, facile identification inhibitors. Herein, we discovered inhibits This newly high- performance testing technique can be employed virological research investigating HIV- processes.

Язык: Английский

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Potential Role of APOBEC3 Family Proteins in SARS-CoV-2 Replication

Viruses, Год журнала: 2024, Номер 16(7), С. 1141 - 1141

Опубликована: Июль 16, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has acquired multiple mutations since its emergence. Analyses of the SARS-CoV-2 genomes from infected patients exhibit a bias toward C-to-U mutations, which are suggested to be caused by apolipoprotein B mRNA editing enzyme polypeptide-like 3 (APOBEC3, A3) cytosine deaminase proteins. However, role A3 enzymes in replication remains unclear. To address this question, we investigated effect family proteins on myeloid leukemia cell line THP-1 lacking A3A A3G genes. The Wuhan, BA.1, and BA.5 variants had comparable viral parent A3A-to-A3G-null cells stably expressing angiotensin-converting (ACE2) protein. On other hand, infectivity these were abolished THP-1-ACE2 series passage experiments over 20 days. In contrast previous reports, observed no evidence A3-induced mutagenesis experiments. Furthermore, our analysis large number publicly available did not reveal conclusive for mutagenesis. Our studies suggest that can positively contribute replication; however, is deaminase-independent.

Язык: Английский

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