Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Design of customized coronavirus receptors

Nature, Journal Year: 2024, Volume and Issue: 635(8040), P. 978 - 986

Published: Oct. 30, 2024

Language: Английский

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HCoV‐HKU1 and TMPRSS2 interaction: uncovering mechanisms of viral invasion

MedComm, Journal Year: 2025, Volume and Issue: 6(1)

Published: Jan. 1, 2025

Three recent studies published in Cell have revealed the intricate interaction between HCoV-HKU1 and transmembrane serine protease 2 (TMPRSS2). These not only pave way for a deeper understanding of mechanism viral invasion but also offer new perspectives on antiviral therapies against coronavirus.1-3 The spike (S) glycoprotein coronaviruses facilitates membrane fusion with host cells, enabling genome delivery. Identified entry receptors coronavirus include angiotensin-converting enzyme (ACE2) SARS-CoV, SARS-CoV-2, HCoV-NL63, bat-derived MERS -related coronaviruses; aminopeptidase N HCoV-229E, CcoV-HuPn-2018, PDCoV, TGEV/PRCV, PEDV; dipeptidyl peptidase 4 MERS-CoV HKU4-related MERS-related TMEM106B, which mediates ACE2-independent SARS-CoV-2 (Figure 1A).1 HCoV-HKU1, seasonally transmitted β-coronavirus,1 is known to cause common colds, respiratory infections, serious complications.1, In 2019, Hulswit et al. identified 9-O-acetylated sialic acids as HCoV-HKU1.4 2023, Saunders that TMPRSS2 direct receptor HCoV-HKU1.3, 5 plays crucial role proteolytic activation S various coronaviruses, including MERS-CoV, well influenza virus hemagglutinins.1 After binds ACE2 attaches cell surface, or other proteases cleave S2' site protein, facilitating necessary conformational change. Notably, characterized by its activity does contribute endocytosis SARS-CoV-2. Conversely, during infection, spike-mediated fusion, even when impaired. This distinction highlights different compared SARS-CoV-2.5 detailed comprehensive explanations sialosides (9-O-Ac-Sia) evaluated species tropism HCoV-HKU1.1-3 McCallum al.1 optimized human (hTMPRSS2) expression vector includes T447C mutation, cleavable N-terminal SUMO an N249-linked glycosylation motif, significantly enhancing yield Expi293 cells. Additionally, they expressed HKU1A receptor-binding domain (RBD) elucidated structures S441A RBD using cryo-electron microscopy (cryo-EM). Their finding electrostatic contacts, salt bridges, van der Waals interactions, hydrogen bonds mediated these proteins. Wang al.2 purified ectodomain HCoV-HKU1A hTMPRSS2, identifying three states S: inactive state, glycan-activated functionally anchored state 1B). 42% trimers exhibited up-conformations.2 When 9-O-Ac-Sia (NTD), trimer transitioned increasing up-conformation from 73%. transition involved 20° inward rotation NTD 92° upward RBD, binding enter 9-O-Ac-Sia, formed four conformations functional anchoring states, 1up 1TMPRSS2 (11.5%), 2up 2TMPRSS2 (37.4%), 3up (11.8%), 3TMPRSS2 (39.3%).2 Fernández found maintains autolytic activation, allowing autocleavage achieve mature active conformation, affinity RBD.1, 3 Nanobody A07 can inhibit TMPRSS2's activity, thereby reducing infection.3, Mutant experiments key mutation analyses sites are Y414, W461, Y469, R470 TMPRSS2, H488, E505, V/Y509, L510, W515, R517, Y528 highly conserved HCoV-HKU1C strains, distinguishing them such MERS-CoV2. zoonotic potential raises significant concerns. analyzed while aligned sequences 23 species, 201 mammalian sequences. They predominantly among mammals (with differences D417, Y469 some macaques, mice, hamsters, ferrets), partially reptiles birds, less amphibians vertebrates.1-3 Mutations at hTMPRSS2 pig-TMPRSS2 (Y414Q) monkey-TMPRSS2 (Y469N), resulted reduced abolished pseudovirus could TMPRSS2-overexpressing cells primates, rodents, artiodactyl, lagomorph, chiropteran, green monkeys, mole rats, ferrets, horseshoe bats.1 further confirmed importance residues through assays infection experiments3 1C). Y414 flank L521 P522 forming clamp-like hydrophobic core. positions disrupt critical TMPRSS2-spike interactions. D417 varies typically comprising non-charged residues, whereas features polar non-polar residues. Furthermore, W461 engage interactions bond network respectively. Variations essential protein.2, findings highlight rodent origin hypotheses HCoV-HKU1. aforementioned elucidate synergistic mechanisms entry,1-3, laying theoretical groundwork development pharmaceuticals, antibodies, vaccines.1, response selective pressures therapies, viruses may evolve harbour drug-resistant mutations. Protease inhibitors, camostat, antibodies targeting potentially suppress providing broad-spectrum effect, help address scarcity effective treatments simultaneously reduce likelihood strains emerging. Nevertheless, inhibitors might produce off-target side effects, resulting unforeseen consequences. Advanced computational methods be employed predict drug targets cell-based protein arrays effectively detect antibody targets. valuable insight into coronavirus.2, Revealing preventing treating diseases associated future. originates has infect humans domestic animals act intermediate hosts, although specific remain unidentified. Analysis homology reveals recognize across interspecies transmission. high frequency recombination rate, evolutionary factors enable adapt efficiently range hosts environments, thus promoting ecological exploration, travel, modern agricultural practices, urbanization spread their natural reservoirs humans, risk infections. Human must replicate within acquire adaptive mutations counteract restriction factors. As undergo continuous processes, enhance virulence facilitate immune evasion. Understanding virus-host spillovers preparing future outbreaks. Zehan Pang: Writing–original draft preparation; review editing; visualization. Huahao Fan: Conceptualization; writing–original funding acquisition. Xiaolong Xu: Writing–review All authors read approved final manuscript. Figure 1 was created BioRender.com. research supported National Natural Science Foundation China (grant nos. 82202592, 82141202), Multidisciplinary Innovation Team Project Traditional Chinese Medicine no. ZYYCXTD-D-202201). declare no conflicts interest. Not applicable.

Language: Английский

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Human HKU1-reactive CD4 T cells are enriched for cytolytic potential that persists in older adults

The Journal of Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

The emergence of SARS-CoV-2 increased interest in cellular immunity established by infections with human coronaviruses (HCoVs). Using PBMC from a cohort subjects collected prior to 2019, we assessed the abundance and phenotype these CD4 T cells using cytokine Elispot assays. Unexpectedly, cytotoxic potential was uniquely enriched amongst HKU1-reactive cells, as measured quantification granzyme producing cells. Also, although dramatic losses HCoV-specific for OC43, NL63 229E-specific were observed older relative younger adults, exhibited minimal age-dependent differences this phenotype.

Language: Английский

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Characterization of spike S1/S2 processing and entry pathways of lentiviral pseudoviruses bearing seasonal human coronaviruses NL63, 229E, and HKU1 spikes

Microbiology Spectrum, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

ABSTRACT Although much has been learned about the entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many details mechanisms seasonal human coronaviruses (HCoVs) remain less well understood. In present study, we used 293T cell lines stably expressing angiotensin converting enzyme (ACE2), aminopeptidase N (APN), or transmembrane serine protease (TMPRSS2), which support high-level transduction lentiviral pseudoviruses bearing spike proteins HCoVs, HCoV-NL63, -229E, -HKU1, respectively, to compare processing and virus pathways among these viruses. Our results showed that -HKU1 into cells is sensitive endosomal acidification inhibitors (chloroquine NH 4 Cl), indicating via endocytosis route. TMPRSS2 expression on target surface was required for HCoV-HKU1 spike-mediated cell–cell fusion, found only domain not activity viral endocytic However, a furin site (RKRR) at S1/S2 junction were essential efficient fusion. Additionally, show dibasic monobasic arginine residues junctions HCoV-NL63 -229E are entry, but multi-basic dispensable entry. findings highlight features HCoVs may development novel treatment strategies. IMPORTANCE Details be fully explored. To investigate CoVs, employed express (TMPRSS2) study respectively. We entered route independently cellular therefore likely depended cathepsin activity. Furthermore, amino acids in spikes provide new insights junctional residues, receptors, requirements HCoV pseudovirus inhibitors.

Language: Английский

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Leveraging Artificial Intelligence and Gene Expression Analysis to Identify Some Potential Bovine Coronavirus (BCoV) Receptors and Host Cell Enzymes Potentially Involved in the Viral Replication and Tissue Tropism

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1328 - 1328

Published: Feb. 4, 2025

Bovine coronavirus (BCoV) exhibits dual tissue tropism, infecting both the respiratory and enteric tracts of cattle. Viral entry into host cells requires a coordinated interaction between viral proteins. However, specific cellular receptors co-receptors facilitating BCoV remain poorly understood. Similarly, roles proteases such as Furin, TMPRSS2, Cathepsin-L (CTS-L), known to assist in replication other coronaviruses, have not been extensively explored for BCoV. This study aims identify novel that modulate tropism. cell lines were infected with isolates from origins, gene expression profiles post-infection analyzed using next-generation sequencing (NGS). Differentially expressed genes encoding potential further assessed in-silico prediction molecular docking analysis. These analyses focused on receptors, including ACE2, NRP1, DPP4, APN, AXL, CEACAM1, their infection. Validation these findings was performed qRT-PCR assays targeting individual genes. We confirmed enzymes some (+/−) lung tissues. Results revealed high binding affinities 9-O-acetylated sialic acid NRP1 spike (S) hemagglutinin-esterase (HE) proteins compared CEACAM1. Additionally, Furin TMPRSS2 predicted interact BCoV-S polybasic cleavage site (RRSRR|A), suggesting S glycoprotein activation. is first explore interactions multiple proteases. Functional studies are recommended confirm infection replication.

Language: Английский

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Genome-wide CRISPR screen reveals host factors for gama- and delta-coronavirus infection in Huh7 cells

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 140728 - 140728

Published: Feb. 1, 2025

Language: Английский

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Five‐Year (2017–2022) Evolutionary Dynamics of Human Coronavirus HKU1 in Southern France With Emergence of Viruses Harboring Spike H512R Substitution

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(2)

Published: Feb. 1, 2025

ABSTRACT HCoV‐HKU1 diversity and evolution were scarcely studied. We performed next‐generation sequencing (NGS) analysis of genomes over 5 years. NGS used Illumina technology on NovaSeq 6000 following whole genome PCR amplification by an in‐house set primers designed using Gemi PrimalScheme. Genome assembly analyses CLC Genomics, Mafft, BioEdit, Nextstrain, Nextclade, MEGA, iTol bioinformatic tools. Spike molecular modeling dynamics simulations Molegro Molecular Viewer Hyperchem programs. Twenty‐eight systems allowed obtaining 158 including 69 89 genotypes A B, respectively. Both co‐circulated during the study period but one predominated each year. total 1683 amino acid substitutions 80 in ≥ 10 detected genotype relatively to a 2004 reference. H512R spike, first 2009 reported as involved antibody neutralization, was found all A, almost always with V387I K478N, predicted here significantly improve cellular TMPRSS2 protein binding. Also, 1802 64 B 2005 This substantially expands global genomes. Genomics structural contributed our understanding evolution.

Language: Английский

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Structural insights into the receptor-binding domain of bat coronavirus ZXC21

Structure, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Structural basis for the interaction between human coronavirus HKU1 spike receptor binding domain and its receptor TMPRSS2

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 8, 2024

Language: Английский

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