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

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

Published: Jan. 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.

Language: Английский

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Evolution of Omicron lineage towards increased fitness in the upper respiratory tract in the absence of severe lung pathology

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 11, 2025

Abstract The emergence of the Omicron lineage represented a major genetic drift in SARS-CoV-2 evolution. This was associated with phenotypic changes including evasion pre-existing immunity and decreased disease severity. Continuous evolution within raised concerns potential increased transmissibility and/or To address this, we evaluate fitness pathogenesis contemporary variants XBB.1.5, XBB.1.16, EG.5.1, JN.1 upper (URT) lower respiratory tract (LRT). We compare vivo infection Syrian hamsters primary human nasal lung epithelium cells assess differences transmissibility, antigenicity, innate immune activation. replicate efficiently URT but display limited pathology lungs compared to previous fail organoids. is attenuated both LRT other fails transmit male hamster model. Our data demonstrate that has favored URT.

Language: Английский

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Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

ABSTRACT Here we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication pathogenesis this new host species. Enhancements associated with amino acid substitutions the viral genome, suggesting IFITM3 limits accumulation adaptive mutations. Mouse-adapted viruses enabled comparative studies mice. caused lung dysfunction altered cilia-associated gene programs, consistent broad antigen distribution lungs. Omicron, which shows low pathogenicity upper respiratory tract preference humans, replicated to high nasal titers while showing restrained spatial lungs diminished inflammatory responses compared Beta. Our findings demonstrate deficiency accelerates coronavirus reveal intrinsic variant traits shape tropism, immunity, across hosts. HIGHLIGHTS is critical barrier species strains enable pathology favors nose large airways, leading mild exhibits replication, driving severe inflammation

Language: Английский

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Interferon signaling in the nasal epithelium distinguishes among lethal and common cold coronaviruses and mediates viral clearance

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(21)

Published: May 17, 2024

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but host viral determinants disease during common cold versus lethal HCoV are poorly understood. We model initial site infection using epithelial cells cultured at an air-liquid interface (ALI). HCoV-229E, HCoV-NL63, human rhinovirus-16 cold-associated that exhibit unique features this model: early antiviral interferon (IFN) signaling, IFN-mediated clearance, preferential replication temperature (33 °C) which confers muted IFN responses. In contrast, SARS-CoV-2 MERS-CoV encode antagonist proteins clearance cultures. Our study identifies shared among viruses, highlighting responses as predictive outcomes nasally directed IFNs potential therapeutics.

Language: Английский

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Pathogenesis and transmission of SARS-CoV-2 D614G, Alpha, Gamma, Delta, and Omicron variants in golden hamsters

npj Viruses, Journal Year: 2025, Volume and Issue: 3(1)

Published: Feb. 24, 2025

Abstract Since the emergence of SARS-CoV-2 in humans, novel variants have evolved to become dominant circulating lineages. These include D614G (B.1 lineage), Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), and Omicron BA.1 (B.1.1.529) BA.2 (B.1.1.529.2) viruses. Here, we compared viral replication, pathogenesis, transmissibility these variants. Replication kinetics innate immune response against viruses were tested ex vivo human nasal epithelial cells (HNEC) induced pluripotent stem cell-derived lung organoids (IPSC-LOs), golden hamster model was employed test pathogenicity potential for transmission by respiratory route. Delta, BA.1, replicated more efficiently, outcompeted D614G, Alpha, an HNEC competition assay. viruses, however, poorly IPSC-LOs other Moreover, virus infection significantly increased secretion IFN-λ1, IFN-λ2, IFN-λ3, IL-6, IL-1RA HNECs relative infection, but not IPSC-LOs. The less effectively lungs variants; while reached titers comparable it caused greater pathology. Lastly, transmitted efficiently route efficiently. findings demonstrate ongoing utility experimental risk assessment as continue evolve.

Language: Английский

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Recent Advances in Nose and Lung Organoid Models for Respiratory Viral Research

Viruses, Journal Year: 2025, Volume and Issue: 17(3), P. 349 - 349

Published: Feb. 28, 2025

Studies on human respiratory viral infections and pathogenesis have historically been conducted using immortalized cells animal models. However, these models are limited in their ability to recapitulate the complex structure of airway or full spectrum disease symptoms observed humans. Recently, nose lung organoids revolutionized culture complexity infection biology demonstrated potential for research virus In this opinion, we review how advances organoid models, which able express all cell types epithelia, i.e., Club, basal, goblet, ciliated cells, provided novel insight into pathogenesis, age-dependent susceptibility, attenuation signature, immune mechanisms viruses such as SARS-CoV-2, syncytial virus, influenza virus. The also studying hitherto uncultivable be useful studies zoonotic risk.

Language: Английский

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The proton-activated chloride channel inhibits SARS-CoV-2 spike protein-mediated viral entry through the endosomal pathway.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

SARS-CoV-2 binds to its obligatory receptor, angiotensin-converting enzyme 2 (ACE2) and capitalizes on decreasing endosomal acidity cathepsin-mediated spike protein cleavage enter cells. Endosomal acidification is driven by V-ATPase which pumps protons (H + ) into the lumen. The driving force for H maintained import of chloride (Cl - mediated intracellular CLC transporters. We have recently identified Proton-Activated Chloride (PAC) channel as a negative regulator acidification. PAC responds low pH releases Cl from lumen prevent hyperacidification. However, role in viral entry remains unexplored. Here, we show that overexpressing ACE2 expressing HEK 293T cells markedly inhibited spike-mediated entry. Several lines evidence suggest this effect was due suppression pathway. First, abilities regulate inhibit pseudoviral were both dependent localization activity. Second, inhibitory similar E64-d, cathepsin inhibitor, while no major additive treatments observed. Third, inhibition also attenuated TMPRSS2, provides alternative pathway through cell surface. Importantly, overexpression number size plaques formed two live isolates (B.1 Omicron XBB.1.16) Vero E6 Altogether, our data indicates plays vital inhibiting identifies potential novel target against infection other viruses, rely

Language: Английский

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Interplay between respiratory viruses and cilia in the airways

European Respiratory Review, Journal Year: 2025, Volume and Issue: 34(175), P. 240224 - 240224

Published: Jan. 1, 2025

The airway epithelium is the first point of contact for inhaled pathogens. role epithelial cells in clearance, infection and colonisation bacteria established. interactions respiratory viruses cilia less understood, but are known to target ciliated entry, replication dissemination. Furthermore, some impair and/or enhance ciliary activity. This review examines what about between viral how effect function with subsequent consequences human health. We discuss models which can be used investigate relationship host airway.

Language: Английский

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Unique signatures of airway and systemic immunity in severe COVID-19 patients infected with alpha to Omicron SARS-CoV-2 variants of concern

Inflammation Research, Journal Year: 2025, Volume and Issue: 74(1)

Published: March 28, 2025

Language: Английский

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The nasal microbiome modulates risk for SARS-CoV-2 infection

EBioMedicine, Journal Year: 2025, Volume and Issue: unknown, P. 105660 - 105660

Published: April 1, 2025

The nasal microbiome may influence host risk for COVID-19 by modulating the expression of key proteins that facilitate SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2), which binds virus, and transmembrane serine protease (TMPRSS2), activates viral entry into epithelial cells. This study examined whether levels ACE2 TMPRSS2 in cavity predict infection modulates their expression. Using 1548 self-collected swabs from a population-based surveillance testing community-dwelling adults Washington D.C., we conducted two retrospective case-control studies (cross-sectional: n = 111 cases 343 controls; longitudinal: 97 cases, 286 controls) (n 428). Cases, defined as individuals with positive test, were matched controls based on age test date. Pre-infection samples analysed. We measured ACE2/TMPRSS2 using RT-qPCR characterized 16S rRNA gene-based qPCR sequencing. used machine learning regression analysis to determine if predicts influences Elevated was associated 3.6-fold increased contracting (95% CI 1.71-7.47) compared those no detectable or TMPRSS2. Before SARS-CoV-2, also had significantly higher more unstable than controls. Having high densities Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis/nonliquefaciens linked In contrast, having Dolosigranulum pigrum decreased These results suggest natural variation impacts near-term adults. Modifying could potentially reduce risk. Research reported this article supported Milken Institute School Public Health, George University National Allergy Infectious Diseases, Institutes Health under award number R01AI168182. content is solely responsibility authors does not necessarily represent official views Health.

Language: Английский

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