SARS-CoV-2 BA.2.86 enters lung cells and evades neutralizing antibodies with high efficiency

Cell, Journal Year: 2024, Volume and Issue: 187(3), P. 596 - 608.e17

Published: Jan. 8, 2024

Language: Английский

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TMPRSS2 Is Essential for SARS-CoV-2 Beta and Omicron Infection

Viruses, Journal Year: 2023, Volume and Issue: 15(2), P. 271 - 271

Published: Jan. 18, 2023

The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells, inhibitors being developed therapy. However, Omicron variant, which currently dominates pandemic, prefers endo/lysosomal cysteine cathepsin L over cell entry, raising doubts as to whether would be suitable treatment of patients infected with variant. Nevertheless, contribution spread in host is largely unclear. In this study, we show that loss strongly reduced replication Beta variant nose, trachea C57BL/6 mice, protected animals from weight disease. infection mice did not cause disease, expected, but again, was essential efficient viral upper lower respiratory tract. These results identify key role infection, highlight an attractive target intervention.

Language: Английский

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Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating

mBio, Journal Year: 2024, Volume and Issue: 15(4)

Published: March 13, 2024

ABSTRACT The SARS-CoV-2 pandemic was marked with emerging viral variants, some of which were designated as variants concern (VOCs) due to selection and rapid circulation in the human population. Here, we elucidate functional features each VOC linked variations replication rate. Patient-derived primary nasal cultures grown at air-liquid interface used model upper respiratory infection compared cell lines derived from lung epithelia. All VOCs replicated higher titers than ancestral virus, suggesting a for efficiency. In cultures, Omicron highest early time points, followed by Delta, paralleling comparative studies population sampling. viruses entered primarily via transmembrane serine protease 2 (TMPRSS2)-dependent pathway, more likely use an endosomal route entry. activated overcame dsRNA-induced cellular responses, including interferon (IFN) signaling, oligoadenylate ribonuclease L degradation, protein kinase R activation. Among VOCs, induced expression most IFN IFN-stimulated genes. Infections resulted damage, compromise barrier integrity loss cilia ciliary beating function, especially during Delta infection. Overall, optimized tract least favorable lower line, cytopathic both cells. Our findings highlight differences among level imply distinct mechanisms pathogenesis infected individuals. IMPORTANCE Comparative analysis infections virus concern, Alpha, Beta, Omicron, indicated that selected efficiency replication. patient-derived infection, reached finding confirmed parallel sampling studies. While all dsRNA-mediated host strongest interferon-stimulated gene response. damaging cells syncytia formation, integrity, function.

Language: Английский

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SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(8)

Published: Aug. 9, 2023

SARS-CoV-2 can enter cells after its spike protein is cleaved by either type II transmembrane serine proteases (TTSPs), like TMPRSS2, or cathepsins. It now widely accepted that the Omicron variant uses TMPRSS2 less efficiently and instead enters via cathepsins, but these findings have yet to be verified in more relevant cell models. Although we could confirm efficient cathepsin-mediated entry for a monkey kidney line, experiments with protease inhibitors showed (BA.1 XBB1.5) did not use cathepsins into human airway organoids utilized TTSPs. Likewise, CRISPR-edited intestinal of BA.1 relied on expression cathepsin L B. Together, data force us rethink concept has adapted indicate TTSP should dismissed as prophylactic therapeutic antiviral strategy against SARS-CoV-2. IMPORTANCE Coronavirus relies host activate viral fusion protein, spike. These determine route, tropism, range, attractive drug targets. Whereas earlier studies using lines suggested changed usage, from surface (TTSPs) endosomal report this case organoid models, suggesting inhibition still viable current variants highlighting importance vitro

Language: Английский

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SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 23, 2023

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation retained for later like BA.5 and XBB remains controversial. We show that isolates were significantly more pathogenic in K18-hACE2 mice than a isolate, showing increased neurotropic potential, resulting fulminant brain infection mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains mice, neurons main target infection, neuronal progenitor cells immature infected. results herein suggest evolving may have increasing potential.

Language: Английский

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Use of a risk assessment tool to determine the origin of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)

Risk Analysis, Journal Year: 2024, Volume and Issue: 44(8), P. 1896 - 1906

Published: March 15, 2024

The origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is contentious. Most studies have focused on a zoonotic origin, but definitive evidence such as an intermediary animal host lacking. We used established risk analysis tool for differentiating natural and unnatural epidemics, the modified Grunow-Finke assessment (mGFT) to study SARS-COV-2. mGFT scores 11 criteria provide likelihood or origin. Using published literature publicly available sources information, we applied SARS-CoV-2. scored 41/60 points (68%), with high inter-rater reliability (100%), indicating greater than This cannot prove SARS-CoV-2 shows that possibility laboratory be easily dismissed.

Language: Английский

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Neutralizing antibodies to block viral entry and for identification of entry inhibitors

Antiviral Research, Journal Year: 2024, Volume and Issue: 224, P. 105834 - 105834

Published: Feb. 17, 2024

Language: Английский

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Delta and Omicron SARS-CoV-2 pneumonia: Comparison of clinical and radiological features

Infectious Diseases Now, Journal Year: 2025, Volume and Issue: unknown, P. 105026 - 105026

Published: Jan. 1, 2025

Computed tomography (CT) is a critical tool for the diagnosis of pneumonia caused by SARS-CoV-2. The Delta and Omicron variants show distinct clinical features, but radiological differences between these have not been extensively studied in patients with oxygen-dependent pneumonia. To compare features hospitalized SARS-CoV-2 infection variants. We performed retrospective single-center study, including October 2021 February 2022. Clinical data were collected compared infected variant those variant. CT scans reviewed radiologist pulmonologist blinded to information. A total 135 48 included. Patients older (median age 75 years [68-83.2] vs 69 [62-77.5], p = 0.004), more immunocompromised (52 % vs. 25 %, < 0.001), had higher vaccination rates (73 51 0.009). Radiologically, ground-glass opacities present 95 patients. There no significant degree lung involvement, type lesions their predominance. Unilateral involvement was common Omicron-infected (8.3 0.74 0.02). While occurred comorbid patients, its largely indistinguishable from variant, except rate unilateral involvement.

Language: Английский

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ACE2 acts as a novel regulator of TMPRSS2-catalyzed proteolytic activation of influenza A virus in airway cells

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(4)

Published: March 12, 2024

The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that TMPRSS2 interacts with carboxypeptidase angiotensin-converting enzyme (ACE2), cell surface protein serves as an entry receptor some coronaviruses. Here, by using activity assays, we determine ACE2 increases enzymatic in non-catalytic manner. Furthermore, demonstrate knockdown inhibits TMPRSS2-mediated cleavage IAV hemagglutinin (HA) Calu-3 human airway cells suppresses titers 100- to 1.000-fold. Transient expression ACE2-deficient increased HA replication. also reduced MERS-CoV prevented S cells. By contrast, proteolytic activation multicycle replication multibasic site typically cleaved furin were not affected knockdown. Co-immunoprecipitation analysis revealed ACE2-TMPRSS2 interaction requires domain ACE2. Together, our data identify new co-factor or stabilizer novel host factor involved spread indicate is TMPRSS2-catalyzed additional MERS-CoV.IMPORTANCEProteolytic viral envelope proteases essential infectivity many relevant provide promising drug targets. has been identified major activating several virus. was previously shown interact (ACE2). report mechanistic details this interaction. We stabilizes TMPRSS2. describe involvement spike These findings expand knowledge factors involved. In addition, results could help elucidate physiological role

Language: Английский

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DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

Journal of Cellular Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 29, 2024

Abstract Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus infection favorable tissue specificity and off‐site toxicity profiles remains limited. Therefore, probing anti‐TMPRSS2 potential enhanced drug delivery systems, such as nanotechnology prodrug has become compelling. We report first in silico study a prodrug, [isopropyl(S)‐2‐((S)‐2‐acetamido‐3‐(1H‐indol‐3‐yl)‐propanamido)‐6‐diazo‐5‐oxo‐hexanoate] also known DRP‐104 synthesized from 6‐Diazo‐5‐oxo‐ l ‐norleucine (DON). performed comparative studies on DON clinically inhibitor, nafamostat, standard 4‐(2‐Aminoethyl) benzenesulfonyl fluoride (AEBSF) found improved inhibition through synergistic binding S1/S1' subdomains. Both had better thermodynamic than AEBSF nafamostat. was to confer structural stability strong positive correlated inter‐residue motions, whereas kinetic restricted residue displacements reduced loop flexibility. Interestingly, Scavenger Receptor Cysteine‐Rich (SRCR) domain may be involved its mechanics. Two previously unidentified loops, designated X (270−275) Y (293−296) underwent minimal major transitions, respectively. In addition, residues 273−277 consistently transitioned turn conformation all ligated unique transitions were identified other transitioning groups each TMPRSS2‐inhibitor complex. Intriguingly, while both showed similar transition patterns, preserved integrity. As evident our systematic using experimentally/clinically validated inhibitors, serve novel inhibitor warrants further clinical investigation.

Language: Английский

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