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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Molecular insights into the adaptive evolution of SARS-CoV-2 spike protein

Journal of Infection, Journal Year: 2024, Volume and Issue: 88(3), P. 106121 - 106121

Published: Feb. 16, 2024

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially damaged global economy and human health. spike (S) protein of coronaviruses plays a pivotal role in viral entry binding to host cell receptors. Additionally, it acts as primary target for neutralizing antibodies those infected is central focus currently utilized or researched vaccines. During virus's adaptation host, S SARS-CoV-2 undergone significant evolution. As pandemic unfolded, new mutations have arisen vanished, giving rise distinctive amino acid profiles within variant concern strains SARS-CoV-2. Notably, many these changes been positively selected, leading substantial alterations characteristics, such heightened transmissibility immune evasion capabilities. This review aims provide an overview our current understanding structural implications associated with key These research findings shed light on intricate dynamic nature evolution, underscoring importance continuous monitoring analysis genomes. Through molecular-level investigations, we can attain deeper insights into adaptive offering valuable guidance designing vaccines developing antiviral drugs combat ever-evolving threats.

Language: Английский

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IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 10, 2023

Abstract SARS-CoV-2 infection is known for causing broncho-alveolar inflammation. Interleukin 9 (IL-9) induces airway inflammation and bronchial hyper responsiveness in respiratory viral illnesses allergic inflammation, however, IL-9 has not been assigned a pathologic role COVID-19. Here we show, K18-hACE2 transgenic (ACE2.Tg) mouse model, that contributes to exacerbates spread caused by infection. ACE2.Tg mice with CD4 + T cell-specific deficiency of the transcription factor Forkhead Box Protein O1 (Foxo1) produce significantly less upon than wild type controls they are resistant severe inflammatory disease characterises control mice. Exogenous increases Foxo1-deficient mice, while blockade reduces suppresses infection, providing further evidence Foxo1 -Il-9 mediated Th pathway playing Collectively, our study provides mechanistic insight into an important thus represents proof principle development host-directed therapeutics mitigate severity.

Language: Английский

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Blood-brain barrier function in response to SARS-CoV-2 and its spike protein

Neurologia i Neurochirurgia Polska, Journal Year: 2023, Volume and Issue: 57(1), P. 14 - 25

Published: Feb. 22, 2023

Language: Английский

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Persistence of SARS‐CoV‐2 infection and viral intra‐ and inter‐host evolution in COVID‐19 hospitalized patients

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(6)

Published: May 28, 2024

Abstract Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) persistence in COVID‐19 patients could play a key role the emergence of variants concern. The rapid intra ‐host evolution SARS‐CoV‐2 may result an increased transmissibility, immune and therapeutic escape which be direct consequence epidemic currents. In this context, longitudinal retrospective study on eight consecutive with persistent infection, from January 2022 to March 2023, was conducted. To characterize ‐ inter viral evolution, whole genome sequencing phylogenetic analysis were performed nasopharyngeal samples collected at different time points. Phylogenetic reconstruction revealed accelerated antigenically divergent variants. Bayesian inference principal coordinate showed host‐based genomic structuring among variants, that might reflect positive effect containment practices, within critical hospital area. All isolates shared wide range amino acidic (aa) changes, particularly Spike (S) glycoprotein, transmissibility (K417N, S477N, N501Y Q498R), enhanced infectivity (R346T, S373P, R408S, T478K, Q498R, Y505H, D614G, H655Y, N679K P681H), caused host (S371L, S375F, T376A, K417N, K444T/R) displayed partial or complete resistance treatments (G339D, R346K/T, S371F/L, D405N, N440K, G446S, N460K, E484A, F486V, Q493R, G496S Q498R). These results suggest multiple novel emerge patient during spread another individual continue evolve. A pro‐active surveillance infected is recommended identify genetically lineages before their diffusion.

Language: Английский

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The immune mechanism of the nasal epithelium in COVID-19–related olfactory dysfunction

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

Published: July 17, 2023

During the first waves of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection, olfactory dysfunction (OD) was reported as a frequent clinical sign. The nasal epithelium is one front-line protections against viral infections, and immune responses mucosa may be associated with OD. Two mechanisms underlying OD occurrence in COVID-19 have been proposed: infection sustentacular cells inflammatory reaction epithelium. former triggers latter likely prolongs These two alternative act parallel; more important for because are to entry point SARS-CoV-2 than neurons susceptible early injury. Furthermore, abundantly express transmembrane protease, serine (TMPRSS2) play major role has revealed crucial roles cells. This review aims elucidate how contribute COVID-19–related Understanding aid development improved medical treatments

Language: Английский

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Decoding the paradox: Understanding Elevated Hospitalization and Reduced Mortality in SARS-CoV-2 Variants

International Journal of Frontiers in Science and Technology Research, Journal Year: 2024, Volume and Issue: 6(2), P. 001 - 020

Published: April 6, 2024

Introduction and aim: SARS-CoV-2 outbreaks occur cyclically, aligning with winter when vitamin D levels are lowest, except after new variant outbreaks. Adequate is crucial for robust immune function. Hypovitaminosis diminishes responses, increasing susceptibility to viral infections. The manuscript explores the discrepancy between increased hospitalizations lower mortality. Method​: mutants, including Delta, BQ, XBB Omicron lineages, developed evasion capabilities, reducing effectiveness of COVID-19 vaccines bivalent boosters. failure prevent infections spread others, coupled exhibited by mutant viruses, contributed continued Interestingly, dominant despite their transmissibility, have caused fewer deaths. This article scrutinizes mentioned incongruity through an analysis published data. Results: Achieving herd immunity eradicating has proven elusive due ongoing mutagenesis evasion, leading recurrent approve repurposed early therapies regulators, as well misinformation weak strategies undertaken health authorities, exacerbated situation. Repurposed agents, ivermectin, demonstrated high efficacy against from beginning, remain unaffected mutations. Despite cost-effectiveness widespread availability, regulatory approval these generic agents in treatment pending. Conclusion: Regulators hesitated cost-effective, primarily safeguard temporary status anti-viral under Emergency Use Authorization, which persists. reluctance overlooked opportunity implement integrated approach alongside vaccines, potentially fatalities preventing outbreaks; this led eradicate becoming endemic. It imperative that regulators now reconsider approving affordable generics effectively control future Non-technical Importance (Lay Abstract) significantly bolster human system—deficiency compromises responses increases susceptibility, particularly viruses. While mutations like less severe, they more infectious adept at evading vaccines; thus, offer a limited spectrum protection duration. Primary reduced disease severity but failed spread, contributing Booster doses had little effect on virus paresis, thus should consider generic, ivermectin adjunct address challenge better prepare pandemics. Proactively integrating supplementation fortify system can mitigate vital outbreaks, alleviate hospital burdens, reduce healthcare costs.

Language: Английский

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Rapid Detection of SARS-CoV-2 RNA Using Reverse Transcription Recombinase Polymerase Amplification (RT-RPA) with Lateral Flow for N-Protein Gene and Variant-Specific Deletion–Insertion Mutation in S-Protein Gene

Viruses, Journal Year: 2023, Volume and Issue: 15(6), P. 1254 - 1254

Published: May 26, 2023

Rapid molecular testing for severe acute respiratory coronavirus 2 (SARS-CoV-2) variants may contribute to the development of public health measures, particularly in resource-limited areas. Reverse transcription recombinase polymerase amplification using a lateral flow assay (RT-RPA-LF) allows rapid RNA detection without thermal cyclers. In this study, we developed two assays detect SARS-CoV-2 nucleocapsid (N) gene and Omicron BA.1 spike (S) gene-specific deletion–insertion mutations (del211/ins214). Both tests had limit 10 copies/µL vitro time was approximately 35 min from incubation detection. The sensitivities RT-RPA-LF by viral load categories were 100% clinical samples with high (>9015.7 copies/µL, cycle quantification (Cq): < 25) moderate (385.5–9015.7 Cq: 25–29.9) load, 83.3% low (16.5–385.5 30–34.9), 14.3% very (<16.5 35–40). 94.9%, 78%, 23.8%, 0%, respectively, specificity against non-BA.1 SARS-CoV-2-positive 96%. seemed more sensitive than antigen samples. Although implementation settings requires additional improvements, successfully detected technique.

Language: Английский

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Long-term neurological and otolaryngological sequelae of COVID-19: a retrospective study

Exploration of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Aim: COVID-19, a multisystemic syndrome caused by SARS-CoV-2, often results in long-term complications collectively referred to as long COVID. This study explores the persistence of neurological and otolaryngological symptoms patients two years after acute infection, with focus on gender differences variant-specific effects. Methods: A retrospective follow-up was conducted January 2024 112 who had been hospitalized for COVID-19. Patients completed questionnaire assessing neuropsychiatric, otolaryngological, systemic symptoms. Results: Findings reveal that 18.3% women reported persistent neuropsychiatric symptoms, such memory deficits, depression, concentration issues, compared 5.7% men. Otolaryngological including anosmia ageusia, largely resolved, only 4.5% reporting issues. Symptom more common older individuals, women, smokers, those severe acute-phase illness. Neuropsychiatric remain prominent, underscoring need targeted care. Conclusions: Vaccination significantly reduces risk severity COVID, particularly emphasizing its role mitigating burden SARS-CoV-2. Future research should explore biomolecular markers imaging techniques better understand address these sequelae.

Language: Английский

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Genome-wide bioinformatics analysis of human protease capacity for proteolytic cleavage of the SARS-CoV-2 spike glycoprotein

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(2)

Published: Jan. 8, 2024

ABSTRACT Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding virus’s spike (S) glycoprotein to angiotensin-converting enzyme 2 receptor on surface, followed proteolytic cleavage host proteases. Studies have identified furin and transmembrane protease serine proteases in priming triggering cleavages of S glycoprotein, converting it into a fusion-competent form initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter through endocytic pathway, where activation is triggered lysosomal cathepsin L. However, other are also suspected be involved both entry routes. In this study, we conducted genome-wide bioinformatics analysis explore capacity human hydrolyzing peptide bonds glycoprotein. Predictive models sequence specificity for 169 were constructed applied together with method predicting structural susceptibility proteolysis protein regions. After validating our approach extensively studied S2′ S1/S2 sites, each bond across all Our results indicate that various members proprotein convertase subtilisin/kexin type, type II family protease, kallikrein families, as well specific coagulation factors, capable cleaving or sites. We potential site L at K790 position within loop. Structural suggests induces conformational changes similar R815 (S2′) position, leading exposure fusion subsequent membrane. Other sites influence mutations common variants efficiency discussed. IMPORTANCE The severe cell, activated proteases, considerably more complex coronaviruses than most viruses not fully understood. There evidence beyond known activate protein. Another example uncertainty alternative route entrance, which still unknown. Bioinformatics methods, modeling estimating regions proteolysis, aid studying topic their thereby substantially reducing amount experimental work. Elucidating mechanisms crucial preventing possible future coronavirus pandemics developing antiviral drugs.

Language: Английский

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