Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

Jäger, Niklas; Hoffmann, Markus; Pöhlmann, Stefan; Krüger, Nadine

doi:10.3390/v14071526

Cited by 5 publications

(6 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Omicron titer was affected the least, suggesting that Omicron is less dependent on the TMPRSS2-mediated entry pathway compared to the other SARS-CoV-2 viruses and, therefore, may use the alternative endosomal route more than other VOCs. Similar results have been reported by others ( 24 , 31 – 33 ). However, it is important to note that while Omicron is the least dependent VOC on the plasma membrane fusion pathway, it still enters primarily by this pathway in Calu3 cells.…”

Section: Resultssupporting

confidence: 93%

“…During virus entry, the SARS-CoV-2 spike protein is cleaved by TMPRSS2, a serine protease which activates the spike to initiate fusion at the plasma membrane ( 23 – 25 ). It is thought that viruses that express spike with an additional basic amino acid(s) in the furin cleavage recognition site than WA1 (Alpha, Delta, Omicron) would likely use the TMPRSS2-dependent plasma membrane route of infection.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Tanneti,

Patel,

Tan

et al. 2024

mBio

View full text Add to dashboard Cite

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

show abstract

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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

Tanneti,

Patel,

Tan

et al. 2024

mBio

View full text Add to dashboard Cite

show abstract

“…During virus entry the SARS-CoV-2 spike protein is cleaved by TMPRSS2, a serine protease which activates the spike to initiate fusion at the plasma membrane (23)(24)(25). It is thought that viruses that express spike with an additional basic amino acid(s) in the furin cleavage recognition site than WA1 (Alpha, Delta, Omicron) would, be likely to use the TMPRSS2 dependent plasma membrane route of infection.…”

Section: Sars-cov-2 Viruses Enter Primarily By the Transmembrane Prot...mentioning

confidence: 99%

“…During virus entry the SARS-CoV-2 spike protein interacts with TMPRSS2, a serine protease which cleaves and activates the spike to initiate fusion at the plasma membrane (14)(15)(16). It has been proposed that viruses with a disrupted furin protease recognition site at the S1/S2 boundary (RRAR in the ancestral virus) such as Omicron, can enter in a TMPRSS2independent endosomal route in some cell types (17)(18)(19)(20)(21).…”

Section: Sars-cov-2 Viruses Enter Primarily By Tmprss2-mediated Plasm...mentioning

confidence: 99%

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

Tanneti,

Patel,

Tan

et al. 2023

Preprint

View full text Add to dashboard Cite

The ongoing SARS-CoV-2 pandemic has been marked with emerging viral variants, some of which were designated as variants of concern (VOCs) due to their selection and rapid circulation in the human population. Here we elucidate functional features of each VOC in patient-derived primary nasal cultures grown at air-liquid-interface (ALI) to model upper-respiratory infection, and human lung epithelial cell lines to model lung infection. All VOCs replicated to higher titers than the ancestral virus, and Omicron reached the higher titer in the upper-respiratory system in both nasal cells and parallel human studies. Delta was most adept at cell-to-cell spread and the most cytopathic to nasal cells by compromising cell-barrier integrity and ciliary beating. All VOCs overcame dsRNA-activated cellular responses including interferon signaling, oligoadenylate ribonuclease L (OAS-RNase L) degradation and protein kinase R (PKR) activation. Our findings highlight the functional differences among VOCs and illuminate distinct mechanisms of pathogenesis in infected individuals.

show abstract

“…Another paper highlighted nafamostat, a serine protease inhibitor, as a drug that could suppress coronavirus-mediated ribosomal frameshift [ 4 ]. The article is followed by a Comment [ 5 ], pointing out the difference in the mechanisms of action of nafamostat in Vero E6, Calu-3, and A549 cell lines. A review published in this Special Issue summarized data on the structure of flavivirus NS2B-NS3 and attempted to develop antivirals based on available cellular and in vivo models [ 6 ].…”

mentioning

confidence: 99%

Broad-Spectrum Antivirals and Antiviral Combinations: An Editorial Update

Kainov

Oksenych

2022

Viruses

View full text Add to dashboard Cite

show abstract

Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has been reported to have caused 18 [...]

Cited by 5 publications

References 30 publications

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

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

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

Broad-Spectrum Antivirals and Antiviral Combinations: An Editorial Update

Contact Info

Product

Resources

About