A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8

Rodriguez-Rodriguez, Bruno A.; Ciabattoni, Grace; Valero-Jimenez, Ana M.; Schinlever, Austin; Rodriguez-Galvan, Joaquin J; Duerr, Ralf; McGrath, Marisa E.; Desvignes, Ludovic; Frieman, Matthew B.; Ortigoza, Mila Brum; Dittmann, Meike

doi:10.1101/2022.10.04.510658

Cited by 6 publications

(5 citation statements)

References 177 publications

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“…In addition to quantifying RNA copy numbers, which can be misleading with RNA viruses, our experiments also quantify infectious viruses. While several useful animal models have been developed to study SARS-CoV-2 (14, 15) we find that our patient-derived nasal epithelia model more faithfully reflects replication kinetics in the human nose, the first site of infection.…”

Section: Introductionmentioning

confidence: 85%

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

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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.

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Section: Introductionmentioning

confidence: 85%

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

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“…The significance of the ORF-6 region in antagonizing interferon signalling during SARS-CoV-1 infections is well-established. However, conflicting findings exist regarding the role of ORF6 in SARS-CoV-2 infection, with studies showing both direct interference with IFN signaling through binding to nucleoprotein Nup98 and contradictory outcomes in animal models, including mice and hamsters [66][67][68][69][70] . Interestingly, there was limited diversity found in the Spike protein.…”

Section: Discussionmentioning

confidence: 99%

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

Kar,

Johnson,

Vanderheiden

et al. 2024

Preprint

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SARS-CoV-2 is the causative agent of COVID-19 and continues to pose a significant public health threat throughout the world. Following SARS-CoV-2 infection, virus-specific CD4+ and CD8+ T cells are rapidly generated to form effector and memory cells and persist in the blood for several months. However, the contribution of T cells in controlling SARS-CoV-2 infection within the respiratory tract are not well understood. Using C57BL/6 mice infected with a naturally occurring SARS-CoV-2 variant (B.1.351), we evaluated the role of T cells in the upper and lower respiratory tract. Following infection, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract and a vast proportion secrete the cytotoxic molecule Granzyme B. Using antibodies to deplete T cells prior to infection, we found that CD4+ and CD8+ T cells play distinct roles in the upper and lower respiratory tract. In the lungs, T cells play a minimal role in viral control with viral clearance occurring in the absence of both CD4+ and CD8+ T cells through 28 days post-infection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent and culturable virus replicating in the nasal compartment through 28 days post-infection. Using in situ hybridization, we found that SARS-CoV-2 infection persisted in the nasal epithelial layer of tandem CD4+ and CD8+ T cell-depleted mice. Sequence analysis of virus isolates from persistently infected mice revealed mutations spanning across the genome, including a deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.

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“…Additionally, 30% of hACE2 KI C57BL/6 mice were seropositive for SARS-CoV-2 antibodies through exposure to respiratory droplets, and successful aerosol inoculation of hACE2 mice required elevated viral concentrations [114]. Rodriguez et al demonstrated that neonatal K18-hACE2 mice aged 4-7 days could release the virus and transmit it among siblings within the same litter, resulting in a 100% mortality rate among the exposed pups [115].…”

Section: Mouse Modelsmentioning

confidence: 99%

SARS-CoV-2 immunity in animal models

Chen,

Yuan,

et al. 2024

Cell Mol Immunol

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The COVID-19 pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide health crisis due to its transmissibility. SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals. These complications encompass symptoms such as coughing, respiratory distress, fever, infectious shock, acute respiratory distress syndrome (ARDS), and even multiple-organ failure. Animal models serve as crucial tools for investigating pathogenic mechanisms, immune responses, immune escape mechanisms, antiviral drug development, and vaccines against SARS-CoV-2. Currently, various animal models for SARS-CoV-2 infection, such as nonhuman primates (NHPs), ferrets, hamsters, and many different mouse models, have been developed. Each model possesses distinctive features and applications. In this review, we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection, as well as the corresponding immune responses and applications of these models. A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients. Finally, we highlighted the current gaps in related research between animal model studies and clinical investigations, underscoring lingering scientific questions that demand further clarification.

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A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8

Cited by 6 publications

References 177 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

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

SARS-CoV-2 immunity in animal models

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