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

Rodriguez-Rodriguez, Bruno A.; Ciabattoni, Grace O.; Duerr, Ralf; Valero-Jimenez, Ana M.; Yeung, Stephen T.; Schinlever, Austin; Bernard-Raichon, Lucie; Galvan, Joaquin Rodriguez; McGrath, Marisa E.; Vashee, Sanjay; Xue, Yong; Loomis, Cynthia A.; Khanna, Kamal M.; Cadwell, Ken; Desvignes, Ludovic; Frieman, Matthew B.; Ortigoza, Mila Brum; Dittmann, Meike

doi:10.1038/s41467-023-38783-0

Cited by 6 publications

(3 citation statements)

References 79 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: 84%

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

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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.

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Section: Introductionmentioning

confidence: 84%

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

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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: Animal Models Of Covid-19mentioning

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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“…Analogous to the inactivation of MHV ORF2 in our system, SARS-CoV-2 ORF8 has acquired premature stop codons in numerous globally successful lineages, including B.1.1.7, XBB.1, XBB.1.5, XBB.1.9, and XBB.1.16., as anecdotally described. ORF8 has been of interest since early in the SARS-CoV-2 pandemic due to a small deletion that emerged in its SARS-CoV ortholog in 200325 , an early cluster of infections in Singapore involving an ORF8 deletion variant26,27 , as well as debate over its role during SARS-CoV-2 infection 6,[27][28][29][30][31][32][33][34] . Despite the intense focus on ORF8 function and loss of full-length protein synthesis, very little attention has been devoted to the evolution of the gene itself.…”

mentioning

confidence: 99%

Hidden evolutionary constraints dictate the retention of coronavirus accessory genes

Goldstein,

Feeley,

Babler

et al. 2023

Preprint

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Genetic innovation is fundamental to the ability of viruses to adapt in the face of host immunity. Coronaviruses exhibit many mechanisms of innovation given flexibility in genomic composition relative to most RNA virus families (1-5). Examples include the acquisition of unique accessory genes that can originate by capture of cellular genes or through duplication and divergence of existing viral genes (6-8). Accessory genes may be influential in dictating viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) with an inactive native phosphodiesterase, NS2, that encodes a complementing cellular AKAP7 gene (9), to simulate the capture of a host gene and found hidden patterns of constraint that determine the fate of coronavirus accessory genes. After courses of serial infection, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. In contrast, the gene encoding inactive NS2, ORF2, remained intact, suggesting it is under cryptic evolutionary constraint. Guided by the retention of ORF2 and hints of similar patterns in related betacoronaviruses, we analyzed the evolution of SARS-CoV-2 ORF8, which arose via gene duplication (6) and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution and extending these findings to viruses currently adapting to humans. Retention of inactive genes challenges assumptions on the dynamics of gene loss in virus genomes and can help guide evolutionary analysis of emerging and pandemic coronaviruses.

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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 79 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

SARS-CoV-2 immunity in animal models

Hidden evolutionary constraints dictate the retention of coronavirus accessory genes

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