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

Bruno A. Rodriguez-Rodriguez, Grace O. Ciabattoni, Ralf Duerr, Ana M. Valero-Jimenez, Stephen T. Yeung, Keaton M. Crosse, Austin R. Schinlever, Lucie Bernard-Raichon, Joaquin Rodriguez Galvan, Marisa E. McGrath, Sanjay Vashee, Yong Xue, Cynthia A. Loomis, Kamal M. Khanna, Ken Cadwell, Ludovic Desvignes, Matthew B. Frieman, Mila B. Ortigoza () and Meike Dittmann ()
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Bruno A. Rodriguez-Rodriguez: New York University Grossman School of Medicine
Grace O. Ciabattoni: New York University Grossman School of Medicine
Ralf Duerr: New York University Grossman School of Medicine
Ana M. Valero-Jimenez: New York University Grossman School of Medicine
Stephen T. Yeung: New York University Grossman School of Medicine
Keaton M. Crosse: New York University Grossman School of Medicine
Austin R. Schinlever: New York University Grossman School of Medicine
Lucie Bernard-Raichon: New York University Grossman School of Medicine
Joaquin Rodriguez Galvan: New York University Grossman School of Medicine
Marisa E. McGrath: University of Maryland School of Medicine
Sanjay Vashee: J. Craig Venter Institute
Yong Xue: J. Craig Venter Institute
Cynthia A. Loomis: New York University Grossman School of Medicine
Kamal M. Khanna: New York University Grossman School of Medicine
Ken Cadwell: University of Pennsylvania Perelman School of Medicine
Ludovic Desvignes: New York University Grossman School of Medicine
Matthew B. Frieman: University of Maryland School of Medicine
Mila B. Ortigoza: New York University Grossman School of Medicine
Meike Dittmann: New York University Grossman School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context.

Date: 2023
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DOI: 10.1038/s41467-023-38783-0

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