OmniVira

Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera.

Raveen Rathnasinghe1,2,3,4 Sonia Jangra1,3 Chengjin Ye5 Anastasija Cupic1,2,3 Gagandeep Singh1,3 Carles Martínez-Romero1,3 Lubbertus C F Mulder1,3 Thomas Kehrer1,2,3 Soner Yildiz1,3 Angela Choi1,2,3,6 Stephen T Yeung7 Ignacio Mena1,3 Virginia Gillespie8 Jana De Vrieze9 Sadaf Aslam1,3 Daniel Stadlbauer1,6 David A Meekins10 Chester D McDowell10 Velmurugan Balaraman10 Michael J Corley7 Juergen A Richt10 Bruno G De Geest9 Lisa Miorin1,3 PVI study group Florian Krammer1 Luis Martinez-Sobrido5 Viviana Simon1,3,11 Adolfo García-Sastre12,13,14,15 Michael Schotsaert16,17
Affiliations 17 institutions
  1. Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
  2. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  3. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
  4. Seqirus, Cambridge, MT, USA.
  5. Texas Biomedical Research Institute, San Antonio, TX, USA.
  6. Moderna Therapeutics, Cambridge, MT, USA.
  7. Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, NY, USA.
  8. Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
  9. Department of Pharmaceutics, Ghent University, Ghent, Belgium.
  10. Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA.
  11. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
  12. Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
  13. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
  14. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
  15. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
  16. Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
  17. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA. [email protected].
PMID35798721 DOI10.1038/s41467-022-30763-0 Year2022 Journal Nature communications Nat Commun Languageeng Statusepublish

Abstract

Due to differences in human and murine angiotensin converting enzyme 2 (ACE-2) receptor, initially available SARS-CoV-2 isolates could not infect mice. Here we show that serial passaging of USA-WA1/2020 strain in mouse lungs results in "mouse-adapted" SARS-CoV-2 (MA-SARS-CoV-2) with mutations in S, M, and N genes, and a twelve-nucleotide insertion in the S gene. MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice. Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs). N501Y in the receptor binding domain of viruses of the B.1.1.7, B.1.351, P.1 and B.1.1.529 lineages (Alpha, Beta, Gamma and Omicron variants) is associated with high transmissibility and allows VoCs to infect wild type mice. We further show that S protein mutations of MA-SARS-CoV-2 do not affect neutralization efficiency by human convalescent and post vaccination sera.

Supporting text Virus Host Location
COVID-19 425 Immune Evasion 25 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 Aged 31 Animals 1949 Humans 1441 Immune Sera 9 Mice 253 Mutation 209 SARS-CoV-2 variants 86 spike protein, SARS-CoV-2 157

Evidence records

2 total
Experimental Infection
1 records · 1 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE6132 Pathogenicity Experiment
Key finding

Experimental infection of mice with MA-SARS-CoV-2 caused mild disease, with more pronounced morbidity in aged and obese animals and depending on mouse genetic background.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice.

Method
experimental infection of mice | observation of clinical disease phenotypes | assessment of morbidity across genetic and physiological conditions
Experimental system
experimental mouse infection model
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE6133 Molecular Adaptation
Key finding

SARS-CoV-2 Spike mutations N501Y and H655Y confer adaptation for infection of mice, overlapping with variants of concern.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs).

Genes or proteins
Spike
Receptors
ACE-2
Mutations
N501Y | H655Y
Mechanism types
host-range expansion | receptor binding | host entry