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

Raveen Rathnasinghe; Sonia Jangra; Chengjin Ye; Anastasija Cupic; Gagandeep Singh; Carles Martínez-Romero; Lubbertus C F Mulder; Thomas Kehrer; Soner Yildiz; Angela Choi; Stephen T Yeung; Ignacio Mena; Virginia Gillespie; Jana De Vrieze; Sadaf Aslam; Daniel Stadlbauer; David A Meekins; Chester D McDowell; Velmurugan Balaraman; Michael J Corley; Juergen A Richt; Bruno G De Geest; Lisa Miorin; PVI study group; Florian Krammer; Luis Martinez-Sobrido; Viviana Simon; Adolfo García-Sastre; Michael Schotsaert

doi:10.1038/s41467-022-30763-0

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

Nat Commun. 2022 Jul 7;13(1):3921. doi: 10.1038/s41467-022-30763-0.

Authors

Raveen Rathnasinghe^#^{1

2

3

4}, Sonia Jangra^#^{1

3}, Chengjin Ye⁵, Anastasija Cupic^{1

2

3}, Gagandeep Singh^{1

3}, Carles Martínez-Romero^{1

3}, Lubbertus C F Mulder^{1

3}, Thomas Kehrer^{1

2

3}, Soner Yildiz^{1

3}, Angela Choi^{1

2

3

6}, Stephen T Yeung⁷, Ignacio Mena^{1

3}, Virginia Gillespie⁸, Jana De Vrieze⁹, Sadaf Aslam^{1

3}, Daniel Stadlbauer^{1

6}, David A Meekins¹⁰, Chester D McDowell¹⁰, Velmurugan Balaraman¹⁰, Michael J Corley⁷, Juergen A Richt¹⁰, Bruno G De Geest⁹, Lisa Miorin^{1

3}; PVI study group; Florian Krammer¹, Luis Martinez-Sobrido⁵, Viviana Simon^{1

3

11}, Adolfo García-Sastre^{12

13

14

15}, Michael Schotsaert^{16

17}

Collaborators

PVI study group:
Giulio Kleiner, Miti Saksena, Komal Srivastava, Charles R Gleason, Maria C Bermúdez-González, Katherine F Beach, Kayla T Russo, Levy A Sominsky, Emily D Ferreri, Rachel L Chernet, Lily Q Eaker, Ashley-Beathrese T Salimbangon, Denise Jurczyszak, Hala Alshammary, Wanni A Mendez, Angela A Amoako, Shelcie Fabre, Mahmoud H Awawda, Amber S Shin

Affiliations

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].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Animals
COVID-19* / virology
Humans
Immune Evasion*
Immune Sera
Mice
Mutation
SARS-CoV-2* / genetics
Spike Glycoprotein, Coronavirus* / genetics

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

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