SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains

Peter Radvak,Je-Nie Phue,James Rozzelle,Hang Xie,Hyung-Joon Kwon,Neeraj Kapoor,Taylor Rabara,Ruoxuan Xiang,Jeff Fairman,Rong-Fong Shen,Uriel Ortega-Rodriguez,Martina Kosikova

doi:10.1038/s41467-021-26803-w

Abstract

SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.

Highlights

SARS-CoV-2 variants of concern (VOC) B.1.1.7 and B.1.351 show increased transmissibility and enhanced antibody neutralization resistance
As early as 5 dpi, K18hACE2 mice inoculated with 102 50% tissue culture infectious dose (TCID50) per mouse of CA (B.1.1.7) or South Africa/KRISP-EC-K005321/2020 (SA) (B.1.351) began to show signs of infection, e.g., becoming motionless, losing body weight (BW) (Fig. 1a), developing hypothermia (Fig. 1b) and quickly reaching a moribund state (Fig. 1c)
Mice infected with SA (B.1.351) lost up to 30% BW (Fig. 1a), exhibited lower body temperature and all succumbed to death by 10 dpi

Summary

Introduction

SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. In December 2019, a highly contagious novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei Province, China[1] From there it has quickly spread around the world through international travelers resulting in the pandemic of coronavirus disease 2019 (COVID-19). As SARS-CoV-2 continues to circulate globally, more SARS-CoV-2 variants have emerged including B.1.1.7 (alpha) and B.1.351 (beta) lineages that were first detected in the UK and South Africa, respectively[8,9] The viruses of these two lineages contain multiple mutations in S in addition to widespread D614G10. The N501Y mutation results in insertion of the aromatic ring of Y501 into a cavity between Y41 and K353 of hACE2, which increases RBD binding affinity to hACE211

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Conclusion