Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice

Fatai S Oladunni,Oscar H Rodriguez,Roy Neal Platt,Colin Chuba,Jesse Martinez,Anna Allué-Guardia,Luis D Giavedoni,Luis Martínez-Sobrido ,Ricardo Carrión ,Jun-Gyu Park,Kendra J Alfson,Corbett Christie,Cory R A Hallam,Shalini Gautam,Varun Dwivedi,Jean L Patterson,Angélica M Olmo-Fontánez ,Shannan Hall-Ursone,Andreu Garcia-Vilanova,Stephanie Earley,Xavier Álvarez ,Michal Gaži ,Katrina N Kavelish,Kevin Chiem,Larry S Schlesinger,Alison Whigham,Anwari Akhter,Stephanie Davis Mdaki,Alyssa Schami,Edward J Dick,Colwyn A Headley ,Renee Escalona,Juan Ignacio García García ,Chengjin Ye,Hilary Staples ,Tim Anderson ,Paula A Pino,Laura M Parodi,Olga González ,Deepak Kaushal,Joanne Turner,Jordi B Torrelles

doi:10.1038/s41467-020-19891-7

Abstract

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

Highlights

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models
By 6 days post infection (DPI), SARS-CoV-2-infected K18 human angiotensin-converting enzyme 2 (hACE2) transgenic mice lost over 20% of their initial body weight, were lethargic with rough fur and hunched appearance, immobile, and did not eat or drink, and succumbed to the infection (Fig. 1a, b)
Differentiating by sex, we observed that SARS-CoV-2-infected male K18 hACE2 transgenic mice lost weight starting 1 DPI, at the rate of ~5% per day whereas SARS-CoV-2-infected female K18 hACE2 transgenic mice did not begin to lose weight until 3 DPI (Supplementary Fig 1)

Summary

Introduction

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. K18 hACE2 transgenic mice are, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease. We infected K18 hACE2 transgenic mice with SARS-CoV-2 to assess the feasibility of its use as an animal model of SARS-CoV-2 infection and associated COVID-19 disease. Contrary to other constitutively or transiently expressing hACE2 mouse models[12,13,14,15,16,17,18,19], K18 hACE2 transgenic mice were highly susceptible to SARS-CoV-2 infection, with all mice rapidly losing weight and succumbing to viral infection by 5–6 days post infection (DPI). Our data provide evidence that K18 hACE2 transgenic mice represent an excellent animal model of SARS-CoV-2 infection and associated severe COVID-19 disease, providing the research community with a much-needed small animal model to evaluate vaccines and/or antivirals for SARS-CoV-2 infection and associated severe COVID-19 disease in vivo

Methods

Results

Conclusion