SARS-CoV-2 Infection in Human ACE2 Transgenic Mice

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become pandemic, resulting in severe morbidity and mortality around the world. COVID-19 pathogenesis includes lung inflammation, cytokine storm and organ failures, but the mechanism underlying the disease remains to be studied. To determine what role(s) the well-characterized type I interferon (IFN-I)-mediated innate antiviral responses might play against SARS-CoV-2 infection, we treated hACE2 transgenic (Tg) mice, AC70 line, with mouse IFN-I receptor-specific monoclonal antibody prior to challenge with 106TCID50 of SARS-CoV-2 (US-WA-1/2020). Both IFN-blocked and-unblocked animals developed clinical signs of disease with body weight loss from day 3 and 100% mortality between 4 and 5 days post-infection with SARS-CoV-2 at high dose (106 TCID50). Although live virus was detected in the lungs and brain of both groups, live virus was detected only in the kidneys, liver, spleen, heart, and gastrointestinal tract of the IFN-blocked group. Elevated expression of proinflammatory cytokines and interferons including IFN-λ were detected in all organs tested in both groups. Immunostaining for SARS-CoV-2 spike protein along with profound histopathological observations in the lungs and brain of both groups show severe COVID-19 disease pathogenesis. Our results show that AC70 Tg mice are highly permissive to SARS-COV-2 infection and develop severe COVID-19. Furthermore, we show type I IFN-mediated signaling pathways play a critical role in restricting viral spread and are ideal for development of medical countermeasures (MCMs) against COVID-19.