A Mouse Model for Betacoronavirus Subgroup 2c Using a Bat Coronavirus Strain HKU5 Variant

Agnihothram, Sudhakar; Yount, Boyd L.; Donaldson, Eric F.; Huynh, Jeremy; Menachery, Vineet D.; Gralinski, Lisa E.; Graham, Rachel L.; Becker, Michelle M.; Tomar, Sakshi; Scobey, Trevor D.; Osswald, Heather L.; Whitmore, Alan; Gopal, Robin; Ghosh, Arun K.; Mesecar, Andrew; Zambon, Maria; Heise, Mark; Denison, Mark R.; Baric, Ralph S.

BtCoV HKU5-SE caused disease in aged but not young BALB/c mice, leading to 10% weight loss by 4 days p.i. In contrast to other coronaviruses, such as mouse hepatitis virus, which can still replicate and produce disease in carcinoembryonic antigen-related cell adhesion molecule 1-deficient (CEACAM1 Ϫ/Ϫ ) animals (44) , the replication and pathogenesis of BtCoV HKU5-SE was completely dependent upon the presence of the mouse ACE2 receptor, as the ACE2 Ϫ/Ϫ mice clearly showed no weight loss or evidence of virus replication. Furthermore, the presence of viral antigen in small airway epithelial cells and in alveolar cells with morphology like type II pneumocytes is characteristic of tropisms reported during SARS-CoV infection in mice and primates (25, 45) . Histopathologic examination demonstrated interstitial pneumonia in only a few aged animals, replicating phenotypes seen after infection with wild-type and mouse-adapted strains of SARS-CoV in humans and mice (20, 25) . The basis for age-related disease phenotypes following SARS-CoV infection has been linked to alteration in prostaglandin expression in lungs that impairs dendritic cell migration, resulting in a diminished T cell response (46) . Further studies are needed to evaluate the basis for the increased Bt-CoV HKU5-SE pathogenesis in the aged-animal models.