Mice are normally unaffected by SARS-CoV-2 infection since the virus does not bind effectively to the murine version of the ACE2 receptor molecule. Here we report that induced mild pulmonary morbidities render SARS-CoV-2 refractive CD-1 mice to be susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low-doses of the acute-lung-injury stimulants bleomycin or ricin caused a severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates of >50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart and serum of low-dose-ricin pretreated, as compared to non-pretreated mice. Furthermore, lung extracts prepared 2-3 days after viral infection contained subgenomic RNA and virus particles capable of replication, only when derived from the pretreated mice. The deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against SARS-CoV-2 RBD. Thus, viral cell entry in the sensitized mice seems to depend on viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. This unique mode of viral entry, observed over a mildly injured tissue background, may contribute to the exacerbation of COVID-19 pathologies in patients with preexisting morbidities.
Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2