ABSTRACT
Severe manifestations of COVID-19 are mostly restricted to persons with comorbidities, and they form a significantly high proportion of those which develop life-endangering lung injury. Nevertheless, COVID-19 animal models established to date are not based on preexistence of comorbidities. Here we report that mild pulmonary injury induced by administration of acute-lung-injury stimulants, renders outbred CD-1 mice to be sensitive to SARS-CoV-2. Following intranasal pretreatment of mice with low doses of ricin or bleomycin, SARS-CoV-2 infection caused a severe disease manifested by sustained body loss and mortality rates of >50%. Low-dose-ricin pretreated mice displayed markedly higher levels of viral RNA than mice not pretreated with ricin, not only in the nasal turbinate, trachea and lungs but also in the serum and heart. The deleterious effects of SARS-CoV-2 infection in ricin-pretreated mice were effectively alleviated by passive transfer of polyclonal and monoclonal antibodies generated against SARS-CoV-2 or SARS-CoV-2 RBD. Notably, viral cell entry in the sensitized mice model seems to involve viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. In summary, we present a novel animal model in mice that express native murine ACE2 yet are susceptible to genetically unaltered SARS-CoV-2, for the study of comorbidity-dependent COVID-19 pathology and treatment.