Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to
Reut Falach1, Liat Bar-On1, Shlomi Lazar2
1Department of Biochemistry and Molecular Genetics.
Abstract:
Mice are normally unaffected by SARS coronavirus 2 (SARS-CoV-2) infection since the virus does not bind effectively to the murine version of the angiotensin-converting enzyme 2 (ACE2) receptor molecule. Here, we report that induced mild pulmonary morbidities rendered SARS-CoV-2-refractive CD-1 mice susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low doses of the acute lung injury stimulants bleomycin or ricin caused severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates greater than 50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart, and serum of low-dose ricin-pretreated mice compared with non-pretreated mice. Furthermore, lung extracts prepared 2-3 days after viral infection contained subgenomic mRNA 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 the SARS-CoV-2 receptor binding domain (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 coronavirus disease 2019 (COVID-19) pathologies in patients with preexisting morbidities.
Insights
Mild lung injury in mice made them susceptible to SARS-CoV-2 infection, leading to severe disease and mortality. This suggests a novel viral entry mechanism that could worsen COVID-19 in patients with existing lung conditions.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Mice are typically resistant to SARS-CoV-2 due to ineffective binding to murine ACE2 receptors.
- Pre-existing lung conditions may alter susceptibility to viral infections.
Purpose of the Study:
- To investigate if induced pulmonary morbidities can render SARS-CoV-2-refractive mice susceptible to infection.
- To explore the mechanism of SARS-CoV-2 entry in sensitized mice and its implications for COVID-19 pathogenesis.
Main Methods:
- CD-1 mice were exposed to low doses of bleomycin or ricin to induce mild pulmonary injury.
- Sensitized mice were infected with SARS-CoV-2, and disease severity was monitored (body weight loss, mortality).
- Viral RNA levels, viral replication, and antibody treatments were assessed in infected mice.
Main Results:
- Mild lung injury sensitized mice to SARS-CoV-2, causing >50% mortality and severe disease.
- Pretreated mice showed higher viral RNA in lungs, heart, and serum.
- Replicating virus and subgenomic mRNA were found only in pretreated mice.
- Antibody treatment against the SARS-CoV-2 RBD alleviated disease severity.
Conclusions:
- Pulmonary injury facilitates SARS-CoV-2 infection in mice via a non-canonical ACE2 pathway.
- This mechanism highlights a potential route for SARS-CoV-2 pathogenesis in individuals with underlying lung morbidities.
- Findings may inform strategies for managing COVID-19 in vulnerable patient populations.
