Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2
Reut Falach, Liat Bar-On, Shlomi Lazar, Tamar Kadar, Ohad Mazor, Moshe Aftalion, David Gur, Yentl Evgy, Ohad Shifman, Tamar Aminov, Ofir Israeli, Inbar Cohen-Gihon, Galia Zaide, Hila Gutman, Yaron Vagima, Efi Makdasi, Dana Stein, Ronit Rosenfeld, Ron Alcalay, Eran Zahavy, Haim Levy, Itai Glinert, Amir Ben-Shmuel, Tomer Israely, Sharon Melamed, Boaz Politi, Hagit Achdout, Shmuel Yitzhaki, Chanoch Kronman, Tamar Sabo
Reut Falach, Liat Bar-On, Shlomi Lazar, Tamar Kadar, Ohad Mazor, Moshe Aftalion, David Gur, Yentl Evgy, Ohad Shifman, Tamar Aminov, Ofir Israeli, Inbar Cohen-Gihon, Galia Zaide, Hila Gutman, Yaron Vagima, Efi Makdasi, Dana Stein, Ronit Rosenfeld, Ron Alcalay, Eran Zahavy, Haim Levy, Itai Glinert, Amir Ben-Shmuel, Tomer Israely, Sharon Melamed, Boaz Politi, Hagit Achdout, Shmuel Yitzhaki, Chanoch Kronman, Tamar Sabo
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Research Article COVID-19

Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2

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.

Authors

Reut Falach, Liat Bar-On, Shlomi Lazar, Tamar Kadar, Ohad Mazor, Moshe Aftalion, David Gur, Yentl Evgy, Ohad Shifman, Tamar Aminov, Ofir Israeli, Inbar Cohen-Gihon, Galia Zaide, Hila Gutman, Yaron Vagima, Efi Makdasi, Dana Stein, Ronit Rosenfeld, Ron Alcalay, Eran Zahavy, Haim Levy, Itai Glinert, Amir Ben-Shmuel, Tomer Israely, Sharon Melamed, Boaz Politi, Hagit Achdout, Shmuel Yitzhaki, Chanoch Kronman, Tamar Sabo

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Figure 1

Effects of SARS-CoV-2 infection on body weight and mortality of CD-1 mice pretreated with ALI/ARDS stimulants.

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Effects of SARS-CoV-2 infection on body weight and mortality of CD-1 mic...
(A–D) Body weights of CD-1 mice (presented as percentage of original weight determined at the time of viral instillation) were monitored over a period of 15 days after i.n. instillation of SARS-CoV-2. Data are mean ± SEM, n = 5–6 per group, analyzed using 2-way ANOVA followed by Bonferroni’s posttests, *P < 0.05, **P < 0.01, ***P < 0.001 compared with no virus. Displayed representative experiment out of 3–5 independent experiments for each treatment. (A) Body weights of mice infected with virus at a dose of 5 × 106 PFU per mouse (black squares) compared with body weights of naive mice (white squares). (B) Mice were administered LPS (1.7 mg/ kg body weight) and 1 day later were infected (black squares) or not (white squares) with virus (5 × 106 PFU/mouse). (C) Mice were administered bleomycin (2 U/kg body weight) and 4 days later were infected (black squares) or not (white squares) with virus (5 × 106 PFU/mouse). Because of significant mortality, only data of 0 to 6 days are presented for bleomycin–SARS-CoV-2 mice. (D) Mice were administered ricin (1.7 μg/ kg body weight) and 2 days later were infected with virus at a dose of 5 × 105 (black triangles) or 5 × 106 (black squares) PFU/mouse or not (white squares). (E) Kaplan-Meier survival curves of the mouse groups exhibiting mortality: dotted line is SARS-CoV-2 (5 × 106 PFU/mouse), thick dashed line is LDR–SARS-CoV-2 (5 × 105 PFU/mouse), black line is LDR–SARS-CoV-2 (5 × 106 PFU/mouse), thin dashed line is bleomycin–SARS-CoV-2 (5 × 106 PFU/mouse). Data were analyzed using log-rank (Mantel-Cox) test. n = 5.