Abstract
New emerging severe acute respiratory syndrome 2 (SARS-CoV-2) has caused a worldwide pandemic. Several animal models of coronavirus disease 2019 (COVID-19) have been developed and applied to antiviral research. In this study, two lethal mouse-adapted SARS-CoV-2 variants (BMA8 and C57MA14) with different virulence were generated from different hosts, which are characterized by high viral replication titers in the upper and lower respiratory tract, pulmonary pathology, cytokine storm, cellular tropism, lymphopenia, and neutrophilia. Two variants exhibit host genetics-related and age-dependent morbidity and mortality in mice, exquisitely reflecting the clinical manifestation of asymptomatic, moderate, and severe COVID-19 patients. Notably, both variants equally weaken the neutralization capacity of the serum derived from COVID-19 convalescent, but the C57MA14 variant showed a much higher virulence than the BMA8 variant in vitro. Q489H substitution in the receptor-binding domain (RBD) of BMA8 and C57MA14 variants results in the receptors of SARS-CoV-2 switching from human angiotensin-converting enzyme 2 (hACE2) to murine angiotensin-converting enzyme 2 (mACE2). Additionally, A22D and A36V mutation in E protein were first reported in our study, which potentially contributed to the virulence difference between the two variants. Of note, the protective efficacy of the novel bacterium-like particle (BLP) vaccine candidate was validated using the BMA8- or C57MA14-infected aged mouse model. The BMA8 variant- and C57MA14 variant-infected models provide a relatively inexpensive and accessible evaluation platform for assessing the efficacy of vaccines and novel therapeutic approaches. This will promote further research in the transmissibility and pathogenicity mechanisms of SARS-CoV-2.
Highlights
The human coronavirus disease 2019 (COVID-19) was declared to enter a global pandemic by the World Health Organization (WHO) on March 11, 2020, as the number of infectious cases continues to increase [1]
In aged BALB/c mice, deaths were not observed in P1/P4-inoculated groups (Figure S1C), but weight loss and persistent hypothermia were observed in P4-inoculated mice from 1 day post infection (Figures S1D, E)
The BMA8 variant-infected young BALB/c or C57BL/6N mouse models resembled the symptoms of COVID-19 patients whose SARS-CoV-2 nucleic acid was detectable but without any clinical symptoms
Summary
The human coronavirus disease 2019 (COVID-19) was declared to enter a global pandemic by the World Health Organization (WHO) on March 11, 2020, as the number of infectious cases continues to increase [1]. The causative agent of COVID-19, severe acute respiratory syndrome 2 (SARS-CoV-2), is a new member of the Coronaviridae family [2,3,4,5,6]. The clinical spectrum of SARS-CoV-2 infection is broad, ranging from asymptomatic, moderate, to severe pneumonia. Patients have been classified as asymptomatic carriers, individuals who are positive for SARS-CoV-2 RNA without demonstrating any clinical symptoms [7,8,9]. Patients with moderate disease exhibit clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) and have pulse oxygen saturation (SpO2) >90% [10]. Severe cases are characterized by pneumonia and lymphopenia and at least one of the following: respiratory rate >30 breaths/min, SpO2
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