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Since the end of 2019, the COVID-19 epidemic caused by the novel coronavirus (SARS-CoV-2) has been circulating globally, and the global mortality rate remains high, which has led to a global public health crisis
.
The clinical symptoms of COVID-19 are diverse, ranging from fever, fatigue, dry cough to dyspnea, from mild pneumonia to acute lung injury (ALI) and acute respiratory distress syndrome in severe cases
.
Similar to SARS-CoV, SARS-CoV-2 belongs to the β-coronavirus genus of the coronavirus family and is an enveloped single-stranded positive RNA virus
.
Human angiotensin-converting enzyme 2 (hACE2) has been confirmed to be a functional receptor for SARS-CoV-2
.
At present, relevant research on SARS-CoV-2 has been carried out in various countries, and some hACE2 expressing mouse models, such as hACE2 transgenic mice, AAV-hACE2 transduced mice and Ad5-hACE2 transduced mice have been developed
.
However, most models only cause mild to moderate lung damage in mice
.
A small animal model that can reproduce the most severe respiratory symptoms and high mortality of COVID-19 is still a top priority
.
Recently, the Qin Chengfeng/Wang Hui team of the Academy of Military Medicine of the Chinese Academy of Military Sciences and the Wang Xiangxi team of the Institute of Biophysics of the Chinese Academy of Sciences published an online publication titled "Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2" in the international journal Nature Communications.
The research paper publicly stated that the team successfully established a severe model of new coronary pneumonia and revealed the molecular mechanism of the new coronavirus cross-species infection
.
DOI: 10.
1038/s41467-021-25903-x First of all, the research team has generated a SARS-CoV-2 (MASCp6) mouse-adapted strain in previous studies, which can cause moderate lung damage in mice
.
On this basis, the researchers further passed 30 consecutive passages to produce a more virulent mouse-adapted strain, and finally produced SARS-CoV-2 (named MASCp36) at the 36th generation
.
Experiments show that after intranasal injection of different doses of BALB/c mice of different months and sexes, 9-month-old mice are highly sensitive to the toxicity of MASCp36, and the toxicity of MASCp36 is dose-dependent
.
All 9-month-old mice were challenged with high-dose MASCp36 and showed typical respiratory symptoms, and showed fur folds, hunched back, and reduced activity
.
In addition, male mice are more sensitive to MASCp36 than female mice
.
The toxicity of MASCp36 to mice of different genders and ages is different.
In order to further determine the pathological results of MASCp36-infected mice, the research team collected lung tissue for histopathology and immunostaining analysis
.
Observation with naked eyes revealed that compared with uninfected control animals, the lung injury of MASCp36-infected mice was severe, with red on both sides and mucus in the lungs
.
Observation under the microscope showed a large number of peeling epithelial cells (yellow arrow) in the bronchioles, large-scale necrosis of alveolar epithelial cells, and infiltration of inflammatory cells in the alveolar wall, mainly neutrophils
.
Severe perivascular edema (cyan arrow) and scattered hemorrhage (blue arrow) indicate that MASCp36 infection induced necrotizing pneumonia and extensive diffuse alveolar damage
.
Acute lung injury in mice caused by MASCp36 infection Finally, the research team conducted a series of in-depth studies on this model.
In-depth sequencing found that MASCp36 detected 12 amino acid mutation sites in serial passages, of which 3 (N501Y, Q493H and K417N) Located in the S protein receptor binding region (RBD), further experiments confirmed that this structure significantly increased the affinity of the MASCp36 virus and murine ACE2.
It was found through electron microscopy that the RBD of the lethal strain MASCp36 and murine ACE2 can form a dense structure that binds stably.
This is highly similar to the structure of wild-type virus RBD and human ACE2
.
RBD mutations in different mouse models and their affinity with hACE2.
In summary, this study produced a new mouse-adapted SARS-CoV-2 strain MASCp36, which can cause severe respiratory symptoms and death Rate
.
The model also shows age- and gender-related death rates similar to those of severe COVID-19
.
In the process of in vivo passage, through deep sequencing of the MASCp36 receptor binding domain (RBD), three amino acid substitutions of N501Y, Q493H and K417N were found
.
This study provides a platform for clarifying the pathogenesis of SARS-CoV-2 and reveals the molecular mechanism of its rapid adaptation and evolution
.
End Reference: [1] https://
.
The clinical symptoms of COVID-19 are diverse, ranging from fever, fatigue, dry cough to dyspnea, from mild pneumonia to acute lung injury (ALI) and acute respiratory distress syndrome in severe cases
.
Similar to SARS-CoV, SARS-CoV-2 belongs to the β-coronavirus genus of the coronavirus family and is an enveloped single-stranded positive RNA virus
.
Human angiotensin-converting enzyme 2 (hACE2) has been confirmed to be a functional receptor for SARS-CoV-2
.
At present, relevant research on SARS-CoV-2 has been carried out in various countries, and some hACE2 expressing mouse models, such as hACE2 transgenic mice, AAV-hACE2 transduced mice and Ad5-hACE2 transduced mice have been developed
.
However, most models only cause mild to moderate lung damage in mice
.
A small animal model that can reproduce the most severe respiratory symptoms and high mortality of COVID-19 is still a top priority
.
Recently, the Qin Chengfeng/Wang Hui team of the Academy of Military Medicine of the Chinese Academy of Military Sciences and the Wang Xiangxi team of the Institute of Biophysics of the Chinese Academy of Sciences published an online publication titled "Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2" in the international journal Nature Communications.
The research paper publicly stated that the team successfully established a severe model of new coronary pneumonia and revealed the molecular mechanism of the new coronavirus cross-species infection
.
DOI: 10.
1038/s41467-021-25903-x First of all, the research team has generated a SARS-CoV-2 (MASCp6) mouse-adapted strain in previous studies, which can cause moderate lung damage in mice
.
On this basis, the researchers further passed 30 consecutive passages to produce a more virulent mouse-adapted strain, and finally produced SARS-CoV-2 (named MASCp36) at the 36th generation
.
Experiments show that after intranasal injection of different doses of BALB/c mice of different months and sexes, 9-month-old mice are highly sensitive to the toxicity of MASCp36, and the toxicity of MASCp36 is dose-dependent
.
All 9-month-old mice were challenged with high-dose MASCp36 and showed typical respiratory symptoms, and showed fur folds, hunched back, and reduced activity
.
In addition, male mice are more sensitive to MASCp36 than female mice
.
The toxicity of MASCp36 to mice of different genders and ages is different.
In order to further determine the pathological results of MASCp36-infected mice, the research team collected lung tissue for histopathology and immunostaining analysis
.
Observation with naked eyes revealed that compared with uninfected control animals, the lung injury of MASCp36-infected mice was severe, with red on both sides and mucus in the lungs
.
Observation under the microscope showed a large number of peeling epithelial cells (yellow arrow) in the bronchioles, large-scale necrosis of alveolar epithelial cells, and infiltration of inflammatory cells in the alveolar wall, mainly neutrophils
.
Severe perivascular edema (cyan arrow) and scattered hemorrhage (blue arrow) indicate that MASCp36 infection induced necrotizing pneumonia and extensive diffuse alveolar damage
.
Acute lung injury in mice caused by MASCp36 infection Finally, the research team conducted a series of in-depth studies on this model.
In-depth sequencing found that MASCp36 detected 12 amino acid mutation sites in serial passages, of which 3 (N501Y, Q493H and K417N) Located in the S protein receptor binding region (RBD), further experiments confirmed that this structure significantly increased the affinity of the MASCp36 virus and murine ACE2.
It was found through electron microscopy that the RBD of the lethal strain MASCp36 and murine ACE2 can form a dense structure that binds stably.
This is highly similar to the structure of wild-type virus RBD and human ACE2
.
RBD mutations in different mouse models and their affinity with hACE2.
In summary, this study produced a new mouse-adapted SARS-CoV-2 strain MASCp36, which can cause severe respiratory symptoms and death Rate
.
The model also shows age- and gender-related death rates similar to those of severe COVID-19
.
In the process of in vivo passage, through deep sequencing of the MASCp36 receptor binding domain (RBD), three amino acid substitutions of N501Y, Q493H and K417N were found
.
This study provides a platform for clarifying the pathogenesis of SARS-CoV-2 and reveals the molecular mechanism of its rapid adaptation and evolution
.
End Reference: [1] https://
