OmniVira

SARS-CoV-2 rapidly adapts in aged BALB/c mice and induces typical pneumonia.

Yufei Zhang1,2,3 Kun Huang1,2,3 Ting Wang1,2,3 Fei Deng4 Wenxiao Gong1,2,3 Xianfeng Hui1,2,3 Ya Zhao1,2,3 Xinlin He1,2,3 Chengfei Li1,2,3 Qiang Zhang1,2,3 Xi Chen2 Changjie Lv1,2,3 Xian Lin5 Ying Yang1,2,3 Xiaomei Sun1,2,3 Zhengli Shi5 Huanchun Chen1,2 Zhong Zou6,2,3 Meilin Jin6,2,3
Affiliations 6 institutions
  1. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, P. R. China.
  2. College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, P. R. China.
  3. Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan, P. R. China.
  4. State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, P. R. China.
  5. CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P. R. China.
  6. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, P. R. China [email protected] [email protected].
PMID33692211 DOI10.1128/JVI.02477-20 Year2021 Journal Journal of virology J Virol Languageeng Statusppublish

Abstract

Age is a risk factor for coronavirus disease 2019 (COVID-19) associated morbidity and mortality in humans; hence, in this study, we compared the course of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in young and aged BALB/c mice. We found that SARS-CoV-2 isolates replicated in the respiratory tracts of 12-month-old (aged) mice and caused pathological features of pneumonia upon intranasal infection. In contrast, rapid viral clearance was observed 5 days following infection in 2-month-old (young) mice with no evidence of pathological changes in the lungs. Infection with SARS-CoV-2 elicited significantly upregulated production of cytokines, especially interleukin 6 and interferon gamma, in aged mice; whereas this response was much weaker in young mice. Subsequent challenge of infected aged BALB/c mice with SARS-CoV-2 resulted in neutralized antibody responses, a significantly reduced viral burden in the lungs, and inflammation mitigation. Deep sequencing showed a panel of mutations potentially associated with the enhanced infection in aged BALB/c mice, such as the Q498H mutations which are located at the receptor binding domain (RBD) of the spike (S) protein. We further found that the isolates can not only multiply in the respiratory tract of mice but also cause disease in aged mice. Overall, viral replication and rapid adaption in aged BALB/c mice were associated with pneumonia, confirming that the age-related susceptibility to SARS-CoV-2 in mice resembled that in humans.ImportanceAged BALB/c model are in use as a model of disease caused by SARS-CoV-2. Our research demonstrated SARS-CoV-2 can rapidly adapt in aged BALB/c mice through causing mutations at the RBD of the S protein. Moreover, SARS-CoV-2-infected aged BALB/c mice indicated that alveolar damage, interstitial pneumonia, and inflammatory immune responses were similar to the clinical manifestations of human infections. Therefore, our aged BALB/c challenge model will be useful for further understanding the pathogenesis of SARS-CoV-2 and for testing vaccines and antiviral agents.

Supporting text Virus Host Location

Evidence records

3 total
Experimental Infection
2 records · 2 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE4599 Pathogenicity Experiment
Key finding

SARS-CoV-2 infection caused pneumonia and lung pathology in aged BALB/c mice following intranasal infection.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

We found that SARS-CoV-2 isolates replicated in the respiratory tracts of 12-month-old (aged) mice and caused pathological features of pneumonia upon intranasal infection.

Method
intranasal infection | histopathological examination
Experimental system
aged BALB/c mouse infection model
Evidence type Host Range Experiment
1 records
OVE4598 Host Range Experiment
Key finding

SARS-CoV-2 replicated in the respiratory tracts of aged BALB/c mice but was rapidly cleared in young BALB/c mice following intranasal infection.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

We found that SARS-CoV-2 isolates replicated in the respiratory tracts of 12-month-old (aged) mice and caused pathological features of pneumonia upon intranasal infection. In contrast, rapid viral clearance was observed 5 days following infection in 2-month-old (young) mice with no evidence of pathological changes in the lungs.

Method
intranasal infection | viral replication assay | pathology assessment
Sample type
respiratory tracts | lungs
Experimental system
in vivo mouse infection model with intranasal SARS-CoV-2 challenge
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE4602 Molecular Adaptation
Key finding

A Q498H substitution in the receptor binding domain of the SARS-CoV-2 spike protein emerged during infection of aged BALB/c mice, indicating host-specific molecular adaptation linked to enhanced infection.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

Deep sequencing showed a panel of mutations potentially associated with the enhanced infection in aged BALB/c mice, such as the Q498H mutations which are located at the receptor binding domain (RBD) of the spike (S) protein.

Genes or proteins
spike (S) protein | receptor binding domain (RBD)
Receptors
ACE2
Mutations
Q498H
Mechanism types
receptor binding | host-range expansion