The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
cell biology immunology/immunity
Authors: Bao et al.
Journal/ Pre-Print: bioRxiv
Key Words: ACE2, mouse model, transgenic mice, pathology, (5 max)
1. Transgenic mice expressing human ACE2 can be infected with SARS-CoV-2 virus, with significantly increased viral load in lung tissue peaking at 3 days post infection (dpi) and increased anti-spike IgG 21 dpi
2. SARS-CoV-2 infection in ACE2+ mice caused pneumonia, alveolar lesions, increased collagen deposition, detachment of bronchiolar epithelium and infiltration of CD3+ T cells, CD19+ B cells and MAC2+ macrophages, peaking at 5 dpi and becoming milder by 7 dpi
3. This study shows that SARS-CoV-2 meets the requirements of Koch’s postulate to formally identify it as the causative pathogen of COVID-19.
Transgenic mice expressing hACE2 can be infected with SARS-CoV-2. qRT-PCR detected increased viral load in lung tissue, peaking at 3 days post infection (dpi) and increased serum anti-spike IgG at 21 dpi. Lung histopathology indicates alveolar lesions, pneumonia, collagen deposition and infiltration of CD3+ T cells, CD19+ B cells and MAC2+ macrophages, peaking at 5 dpi. hACE2 and SARS-2-S colocalised on alveolar epithelial cells and viral antigens were detected in alveolar macrophages. This study shows SARS-CoV-2 fulfils Koch’s postulate and presents transgenic ACE2+ mice as a potentially effective in vivo model for SARS-CoV-2 infection.
IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS
Understand the virology and/or cell biology of SARS-CoV2/COVID19. This study confirms in an in vivo mouse model that ACE2 is required for SARS-2-CoV infection, and it is the necessary attachment receptor.
Others: Provides biological model to facilitate SARS-2-CoV-2/COVID19 research. This transgenic mouse model seems to reliably model human COVID19 and has potential to be used to test vaccines and treatments.
In vivo mouse study
STRENGTHS AND LIMITATIONS OF THE PAPER
Novelty: The study is the first to formally show that SARS-CoV-2 fulfils Koch’s postulate and is therefore the causative pathogen of COVID-19. It also presents transgenic hACE2+ mice as a novel in vivo model for COVID-19 research.
Standing in the field: The findings are supported by extensive research identifying hACE2 as the attachment receptor for SARS-CoV-2.
Appropriate statistics: Yes, simple statistics (t-test and ANOVA) were used.
Viral model used: Authentic SARS-CoV-2 was used
Translatability: Study does not focus on translatable research.
Main limitations: Although hACE2 was identified as the required attachment receptor, the study did not validate whether the same cellular proteases are used for S protein priming in mice as in humans (TMPRSS2 and CatB/L). If this is not the case it could significantly hinder this model for use in testing treatments for COVID19