Development and Characterization of a novel humanized ACE2 mouse model to study the pathogenesis of viral lung infection by variable SARS-CoV-2 strains

Abstract Despite global efforts to end the pandemic of COVID19 which has claimed millions of lives in the past few years, there is no sign of the ending in foresee near future. One of the obstacles to end the pandemic is lack of proper animal models to better understand the pathogenesis and test preventive and therapeutic strategies. To answer this call, our group created a novel humanized ACE2 mouse line by removing mouse Ace2 exon 1–9 using CRISPR/Cas9 techinque and put full length human ACE2 cDNA into the same loci. So, the human ACE2 expression is driven by mouse Ace2 promoter. Our validation results indicate that the mice express human ACE2 in a pattern similar to that of mouse Ace2 are expressed. Moreover, inoculating young adult mice (6 weeks old) with variable strains of SARS-CoV-2 (SCV2, Washington or Delta or Omicron strain, 5 × 10 5PFU/mouse) by nasal instillation resulted in differential phenotypes, including viral loads in lung, trachea and nasal turbinate, weight loss, pro-inflammatory cytokine profile, although no mortality was observed in such age grouped mice. In addition, we detected brain pathological protein related to Alzheimer’s disease, Tau protein after 6 days of the viral lung infection, indicating our mouse model has the potential to be used for preclinical studies of long COVID diseases. In summary, our novel humanized ACE2 mouse line has great potential in COVID19 related research. Our ongoing research focuses on further characterize the age and strain dependent SCV2 infection of the mouse line and understanding the pathogenesis and therapeutic strategies for long COVID diseases. Supported by grants from NIH (1R01AI148446-01A1)