A humanized ACE2 mouse model recapitulating age- and sex-dependent immunopathogenesis of COVID-19 

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B240
Abstract ID: 5351

Presenting Author:
Uni Park , Postdoctoral fellow at Seoul Natl. Univ. Col. of Med.

Abstract:

The COVID-19 pandemic underscores the critical requirement for robust animal models to elucidate the immunological and pathological repercussions of emerging pathogens. In this study, we introduce a novel humanized ACE2 mouse model (hACE2-E1/2/8) developed through precise CRISPR-based substitution of nine human ACE2 amino acids (N24Q, N30D, N31K, Q34H, T79L, S82M, F83Y, S84P, and H353K). This model maintains mouse ACE2 physiological function, exhibiting heightened susceptibility to SARS-CoV-2 without inducing brain damage, thus faithfully representing human COVID-19 pathology. Following infection with the mouse-adapted SARS-CoV-2 strain (MAp30), middle-aged hACE2-E1/2/8 mice exhibit more severe symptoms compared to their younger counterparts, with male mice showing more pronounced symptoms than females. Notably, middle-aged male mice develop long COVID-like symptoms, including persistent weight loss and sustained lung pathology post-acute infection recovery. Furthermore, our model replicates intricate immune responses observed in human COVID-19, such as heightened type I interferon levels and enhanced inflammation associated with neutrophils and eosinophils in plasma. Additionally, mice subjected to eosinophil or neutrophil depletion during early infection stages display milder disease symptoms. This model demonstrates substantial potential to facilitate in-depth exploration of COVID-19 and influence implications for therapeutic and preventative strategies.