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

In the ongoing battle against coronavirus disease 2019 (COVID-19), understanding its pathogenesis and developing effective treatments remain critical challenges. The creation of animal models that closely replicate human infection stands as a critical step forward in this research. Here, we present a genetically engineered mouse model with specifically-humanized knock-in ACE2 (hiACE2) receptors. This model, featuring nine specific amino acid substitutions for enhanced interaction with the viral spike protein, enables efficient severe acute respiratory syndrome coronavirus 2 replication in respiratory organs without detectable infection in the central nervous system. Moreover, it mirrors the age- and sex-specific patterns of morbidity and mortality, as well as the immunopathological features observed in human COVID-19 cases. Our findings further demonstrate that the depletion of eosinophils significantly reduces morbidity and mortality, depending on the infecting viral dose and the sex of the host. This reduction is potentially achieved by decreasing the pathogenic contribution of eosinophil-mediated inflammation, which is strongly correlated with neutrophil activity in human patients. This underscores the model's utility in studying the immunopathological aspects of COVID-19 and represents a significant advancement in COVID-19 modeling. It offers a valuable tool for testing vaccines and therapeutics, enhancing our understanding of the disease mechanisms and potentially guiding more targeted and effective treatments.

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Publication Details

Journal
Journal of Medical Virology
Published
2024-09-01
DOI
https://doi.org/10.1002/jmv.29915
Citations
3
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.17

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article

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

Nam‐Hyuk Cho, Songhyeok Oh, Sang Ho Yoon, Jeong Ho Seok et al.
3 citations
Journal of Medical Virology
SARS-CoV-2 and COVID-19 Research
1.17
article

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

Nam‐Hyuk Cho, Songhyeok Oh, Sang Ho Yoon, Jeong Ho Seok, Min Yeong Lim, Kyeongseok Jeon, Hye Ran Kim, Yin Hua Zhang, Uni Park, Ju-Il Kang, Uijin Kim, Mi Yeon Park, Myung‐Shin Lee, Myoung‐Hwan Kim, Jun‐Gu Kang, Hye Young Kim, Taehun Kim, Jae Hoon Lee, Yuri Kim, Da‐Eun Jeong, Liyuan Jin, Seung Ro Han, Hyun‐Soo Cho, Han‐Woong Lee, Sun Ha Park, Ga‐Yeon Yoon, Yoon Kyung Jeon, Yoojin Ahn
article en
3 citations

Abstract

In the ongoing battle against coronavirus disease 2019 (COVID-19), understanding its pathogenesis and developing effective treatments remain critical challenges. The creation of animal models that closely replicate human infection stands as a critical step forward in this research. Here, we present a genetically engineered mouse model with specifically-humanized knock-in ACE2 (hiACE2) receptors. This model, featuring nine specific amino acid substitutions for enhanced interaction with the viral spike protein, enables efficient severe acute respiratory syndrome coronavirus 2 replication in respiratory organs without detectable infection in the central nervous system. Moreover, it mirrors the age- and sex-specific patterns of morbidity and mortality, as well as the immunopathological features observed in human COVID-19 cases. Our findings further demonstrate that the depletion of eosinophils significantly reduces morbidity and mortality, depending on the infecting viral dose and the sex of the host. This reduction is potentially achieved by decreasing the pathogenic contribution of eosinophil-mediated inflammation, which is strongly correlated with neutrophil activity in human patients. This underscores the model's utility in studying the immunopathological aspects of COVID-19 and represents a significant advancement in COVID-19 modeling. It offers a valuable tool for testing vaccines and therapeutics, enhancing our understanding of the disease mechanisms and potentially guiding more targeted and effective treatments.

Journal of Medical VirologyVol. 96(9)
Seoul National University (KR), Yonsei University (KR), Eulji University (KR), Seoul National University Hospital (KR), Seoul National University Bundang Hospital (KR), Jeonbuk National University (KR)
National Research Foundation, Seoul National University, National Research Foundation of Korea, College of Medicine, Seoul National University
Good health and well-being
Openalex Percentile: Top 21%
SARS-CoV-2 and COVID-19 Research
1.17
DOIOpen Access PDFOpenAlex
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