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Background <p>Many humanized angiotensin-converting enzyme 2 (<i>ACE2</i>) mouse models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection do not replicate human ACE2 protein expression and thus exhibit pathology infrequently observed in humans. To address this limitation, we designed and characterized a fully humanized <i>ACE2</i> (h<i>ACE2</i>) mouse by replacing all exons/introns of the mouse <i>Ace2</i> locus with human DNA comprising the entire <i>ACE2</i> gene and an upstream long noncoding RNA (LncRNA).</p> Results <p>Compared to the popular Keratin18 <i>ACE2</i> (<i>KRT18-ACE2</i>, <i>K18</i>) mouse model of SARS-CoV-2 infection, h<i>ACE2</i> mice displayed a similar tissue expression profile of ACE2 as that seen in human tissues. Further, h<i>ACE2</i> mice showed comparable blood pressure, angiotensin II metabolism, and renal cortical transcriptome as wild-type mice. Intranasal infection of <i>K18</i> mice with the beta variant of SARS-CoV-2 resulted in high viral replication and inflammation of the lung and brain, weight loss, and compassionate euthanasia five days post-infection (PI). Similarly infected h<i>ACE2</i> mice displayed viral replication and inflammation in the lung (but not in brain), sustained weight, and 100% survival up to 12&#xa0;days PI, with clear evidence of acquired immunity. CRISPR-mediated disruption of the upstream&#xa0;LncRNA caused minimal effects on ACE2 mRNA and protein.</p> Conclusions <p>The h<i>ACE2</i> model offers a more accurate approach to studying mechanisms underlying tissue-restricted expression of <i>ACE2</i>, elucidating noncoding sequence variants and an upstream LncRNA, and defining pathways relevant to human disease and associated co-morbidities.</p>

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Development and characterization of a fully humanized ACE2 mouse model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

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  • Chunyu Ge,
  • Amr R. Salem,
  • Amany Elsharkawy,
  • Janhavi Natekar,
  • Anchala Guglani,
  • Jaser Doja,
  • Osarume Ogala,
  • Gavin Wang,
  • Susan H. Griffin,
  • Orazio J. Slivano,
  • Robin Shoemaker,
  • Benard O. Ogola,
  • Christopher F. Basler,
  • Ajay Kumar,
  • W. Bart Bryant,
  • Mukesh Kumar,
  • Joseph M. Miano

摘要

Background

Many humanized angiotensin-converting enzyme 2 (ACE2) mouse models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection do not replicate human ACE2 protein expression and thus exhibit pathology infrequently observed in humans. To address this limitation, we designed and characterized a fully humanized ACE2 (hACE2) mouse by replacing all exons/introns of the mouse Ace2 locus with human DNA comprising the entire ACE2 gene and an upstream long noncoding RNA (LncRNA).

Results

Compared to the popular Keratin18 ACE2 (KRT18-ACE2, K18) mouse model of SARS-CoV-2 infection, hACE2 mice displayed a similar tissue expression profile of ACE2 as that seen in human tissues. Further, hACE2 mice showed comparable blood pressure, angiotensin II metabolism, and renal cortical transcriptome as wild-type mice. Intranasal infection of K18 mice with the beta variant of SARS-CoV-2 resulted in high viral replication and inflammation of the lung and brain, weight loss, and compassionate euthanasia five days post-infection (PI). Similarly infected hACE2 mice displayed viral replication and inflammation in the lung (but not in brain), sustained weight, and 100% survival up to 12 days PI, with clear evidence of acquired immunity. CRISPR-mediated disruption of the upstream LncRNA caused minimal effects on ACE2 mRNA and protein.

Conclusions

The hACE2 model offers a more accurate approach to studying mechanisms underlying tissue-restricted expression of ACE2, elucidating noncoding sequence variants and an upstream LncRNA, and defining pathways relevant to human disease and associated co-morbidities.