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Review
. 2020 Jun 4;14(1):20.
doi: 10.1186/s40246-020-00272-6.

COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice

Cathleen Lutz  1 , Leigh Maher  2 , Charles Lee  2   3 , Wonyoung Kang  4
Affiliations
Review

COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice

Cathleen Lutz et al. Hum Genomics. .

Abstract

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and other epithelia and have shown to develop a rapidly lethal infection after intranasal inoculation with SARS-CoV, the pathogen of SARS. This literature review aims to present the importance of utilizing the human ACE2 transgenic mouse model to better understand the pathogenesis of COVID-19 and develop both therapeutics and vaccines.

Keywords: Angiotensin-converting enzyme 2 (ACE2); COVID-19; Coronavirus; SARS-CoV-2; Transgenic mouse.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The role of the ACE2 and the adverse effect of SARS-CoV in the RAAS. Renin cleaves angiotensinogen into angiotensin I (Ang I), and the circulating Ang I is hydrolyzed to Ang II by ACE. Ang II activates the AT1R to lead the pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, vasoconstrictor response, and increase aldosterone synthesis. ACE2 directly hydrolyzes Ang I and Ang II to generate Ang1–9 and Ang1–7, respectively. Ang1–7 binds to the MasR which leads to the cellular signaling that opposite to the tissue injury effects of Ang II and does not stimulate aldosterone secretion. The SARS-CoV destroys the balance of RAAS by downregulating the ACE2 expression levels. Conclusively, the disproportion between AT1R and MasR axes in SARS-CoV infected patients contributes to the development of tissue injury and more severe inflammatory reactions
Fig. 2
Fig. 2
The potential pathogenic events in the SARS-CoV-2 infected K18-hACE2 mouse model. This diagram shows the pathogenic events that likely occur in SARS-CoV-2 infected hACE2 Tg mice using the examples of K18-hACE2 responses by SARS-CoV infection. K18-hACE2 Tg mice showed severe lung injury and neuronal damage in CNS by SARS-CoV infection, which were associated with the viral replication levels in each organ. The viral spike protein binds to the hACE2 expressed on neuronal cells or epithelial cells of the air tracks. The viral particles-hACE2 complex is internalized into cells. The virus replicates the viral RNA and generates the viral structure proteins to propagate themselves and infect other cells again. The cell damages, apoptosis, and infiltrated inflammatory cells by SARS-CoV-2 infection cause the tissue damage along with the cytokine and chemokine increases in the infected area, resulting in severe organ damages
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