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The ancient cardioprotective mechanisms of ACE2 bestow SARS-CoV-2 with a wide host range

Gianni M. Castiglione, Lingli Zhou, Zhenhua Xu, Zachary Neiman, Chien-Fu Hung, Elia J. Duh
doi: https://doi.org/10.1101/2021.01.03.425115
Gianni M. Castiglione
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Lingli Zhou
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Zhenhua Xu
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Zachary Neiman
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Chien-Fu Hung
2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Elia J. Duh
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • For correspondence: eduh@jhmi.edu
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Abstract

SARS-CoV-2 infects a broader range of mammalian species than previously anticipated, suggesting there may be additional unknown hosts wherein the virus can evolve and potentially circumvent effective vaccines. We find that SARS-CoV-2 gains a wide host range by binding ACE2 sites essential for ACE2 carboxypeptidase activity. Six mutations found only in rodent species immune to SARS-CoV-2 are sufficient to abolish viral binding to human and dog ACE2. This is achieved through context-dependent mutational effects (intramolecular epistasis) conserved despite ACE2 sequence divergence between species. Across mammals, this epistasis generates sequence-function diversity, but through structures all bound by SARS-CoV-2. Mutational trajectories to the mouse conformation not bound by SARS-CoV-2 are blocked, by single mutations functionally deleterious in isolation, but compensatory in combination, explaining why human polymorphisms at these sites are virtually non-existent. Closed to humans, this path was opened to rodents via permissive cardiovascular phenotypes and ancient increases to ACE2 activity, serendipitously granting SARS-CoV-2 immunity. This reveals how ancient evolutionary trajectories are linked with unprecedented phenotypes such as COVID-19 and suggests extreme caution should be taken to monitor and prevent emerging animal reservoirs of SARS-CoV-2.

One sentence summary A conserved mechanism essential for ACE2 catalytic activity is exploited by SARS-CoV-2 binding, allowing the virus to infect a wide range of species.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 04, 2021.
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The ancient cardioprotective mechanisms of ACE2 bestow SARS-CoV-2 with a wide host range
Gianni M. Castiglione, Lingli Zhou, Zhenhua Xu, Zachary Neiman, Chien-Fu Hung, Elia J. Duh
bioRxiv 2021.01.03.425115; doi: https://doi.org/10.1101/2021.01.03.425115
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The ancient cardioprotective mechanisms of ACE2 bestow SARS-CoV-2 with a wide host range
Gianni M. Castiglione, Lingli Zhou, Zhenhua Xu, Zachary Neiman, Chien-Fu Hung, Elia J. Duh
bioRxiv 2021.01.03.425115; doi: https://doi.org/10.1101/2021.01.03.425115

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