Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

Batlle, Daniel; Monteil, Vanessa; Garreta, Elena; Hassler, Luise; Wysocki, Jan; Chandar, Vasuretha; Schwartz, Robert E.; Mirazimi, Alì; Montserrat, Núria; Bäder, Michael; Penninger, Josef

doi:10.1016/j.cell.2022.05.004

Cited by 21 publications

(36 citation statements)

References 13 publications

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“…We are sorry to see that Batlle et al. (2022) were not able to draw the same conclusion from their data (Figure S1A in Batlle et al., 2022 ) as we did in our previous study, despite using the experimental conditions that we provided via the editors of Cell ( Methods S1 ). Below are key differences in the experimental conditions between the two studies, which may have contributed to the discrepancies.…”

Section: Main Textmentioning

confidence: 61%

“…Although the authors used the APN01, with higher in vivo stability than its naturally occurring form (Figure 20 in patent US8586319), only ∼2 μg/mL of rACE2 could be detected in serum samples taken from rhesus macaques and piglets shortly after the administration of a high dose of rACE2 (i.e., milligram level of rACE2, depending on the animal species) (Figure 7 in patent US8586319). The initial serum concentrations of rACE2 in these animals were already about 10–100 times lower than the reported doses required for SARS-CoV-2 inhibition in organoids (Figures S1B, S1C, and S1F in Batlle et al., 2022 ). Moreover, given the half-life of rACE2, it would be difficult to maintain high concentrations for extended periods.…”

Section: Main Textmentioning

confidence: 68%

“…Although the APN01 may represent an improved form of rACE2 for therapeutic use, it is not suitable for testing the biological activity of native sACE2. Despite the different rACE2 forms, we noted that super-physiological concentrations of rACE2 (20–200 μg/mL) were required to inhibit SARS-CoV-2 infection in lung- and kidney-derived organoids (Figures S1C–S1E in Batlle et al., 2022 ). Administration of such high levels of rACE2 in patients would be practically difficult.…”

Section: Main Textmentioning

confidence: 96%

“…The letter written by Batlle et al. (2022) reports that SARS-CoV-2 infection could be inhibited by treatment with rACE2 using organoid models at super-physiological concentrations (20–200 μg/mL).…”

Section: Main Textmentioning

confidence: 99%

“…Use of different forms of ACE2. Batlle et al. (2022) used an engineered dimeric form of ACE2 (APN01) instead of the native sACE2 that we used in our previous study ( Yeung et al., 2021 ).…”

Section: Main Textmentioning

confidence: 99%

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Response to Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

Yeung

Teng

Yuen

2022

Cell

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Section: Main Textmentioning

confidence: 61%

Section: Main Textmentioning

confidence: 68%

Section: Main Textmentioning

confidence: 96%

Section: Main Textmentioning

confidence: 99%

“…Use of different forms of ACE2. Batlle et al. (2022) used an engineered dimeric form of ACE2 (APN01) instead of the native sACE2 that we used in our previous study ( Yeung et al., 2021 ).…”

Section: Main Textmentioning

confidence: 99%

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Response to Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

Yeung

Teng

Yuen

2022

Cell

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On the essentiality of the angiotensin converting enzyme 2 receptor for SARS‐CoV‐2 infection and the potential of soluble angiotensin converting enzyme 2 proteins as universal approach for variants causing COVID‐19

Hassler

Penninger

Batlle

2022

Clinical & Translational Med

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After the outbreak of severe actute respiratory syndrom coronavirus (SARS-CoV) in 2003, it was shown that angiotensin converting enzyme 2 (ACE2) was the receptor for this coronavrius. 1 As early as January 2020, it was reported that ACE2 was also the main cell entry receptor for SARS-CoV-2. 2 There have been various reports on additional potential receptors for SARS-CoV-2 cell entry. [3][4][5] The importance of these additional proteins for SARS-CoV-2 cell entry, however, remains unclear. Here, we want to emphasize the evidence in favour of the essentiality of ACE2 for SARS-CoV-2 infection. Normally, human organoids, like human and monkey cell lines, can be easily infected with SARS-CoV-2 when they expre both ACE2 as well as TMPRSS2, one of the proteases critical for the activation of the SARS-CoV-2-ACE2 complex prior to internalization. 6,7 We have provided evidence that kidney organoids derived from cell lines that lack ACE2 could not be infected with SARS-CoV-2 as judged by lack of nucleoprotein staining and ACE2 mRNA and protein levels after exposure to a high dose of SARS-CoV-2. 8 Further evidence in vivo supports the essentiality of ACE2 for SARS-CoV-2 infectivity. Using ACE2-deficient mice inoculated with a mouse-adapted SARS-CoV-2 variant, it was shown that these mice were not susceptible to SARS-CoV-2 infection. 9This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment

Chauhan

Cecon

Labani

et al. 2023

European Journal of Medicinal Chemistry

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Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

Cited by 21 publications

References 13 publications

Response to Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

Response to Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

On the essentiality of the angiotensin converting enzyme 2 receptor for SARS‐CoV‐2 infection and the potential of soluble angiotensin converting enzyme 2 proteins as universal approach for variants causing COVID‐19

Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment

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