Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells

Hattori, Takanari; Saito, Takeshi; Okuya, Kosuke; Takahashi, Yuji; Miyamoto, Hiroko; Kajihara, Masahiro; Igarashi, Manabu; Takada, Ayato

doi:10.1128/spectrum.00870-22

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…ACE2 is an important regulator of renin-angiotensin system that regulates blood pressure, fluid, and electrolyte balance, etc, and its polymorphism in humans has been discovered about 20 years ago [29,30] and has been linked to cardiovascular diseases, hypertension, and diabetic mellitus, etc [31][32][33]. Given that cardiovascular diseases, hypertension, and diabetic mellitus are important comorbidity factors for COVID-19, it is not surprising that recently the ACE2 polymorphism has also been found to not only be associated with entry efficiency of SARS-CoV-2 [34,35] but also with COVID-19 outcome [36], indicating that ACE2 polymorphism plays important roles in COVID pathogenesis. Many SARS-CoV related (SC1r-CoV) and SARS-CoV-2 related (SC2r-CoV) bat CoVs including RaTG13 also use human and bat ACE2 as the entry receptor [37][38][39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses

Liu

et al. 2023

PLoS Pathog

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Bat coronavirus RaTG13 shares about 96.2% nucleotide sequence identity with that of SARS-CoV-2 and uses human and Rhinolophus affinis (Ra) angiotensin-converting enzyme 2 (ACE2) as entry receptors. Whether there are bat species other than R. affinis susceptible to RaTG13 infection remains elusive. Here, we show that, among 18 different bat ACE2s tested, only RaACE2 is highly susceptible to transduction by RaTG13 S pseudovirions, indicating that the bat species harboring RaTG13 might be very limited. RaACE2 has seven polymorphic variants, RA-01 to RA-07, and they show different susceptibilities to RaTG13 S transduction. Sequence and mutagenesis analyses reveal that residues 34, 38, and 83 in RaACE2 might play critical roles in interaction with the RaTG13 S protein. Of note, RaACE2 polymorphisms have minimal effect on S proteins of SARS-CoV-2 and several SARS-CoV-2 related CoVs (SC2r-CoV) including BANAL-20-52 and BANAL-20-236 in terms of binding, membrane fusion, and pseudovirus entry. Further mutagenesis analyses identify residues 501 and 505 in S proteins critical for the recognition of different RaACE2 variants and pangolin ACE2 (pACE2), indicating that RaTG13 might have not been well adapted to R. affinis bats. While single D501N and H505Y changes in RaTG13 S protein significantly enhance the infectivity and minimize the difference in susceptibility among different RaACE2 variants, an N501D substitution in SARS-CoV-2 S protein displays marked disparity in transduction efficiencies among RaACE2 variants with a significant reduction in infectivity on several RaACE2 variants. Finally, a T372A substitution in RaTG13 S protein not only significantly increases infectivity on all RaACE2 variants, but it also markedly enhances entry on several bat ACE2s including R. sinicus YN, R. pearsonii, and R. ferrumeiqunum. However, the T372A mutant is about 4-fold more sensitive to neutralizing sera from mice immunized with BANAL-20-52 S, suggesting that the better immune evasion ability of T372 over A372 might contribute to the natural selective advantage of T372 over A372 among bat CoVs. Together, our study aids a better understanding of coronavirus entry, vaccine design, and evolution.

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Section: Discussionmentioning

confidence: 99%

Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses

Liu

et al. 2023

PLoS Pathog

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“…However, this problem is beyond the scope of our review, and the reader can find relevant information in the recent review 312 and original papers. 186,193,[313][314][315] 5. Virus entry into human cells by binding to neuropilin-1 and other receptors ACE2 is widely recognized as the host cell receptor for SARS-CoV-2.…”

Section: Machine Learning and Alchemical Free Energy Methods For Pred...mentioning

confidence: 99%

“…However, this problem is beyond the scope of our review, and the reader can find relevant information in the recent review 312 and original papers. 186,193,313–315…”

Section: Interaction Of Sars-cov-2 Variants Of Concern With Ace2mentioning

confidence: 99%

Interaction of SARS-CoV-2 with host cells and antibodies: experiment and simulation

Nguyen,

Lan

et al. 2023

Chem. Soc. Rev.

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“…Thus, individuals carrying these variant forms of ACE2 are predicted to be less susceptible to SARS-CoV-2 infection. Notably, the E 37 K polymorphism was found to decrease the ability of VSVDG*-SCoV-2 Beta (K 417 N/E 484 K-N 501 Y) to infect cells expressing such an ACE2 variant compared to the wild type ACE2 ( Hattori et al, 2022 ). In contrast, these authors found that two substitutions uncommon in the global population, H 505 R (MAF = 0.001%) and Y 515 C (MAF = 0.004%), enhanced the entry of Alpha and Delta (L 452 R-T 478 K) variants and the Delta variants respectively, compared to the wild type ACE2.…”

Section: Human Ace2 Polymorphism Supports the Hypothesis That The Ace...mentioning

confidence: 99%

“…Two ACE2 variants (E 35 K and F 72 V) possibly conferring resistance to the virus have higher allele frequencies in East Asian populations, while they have shown very low MAFs in European populations ( Chen et al, 2021 ). The E 35 K substitution, uncommon in the global population (MAF = 0.001%) but more frequently found in East Asian population (MAF = 0.01%) seems to be neutral for the entry of the SARS-CoV-2 Alpha variant but decreases the infectivity of the Beta (K 417 N/E 484 K-N 501 Y) variant ( Hattori et al, 2022 ). In the virus S protein, the apparent importance of K 417 and E 484 for interaction with ACE2 suggests the possibility that K 417 N and E 484 K substitutions should negatively affect binding to the ACE2 E 35 K mutant.…”

Section: Human Ace2 Polymorphism Supports the Hypothesis That The Ace...mentioning

confidence: 99%

ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus

Devaux

Fantini

2023

Front. Microbiol.

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Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus’s affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare E329G allele of ACE2 with higher allele frequencies in European populations exhibit a improved affinity for the SARS-CoV-2 spike N501Y variant of the virus. This may suggest that this viral N501Y variant emerged in the human population after SARS-CoV-2 had infected a human carrying the rare E329G allele of ACE2. In addition, this viral evolution could impact viral replication as well as the ability of the adaptive humoral response to control infection with RBD-specific neutralizing antibodies. In a shifting landscape, this ACE2-driven genetic drift of SARS-CoV-2 which we have named the ‘boomerang effect’, could complicate the challenge of preventing COVID with a SARS-CoV-2 spike-derived vaccine.

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Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells

Abstract: SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells.

Cited by 7 publications

References 46 publications

Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses

Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses

Interaction of SARS-CoV-2 with host cells and antibodies: experiment and simulation

ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus

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