tetano
Editor, Senior Moderator
PLoS Pathog
. 2023 Jan 23;19(1):e1011116.
doi: 10.1371/journal.ppat.1011116. Online ahead of print.
Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses
Pei Li[SUP] 1 [/SUP], Jiaxin Hu[SUP] 1 [/SUP], Yan Liu[SUP] 1 [/SUP], Xiuyuan Ou[SUP] 1 [/SUP], Zhixia Mu[SUP] 1 [/SUP], Xing Lu[SUP] 1 [/SUP], Fuwen Zan[SUP] 1 [/SUP], Mengmeng Cao[SUP] 1 [/SUP], Lin Tan[SUP] 1 [/SUP], Siwen Dong[SUP] 1 [/SUP], Yao Zhou[SUP] 1 [/SUP], Jian Lu[SUP] 2 [/SUP], Qi Jin[SUP] 1 [/SUP], Jianwei Wang[SUP] 1 [/SUP], Zhiqiang Wu[SUP] 1 [/SUP], Yingtao Zhang[SUP] 3 [/SUP], Zhaohui Qian[SUP] 1 [/SUP]
Affiliations
Abstract
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.
. 2023 Jan 23;19(1):e1011116.
doi: 10.1371/journal.ppat.1011116. Online ahead of print.
Effect of polymorphism in Rhinolophus affinis ACE2 on entry of SARS-CoV-2 related bat coronaviruses
Pei Li[SUP] 1 [/SUP], Jiaxin Hu[SUP] 1 [/SUP], Yan Liu[SUP] 1 [/SUP], Xiuyuan Ou[SUP] 1 [/SUP], Zhixia Mu[SUP] 1 [/SUP], Xing Lu[SUP] 1 [/SUP], Fuwen Zan[SUP] 1 [/SUP], Mengmeng Cao[SUP] 1 [/SUP], Lin Tan[SUP] 1 [/SUP], Siwen Dong[SUP] 1 [/SUP], Yao Zhou[SUP] 1 [/SUP], Jian Lu[SUP] 2 [/SUP], Qi Jin[SUP] 1 [/SUP], Jianwei Wang[SUP] 1 [/SUP], Zhiqiang Wu[SUP] 1 [/SUP], Yingtao Zhang[SUP] 3 [/SUP], Zhaohui Qian[SUP] 1 [/SUP]
Affiliations
- PMID: 36689489
- DOI: 10.1371/journal.ppat.1011116
Abstract
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.