tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2021 Mar 23;118(12):e2025373118.
doi: 10.1073/pnas.2025373118.
Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2
Yinghui Liu[SUP] 1 [/SUP], Gaowei Hu[SUP] 2 [/SUP], Yuyan Wang[SUP] 2 [/SUP], Wenlin Ren[SUP] 1 [/SUP], Xiaomin Zhao[SUP] 1 [/SUP], Fansen Ji[SUP] 1 [/SUP], Yunkai Zhu[SUP] 2 [/SUP], Fei Feng[SUP] 2 [/SUP], Mingli Gong[SUP] 1 [/SUP], Xiaohui Ju[SUP] 1 [/SUP], Yuanfei Zhu[SUP] 2 [/SUP], Xia Cai[SUP] 2 [/SUP], Jun Lan[SUP] 3 [/SUP], Jianying Guo[SUP] 1 [/SUP], Min Xie[SUP] 1 [/SUP], Lin Dong[SUP] 1 [/SUP], Zihui Zhu[SUP] 1 [/SUP], Jie Na[SUP] 1 [/SUP], Jianping Wu[SUP] 4 5 [/SUP], Xun Lan[SUP] 1 [/SUP], Youhua Xie[SUP] 2 [/SUP], Xinquan Wang[SUP] 3 6 [/SUP], Zhenghong Yuan[SUP] 7 [/SUP], Rong Zhang[SUP] 7 [/SUP], Qiang Ding[SUP] 8 6 [/SUP]
Affiliations
Abstract
The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.
Keywords: ACE2; COVID-19; SARS-CoV-2; host range; intermediate host.
. 2021 Mar 23;118(12):e2025373118.
doi: 10.1073/pnas.2025373118.
Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2
Yinghui Liu[SUP] 1 [/SUP], Gaowei Hu[SUP] 2 [/SUP], Yuyan Wang[SUP] 2 [/SUP], Wenlin Ren[SUP] 1 [/SUP], Xiaomin Zhao[SUP] 1 [/SUP], Fansen Ji[SUP] 1 [/SUP], Yunkai Zhu[SUP] 2 [/SUP], Fei Feng[SUP] 2 [/SUP], Mingli Gong[SUP] 1 [/SUP], Xiaohui Ju[SUP] 1 [/SUP], Yuanfei Zhu[SUP] 2 [/SUP], Xia Cai[SUP] 2 [/SUP], Jun Lan[SUP] 3 [/SUP], Jianying Guo[SUP] 1 [/SUP], Min Xie[SUP] 1 [/SUP], Lin Dong[SUP] 1 [/SUP], Zihui Zhu[SUP] 1 [/SUP], Jie Na[SUP] 1 [/SUP], Jianping Wu[SUP] 4 5 [/SUP], Xun Lan[SUP] 1 [/SUP], Youhua Xie[SUP] 2 [/SUP], Xinquan Wang[SUP] 3 6 [/SUP], Zhenghong Yuan[SUP] 7 [/SUP], Rong Zhang[SUP] 7 [/SUP], Qiang Ding[SUP] 8 6 [/SUP]
Affiliations
- PMID: 33658332
- DOI: 10.1073/pnas.2025373118
Abstract
The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.
Keywords: ACE2; COVID-19; SARS-CoV-2; host range; intermediate host.