Proc Natl Acad Sci U S A . Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2

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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 ¹ , Gaowei Hu ² , Yuyan Wang ² , Wenlin Ren ¹ , Xiaomin Zhao ¹ , Fansen Ji ¹ , Yunkai Zhu ² , Fei Feng ² , Mingli Gong ¹ , Xiaohui Ju ¹ , Yuanfei Zhu ² , Xia Cai ² , Jun Lan ³ , Jianying Guo ¹ , Min Xie ¹ , Lin Dong ¹ , Zihui Zhu ¹ , Jie Na ¹ , Jianping Wu ^{4 5} , Xun Lan ¹ , Youhua Xie ² , Xinquan Wang ^{3 6} , Zhenghong Yuan ⁷ , Rong Zhang ⁷ , Qiang Ding ^{8 6}



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.