1. The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins
- Author
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Dagmara Bialy, Phoebe Stevenson-Leggett, Matthew Tully, Carina Conceicao, James T. Kelly, Helena J. Maier, Isabelle Dietrich, Erica Bickerton, Christopher Chiu, Katy Moffat, Adrian K. Zagrajek, Leanne Logan, Sushant Bhat, Adrian Paul Silesian, Michal Varga, Christina Tsirigoti, Nazia Thakur, Stacey Human, Philippa Hollinghurst, Dalan Bailey, Stephen C. Graham, John A. Hammond, Holly Shelton, Thakur, Nazia [0000-0002-4450-5911], Human, Stacey [0000-0003-4735-2065], Kelly, James T. [0000-0002-8307-507X], Bhat, Sushant [0000-0003-1869-6176], Stevenson-Leggett, Phoebe [0000-0002-6509-3354], Varga, Michal [0000-0002-7437-1723], Tully, Matthew [0000-0002-1395-1775], Moffat, Katy [0000-0003-0120-7196], Silesian, Adrian Paul [0000-0002-4100-9269], Hammond, John A. [0000-0002-2213-3248], Bickerton, Erica [0000-0002-4012-1283], Dietrich, Isabelle [0000-0002-6300-109X], Graham, Stephen C. [0000-0003-4547-4034], Bailey, Dalan [0000-0002-5640-2266], Apollo - University of Cambridge Repository, Kelly, James T [0000-0002-8307-507X], Hammond, John A [0000-0002-2213-3248], and Graham, Stephen C [0000-0003-4547-4034]
- Subjects
RNA viruses ,Coronaviruses ,viruses ,Host tropism ,Viral Zoonoses ,Poultry ,Cell Fusion ,Bats ,Gamefowl ,Biology (General) ,Receptor ,skin and connective tissue diseases ,Pathology and laboratory medicine ,chemistry.chemical_classification ,Mammals ,0303 health sciences ,General Neuroscience ,Fruit Bats ,virus diseases ,Eukaryota ,Medical microbiology ,3. Good health ,Viruses ,Vertebrates ,Host-Pathogen Interactions ,Spike Glycoprotein, Coronavirus ,Hamsters ,Angiotensin-Converting Enzyme 2 ,Rabbits ,SARS CoV 2 ,Pathogens ,General Agricultural and Biological Sciences ,Research Article ,Cell Physiology ,SARS coronavirus ,QH301-705.5 ,Guinea Pigs ,Mutagenesis (molecular biology technique) ,Virus Attachment ,Biology ,Transfection ,Research and Analysis Methods ,Microbiology ,Rodents ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Birds ,03 medical and health sciences ,Dogs ,Viral entry ,Animals ,Humans ,Molecular Biology Techniques ,Molecular Biology ,Tropism ,030304 developmental biology ,Medicine and health sciences ,Binding Sites ,General Immunology and Microbiology ,Biology and life sciences ,030306 microbiology ,SARS-CoV-2 ,fungi ,Organisms ,Viral pathogens ,Cell Biology ,Virology ,Microbial pathogens ,Rats ,body regions ,Viral Tropism ,HEK293 Cells ,chemistry ,Amino Acid Substitution ,Fowl ,Amniotes ,Tissue tropism ,Cats ,Cattle ,Glycoprotein ,Zoology ,Chickens - Abstract
SARS Coronavirus 2 (SARS-CoV-2) emerged in late 2019, leading to the Coronavirus Disease 2019 (COVID-19) pandemic that continues to cause significant global mortality in human populations. Given its sequence similarity to SARS-CoV, as well as related coronaviruses circulating in bats, SARS-CoV-2 is thought to have originated in Chiroptera species in China. However, whether the virus spread directly to humans or through an intermediate host is currently unclear, as is the potential for this virus to infect companion animals, livestock, and wildlife that could act as viral reservoirs. Using a combination of surrogate entry assays and live virus, we demonstrate that, in addition to human angiotensin-converting enzyme 2 (ACE2), the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in the amino acids at the Spike receptor binding site on these proteins. Of the 22 different hosts we investigated, ACE2 proteins from dog, cat, and cattle were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors. The absence of a significant tropism for any of the 3 genetically distinct bat ACE2 proteins we examined indicates that SARS-CoV-2 receptor usage likely shifted during zoonotic transmission from bats into people, possibly in an intermediate reservoir. Comparison of SARS-CoV-2 receptor usage to the related coronaviruses SARS-CoV and RaTG13 identified distinct tropisms, with the 2 human viruses being more closely aligned. Finally, using bioinformatics, structural data, and targeted mutagenesis, we identified amino acid residues within the Spike–ACE2 interface, which may have played a pivotal role in the emergence of SARS-CoV-2 in humans. The apparently broad tropism of SARS-CoV-2 at the point of viral entry confirms the potential risk of infection to a wide range of companion animals, livestock, and wildlife., A study using a combination of surrogate entry assays and live virus suggests that SARS-CoV-2 may have a broad host-range, revealing that the virus's spike protein can use a broad range of host ACE2 receptors to enter cells and that the sequence of this protein might have changed during the zoonotic jump into humans.
- Published
- 2020