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Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus.
mBio. 2017 04 04; 8(2)MBIO

Abstract

The evolutionary origins of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) are unknown. Current evidence suggests that insectivorous bats are likely to be the original source, as several 2c CoVs have been described from various species in the family Vespertilionidae Here, we describe a MERS-like CoV identified from a Pipistrellus cf. hesperidus bat sampled in Uganda (strain PREDICT/PDF-2180), further supporting the hypothesis that bats are the evolutionary source of MERS-CoV. Phylogenetic analysis showed that PREDICT/PDF-2180 is closely related to MERS-CoV across much of its genome, consistent with a common ancestry; however, the spike protein was highly divergent (46% amino acid identity), suggesting that the two viruses may have different receptor binding properties. Indeed, several amino acid substitutions were identified in key binding residues that were predicted to block PREDICT/PDF-2180 from attaching to the MERS-CoV DPP4 receptor. To experimentally test this hypothesis, an infectious MERS-CoV clone expressing the PREDICT/PDF-2180 spike protein was generated. Recombinant viruses derived from the clone were replication competent but unable to spread and establish new infections in Vero cells or primary human airway epithelial cells. Our findings suggest that PREDICT/PDF-2180 is unlikely to pose a zoonotic threat. Recombination in the S1 subunit of the spike gene was identified as the primary mechanism driving variation in the spike phenotype and was likely one of the critical steps in the evolution and emergence of MERS-CoV in humans.IMPORTANCE Global surveillance efforts for undiscovered viruses are an important component of pandemic prevention initiatives. These surveys can be useful for finding novel viruses and for gaining insights into the ecological and evolutionary factors driving viral diversity; however, finding a viral sequence is not sufficient to determine whether it can infect people (i.e., poses a zoonotic threat). Here, we investigated the specific zoonotic risk of a MERS-like coronavirus (PREDICT/PDF-2180) identified in a bat from Uganda and showed that, despite being closely related to MERS-CoV, it is unlikely to pose a threat to humans. We suggest that this approach constitutes an appropriate strategy for beginning to determine the zoonotic potential of wildlife viruses. By showing that PREDICT/PDF-2180 does not infect cells that express the functional receptor for MERS-CoV, we further show that recombination was likely to be the critical step that allowed MERS to emerge in humans.

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Authors+Show Affiliations

Anthony SJ
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA sja2127@cumc.columbia.edu. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA. EcoHealth Alliance, New York, New York, USA.
Gilardi K
One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, California, USA.
Menachery VD
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Goldstein T
One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, California, USA.
Ssebide B
Gorilla Doctors, c/o MGVP, Inc., Davis, California, USA.
Mbabazi R
Gorilla Doctors, c/o MGVP, Inc., Davis, California, USA.
Navarrete-Macias I
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.
Liang E
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA. EcoHealth Alliance, New York, New York, USA.
Wells H
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.
Hicks A
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.
Petrosov A
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.
Byarugaba DK
Makerere University Walter Reed Project, Kampala, Uganda. Makerere University, College of Veterinary Medicine, Kampala, Uganda.
Debbink K
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Dinnon KH
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Scobey T
Department of Epidemiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Randell SH
Department of Cell Biology and Physiology and Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Yount BL
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Cranfield M
One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, California, USA. Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Johnson CK
One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, California, USA.
Baric RS
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Lipkin WI
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
Mazet JA
One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, California, USA.

MeSH

AnimalsChiropteraEvolution, MolecularGenome, ViralMiddle East Respiratory Syndrome CoronavirusPhylogenyReceptors, VirusSpike Glycoprotein, CoronavirusSyntenyUgandaVirus Attachment

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

28377531

Citation

Anthony, S J., et al. "Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus." MBio, vol. 8, no. 2, 2017.
Anthony SJ, Gilardi K, Menachery VD, et al. Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. mBio. 2017;8(2).
Anthony, S. J., Gilardi, K., Menachery, V. D., Goldstein, T., Ssebide, B., Mbabazi, R., Navarrete-Macias, I., Liang, E., Wells, H., Hicks, A., Petrosov, A., Byarugaba, D. K., Debbink, K., Dinnon, K. H., Scobey, T., Randell, S. H., Yount, B. L., Cranfield, M., Johnson, C. K., ... Mazet, J. A. (2017). Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. MBio, 8(2). https://doi.org/10.1128/mBio.00373-17
Anthony SJ, et al. Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. mBio. 2017 04 4;8(2) PubMed PMID: 28377531.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus. AU - Anthony,S J, AU - Gilardi,K, AU - Menachery,V D, AU - Goldstein,T, AU - Ssebide,B, AU - Mbabazi,R, AU - Navarrete-Macias,I, AU - Liang,E, AU - Wells,H, AU - Hicks,A, AU - Petrosov,A, AU - Byarugaba,D K, AU - Debbink,K, AU - Dinnon,K H, AU - Scobey,T, AU - Randell,S H, AU - Yount,B L, AU - Cranfield,M, AU - Johnson,C K, AU - Baric,R S, AU - Lipkin,W I, AU - Mazet,J A K, Y1 - 2017/04/04/ PY - 2017/4/6/entrez PY - 2017/4/6/pubmed PY - 2018/1/9/medline KW - MERS coronavirus KW - Uganda KW - bat KW - spike KW - zoonoses JF - mBio JO - mBio VL - 8 IS - 2 N2 - The evolutionary origins of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) are unknown. Current evidence suggests that insectivorous bats are likely to be the original source, as several 2c CoVs have been described from various species in the family Vespertilionidae Here, we describe a MERS-like CoV identified from a Pipistrellus cf. hesperidus bat sampled in Uganda (strain PREDICT/PDF-2180), further supporting the hypothesis that bats are the evolutionary source of MERS-CoV. Phylogenetic analysis showed that PREDICT/PDF-2180 is closely related to MERS-CoV across much of its genome, consistent with a common ancestry; however, the spike protein was highly divergent (46% amino acid identity), suggesting that the two viruses may have different receptor binding properties. Indeed, several amino acid substitutions were identified in key binding residues that were predicted to block PREDICT/PDF-2180 from attaching to the MERS-CoV DPP4 receptor. To experimentally test this hypothesis, an infectious MERS-CoV clone expressing the PREDICT/PDF-2180 spike protein was generated. Recombinant viruses derived from the clone were replication competent but unable to spread and establish new infections in Vero cells or primary human airway epithelial cells. Our findings suggest that PREDICT/PDF-2180 is unlikely to pose a zoonotic threat. Recombination in the S1 subunit of the spike gene was identified as the primary mechanism driving variation in the spike phenotype and was likely one of the critical steps in the evolution and emergence of MERS-CoV in humans.IMPORTANCE Global surveillance efforts for undiscovered viruses are an important component of pandemic prevention initiatives. These surveys can be useful for finding novel viruses and for gaining insights into the ecological and evolutionary factors driving viral diversity; however, finding a viral sequence is not sufficient to determine whether it can infect people (i.e., poses a zoonotic threat). Here, we investigated the specific zoonotic risk of a MERS-like coronavirus (PREDICT/PDF-2180) identified in a bat from Uganda and showed that, despite being closely related to MERS-CoV, it is unlikely to pose a threat to humans. We suggest that this approach constitutes an appropriate strategy for beginning to determine the zoonotic potential of wildlife viruses. By showing that PREDICT/PDF-2180 does not infect cells that express the functional receptor for MERS-CoV, we further show that recombination was likely to be the critical step that allowed MERS to emerge in humans. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/28377531/Further_Evidence_for_Bats_as_the_Evolutionary_Source_of_Middle_East_Respiratory_Syndrome_Coronavirus_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=28377531 DB - PRIME DP - Unbound Medicine ER -