Replication of MERS and SARS coronaviruses in bat cells offers insights to their ancestral origins

Lau, S.; Fan, R. Y.; Luk, H. K. H.; Zhu, L.; Fung, J.; Li, K. S.; Wong, E. Y. M.; Ahmed, S. S.; Chan, J. F. W.; Kok, K.-H.; Chan, K.-H.; Wernery, U.; Yuen, K.-y.; Woo, P. C. Y.

doi:10.1101/326538

bioRxiv · 10.1101/326538

Replication of MERS and SARS coronaviruses in bat cells offers insights to their ancestral origins

Lau, S.·Fan, R. Y.·Luk, H. K. H.·Zhu, L.·Fung, J.·Li, K. S.·Wong, E. Y. M.·Ahmed, S. S.·Chan, J. F. W.·Kok, K.-H.·Chan, K.-H.·Wernery, U.·Yuen, K.-y.·Woo, P. C. Y.

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Abstract

Previous findings of Middle East Respiratory Syndrome coronavirus (MERS-CoV)-related viruses in bats, and the ability of Tylonycteris-BatCoV HKU4 spike protein to utilize MERS-CoV receptor, human dipeptidyl peptidase 4 hDPP4, suggest a bat ancestral origin of MERS-CoV. We developed 12 primary bat cell lines from seven bat species, including Tylonycteris pachypus, Pipistrellus abramus and Rhinolophus sinicus (hosts of Tylonycteris-BatCoV HKU4, Pipistrellus-BatCoV HKU5 and SARS-related-CoV respectively), and tested their susceptibilities to MERS-CoVs, SARS-CoV and human coronavirus 229E (HCoV-229E). Five cell lines, including P. abramus and R. sinicus but not T. pachypus cells, were susceptible to human MERS-CoV EMC/2012. However, three tested camel MERS-CoV strains showed different infectivities, with only two strains capable of infecting three and one cell lines respectively. SARS-CoV can only replicate in R. sinicus cells, while HCoV-229E cannot replicate in any bat cells. Bat dipeptidyl peptidase 4 (DPP4) sequences were closely related to those of human and non-human primates but distinct from dromedary DPP4 sequence. Critical residues for binding to MERS-CoV spike protein were mostly conserved in bat DPP4. DPP4 was expressed in the five bat cells susceptible to MERS-CoV, with significantly higher mRNA expression levels than those in non-susceptible cells (P=0.0174), supporting that DPP4 expression is critical for MERS-CoV infection in bats. However, overexpression of T. pachypus DPP4 failed to confer MERS-CoV susceptibility in T. pachypus cells, suggesting other cellular factors in determining viral replication. The broad cellular tropism of MERS-CoV should prompt further exploration of host diversity of related viruses to identify its ancestral origin.

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Lau, S., Fan, R. Y., Luk, H. K. H., Zhu, L., Fung, J., Li, K. S., Wong, E. Y. M., Ahmed, S. S., Chan, J. F. W., Kok, K.-H., Chan, K.-H., Wernery, U., Yuen, K.-y., Woo, P. C. Y.. 2018-05-20. Replication of MERS and SARS coronaviruses in bat cells offers insights to their ancestral origins. https://doi.org/10.1101/326538

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