Recombination analysis on the receptor switching event of MERS-CoV and its close relatives: implications for the emergence of MERS-CoV

Tolentino, J. E., Lytras, S., Ito, J. and Sato, K. (2024) Recombination analysis on the receptor switching event of MERS-CoV and its close relatives: implications for the emergence of MERS-CoV. Virology Journal, 21, 84. (doi: 10.1186/s12985-024-02358-2) (PMID:38600521) (PMCID:PMC11008012)

Abstract

Background: PlMERS-CoV is a coronavirus known to cause severe disease in humans, taxonomically classified under the subgenus Merbecovirus. Recent findings showed that the close relatives of MERS-CoV infecting vespertillionid bats (family Vespertillionidae), named NeoCoV and PDF-2180, use their hosts’ ACE2 as their entry receptor, unlike the DPP4 receptor usage of MERS-CoV. Previous research suggests that this difference in receptor usage between these related viruses is a result of recombination. However, the precise location of the recombination breakpoints and the details of the recombination event leading to the change of receptor usage remain unclear. Methods: We used maximum likelihood-based phylogenetics and genetic similarity comparisons to characterise the evolutionary history of all complete Merbecovirus genome sequences. Recombination events were detected by multiple computational methods implemented in the recombination detection program. To verify the influence of recombination, we inferred the phylogenetic relation of the merbecovirus genomes excluding recombinant segments and that of the viruses’ receptor binding domains and examined the level of congruency between the phylogenies. Finally, the geographic distribution of the genomes was inspected to identify the possible location where the recombination event occurred. Results: Similarity plot analysis and the recombination-partitioned phylogenetic inference showed that MERS-CoV is highly similar to NeoCoV (and PDF-2180) across its whole genome except for the spike-encoding region. This is confirmed to be due to recombination by confidently detecting a recombination event between the proximal ancestor of MERS-CoV and a currently unsampled merbecovirus clade. Notably, the upstream recombination breakpoint was detected in the N-terminal domain and the downstream breakpoint at the S2 subunit of spike, indicating that the acquired recombined fragment includes the receptor-binding domain. A tanglegram comparison further confirmed that the receptor binding domain-encoding region of MERS-CoV was acquired via recombination. Geographic mapping analysis on sampling sites suggests the possibility that the recombination event occurred in Africa. Conclusion: Together, our results suggest that recombination can lead to receptor switching of merbecoviruses during circulation in bats. These results are useful for future epidemiological assessments and surveillance to understand the spillover risk of bat coronaviruses to the human population.

• Item Type: Articles
• Additional Information: Funding: This study was supported in part by AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Center “UTOPIA” (JP223fa627001, to Kei Sato), AMED SCARDA Program on RandD of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium and Kei Sato; JP21fk0108425, to Kei Sato; JP21fk0108432, to Kei Sato; JP22fk0108511, to G2P-Japan Consortium and Kei Sato; JP22fk0108516, to Kei Sato; JP22fk0108506, to Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410039, to Kei Sato); JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to Kei Sato); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (23K14526, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, Kei Sato); The Tokyo Biochemical Research Foundation (to Kei Sato); The Mitsubishi Foundation (to Kei Sato), Japanese Government MEXT Scholarship-Research Category (220235, to Jarel Elgin M Tolentino).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sato, Professor Kei and Lytras, Mr Spyros
• Authors: Tolentino, J. E., Lytras, S., Ito, J., and Sato, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Virology Journal
• Publisher: BioMed Central
• ISSN: 1743-422X
• ISSN (Online): 1743-422X
• Copyright Holders: Copyright © The Author(s) 2024
• First Published: First published in Virology Journal 21:84
• Publisher Policy: Reproduced under a creative commons licence