1887

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged to cause widespread infections in humans. SARS-CoV-2 infections have been reported in the Kingdom of Saudi Arabia, where Middle East respiratory syndrome coronavirus (MERS-CoV) causes seasonal outbreaks with a case fatality rate of ~37 %. Here we show that there exists a theoretical possibility of future recombination events between SARS-CoV-2 and MERS-CoV RNA. Through computational analyses, we have identified homologous genomic regions within the ORF1ab and S genes that could facilitate recombination, and have analysed co-expression patterns of the cellular receptors for SARS-CoV-2 and MERS-CoV, ACE2 and DPP4, respectively, to identify human anatomical sites that could facilitate co-infection. Furthermore, we have investigated the likely susceptibility of various animal species to MERS-CoV and SARS-CoV-2 infection by comparing known virus spike protein–receptor interacting residues. In conclusion, we suggest that a recombination between SARS-CoV-2 and MERS-CoV RNA is possible and urge public health laboratories in high-risk areas to develop diagnostic capability for the detection of recombined coronaviruses in patient samples.

Funding
This study was supported by the:
  • Karen Mossman , Canadian Institutes for Health Research
  • Karen Mossman , Natural Sciences and Engineering Research Council
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001491
2020-09-09
2020-10-30
Loading full text...

Full text loading...

/deliver/fulltext/jgv/10.1099/jgv.0.001491/jgv001491.html?itemId=/content/journal/jgv/10.1099/jgv.0.001491&mimeType=html&fmt=ahah

References

  1. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270–273 [CrossRef][PubMed]
    [Google Scholar]
  2. Boni MF, Lemey P, Jiang X, Lam TT-Y, Perry BW et al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol 2020 [CrossRef][PubMed]
    [Google Scholar]
  3. Lam TT-Y, Jia N, Zhang Y-W, Shum MH-H, Jiang J-F et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature 2020; 583:282–285 [CrossRef][PubMed]
    [Google Scholar]
  4. Anthony SJ, Johnson CK, Greig DJ, Kramer S, Che X et al. Global patterns in coronavirus diversity. Virus Evol 2017; 3:vex012 [CrossRef][PubMed]
    [Google Scholar]
  5. Wang Q, Qi J, Yuan Y, Xuan Y, Han P et al. Bat origins of MERS-CoV supported by bat coronavirus HKU4 usage of human receptor CD26. Cell Host Microbe 2014; 16:328–337 [CrossRef][PubMed]
    [Google Scholar]
  6. de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016; 14:523–534 [CrossRef][PubMed]
    [Google Scholar]
  7. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier RAM. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367:1814–1820 [CrossRef][PubMed]
    [Google Scholar]
  8. Ramadan N, Shaib H. Middle East respiratory syndrome coronavirus (MERS-CoV): a review. Germs 2019; 9:35–42 [CrossRef][PubMed]
    [Google Scholar]
  9. WHO Middle East respiratory syndrome coronavirus. Available from https://www.who.int/emergencies/mers-cov/en/; 2020
  10. Ruan S. Likelihood of survival of coronavirus disease 2019. Lancet Infect Dis 2020; 20:630–631 [CrossRef][PubMed]
    [Google Scholar]
  11. Lai MM, Cavanagh D. The molecular biology of coronaviruses. Adv Virus Res 1997; 48:1–100[PubMed]
    [Google Scholar]
  12. Lai MM. Coronavirus: organization, replication and expression of genome. Annu Rev Microbiol 1990; 44:303–333 [CrossRef][PubMed]
    [Google Scholar]
  13. Graham RL, Baric RS. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. J Virol 2010; 84:3134–3146 [CrossRef][PubMed]
    [Google Scholar]
  14. Temperton NJ, Chan PK, Simmons G, Zambon MC, Tedder RS et al. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg Infect Dis 2005; 11:411–416 [CrossRef][PubMed]
    [Google Scholar]
  15. Lu S, Wang Y, Chen Y, Wu B, Qin K et al. Discovery of a novel canine respiratory coronavirus support genetic recombination among betacoronavirus1. Virus Res 2017; 237:7–13 [CrossRef][PubMed]
    [Google Scholar]
  16. Zhang Y, Li J, Xiao Y, Zhang J, Wang Y et al. Genotype shift in human coronavirus OC43 and emergence of a novel genotype by natural recombination. J Infect 2015; 70:641–650 [CrossRef][PubMed]
    [Google Scholar]
  17. Woo PCY, Lau SKP, Yip CCY, Huang Y, Tsoi H-W et al. Comparative analysis of 22 coronavirus HKU1 genomes reveals a novel genotype and evidence of natural recombination in coronavirus HKU1. J Virol 2006; 80:7136–7145 [CrossRef][PubMed]
    [Google Scholar]
  18. Woo PCY, Lau SKP, Huang Y, Tsoi H-W, Chan K-H et al. Phylogenetic and recombination analysis of coronavirus HKU1, a novel coronavirus from patients with pneumonia. Arch Virol 2005; 150:2299–2311 [CrossRef][PubMed]
    [Google Scholar]
  19. Lau SKP, Li KSM, Huang Y, Shek C-T, Tse H et al. Ecoepidemiology and complete genome comparison of different strains of severe acute respiratory syndrome-related Rhinolophus bat coronavirus in China reveal bats as a reservoir for acute, self-limiting infection that allows recombination events. J Virol 2010; 84:2808–2819 [CrossRef][PubMed]
    [Google Scholar]
  20. Sabir JSM, Lam TT-Y, Ahmed MMM, Li L, Shen Y et al. Co-circulation of three camel coronavirus species and recombination of MERS-CoVs in Saudi Arabia. Science 2016; 351:81–84 [CrossRef][PubMed]
    [Google Scholar]
  21. Wang Y, Liu D, Shi W, Lu R, Wang W et al. Origin and possible genetic recombination of the middle East respiratory syndrome coronavirus from the first imported case in China: phylogenetics and coalescence analysis. mBio 2015; 6:e01280–15 [CrossRef][PubMed]
    [Google Scholar]
  22. Nassar MS, Bakhrebah MA, Meo SA, Alsuabeyl MS, Zaher WA. Global seasonal occurrence of middle East respiratory syndrome coronavirus (MERS-CoV) infection. Eur Rev Med Pharmacol Sci 2018; 22:3913–3918 [CrossRef][PubMed]
    [Google Scholar]
  23. Wright ES. Using DECIPHER v2.0 to analyze big biological sequence data in R. R J 2016; 8:352–359 [CrossRef]
    [Google Scholar]
  24. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 2011; 7:539 [CrossRef][PubMed]
    [Google Scholar]
  25. RCoreTeam R. R: a language and environment for statistical computing. Available from: https://www.r-project.org; 2017
  26. Gao Y, Yan L, Huang Y, Liu F, Zhao Y et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 2020; 368:779–782 [CrossRef][PubMed]
    [Google Scholar]
  27. GTEx Consortium The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45:580–585 [CrossRef][PubMed]
    [Google Scholar]
  28. Vancamelbeke M, Vanuytsel T, Farré R, Verstockt S, Ferrante M et al. Genetic and transcriptomic bases of intestinal epithelial barrier dysfunction in inflammatory bowel disease. Inflamm Bowel Dis 2017; 23:1718–1729 [CrossRef][PubMed]
    [Google Scholar]
  29. Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8:118–127 [CrossRef][PubMed]
    [Google Scholar]
  30. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016; 44:W90–W97 [CrossRef][PubMed]
    [Google Scholar]
  31. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 2013; 30:772–780 [CrossRef][PubMed]
    [Google Scholar]
  32. Katoh K, Misawa K, Kuma K-ichi, Miyata T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res 2002; 30:3059–3066 [CrossRef][PubMed]
    [Google Scholar]
  33. Stamatakis A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 2014; 30:1312–1313 [CrossRef][PubMed]
    [Google Scholar]
  34. Kozlov AM, Darriba D, Flouri T, Morel B, Stamatakis A. RAxML-NG: a fast, scalable and user-friendly tool for maximum likelihood phylogenetic inference. Bioinformatics 2019; 35:4453–4455 [CrossRef][PubMed]
    [Google Scholar]
  35. Waterhouse AM, Procter JB, Martin DMA, Clamp M, Barton GJ. Jalview Version 2--a multiple sequence alignment editor and analysis workbench. Bioinformatics 2009; 25:1189–1191 [CrossRef][PubMed]
    [Google Scholar]
  36. Paradis E, Schliep K. ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. Bioinformatics 2019; 35:526–528 [CrossRef][PubMed]
    [Google Scholar]
  37. Madeira F, Park YM, Lee J, Buso N, Gur T et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 2019; 47:W636–W641 [CrossRef][PubMed]
    [Google Scholar]
  38. Sarachu M, Colet M. wEMBOSS: a web interface for EMBOSS. Bioinformatics 2005; 21:540–541 [CrossRef][PubMed]
    [Google Scholar]
  39. Wagih O. ggseqlogo: a versatile R package for drawing sequence logos. Bioinformatics 2017; 33:3645–3647 [CrossRef][PubMed]
    [Google Scholar]
  40. Pasternak AO, Spaan WJM, Snijder EJ. Nidovirus transcription: how to make sense.?. J Gen Virol 2006; 87:1403–1421 [CrossRef][PubMed]
    [Google Scholar]
  41. Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 2009; 7:439–450 [CrossRef][PubMed]
    [Google Scholar]
  42. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 2015; 1282:1–23 [CrossRef][PubMed]
    [Google Scholar]
  43. Nagy PD. The roles of host factors in tombusvirus RNA recombination. Adv Virus Res 2011; 81:63–84 [CrossRef][PubMed]
    [Google Scholar]
  44. Hu B, Zeng L-P, Yang X-L, Ge X-Y, Zhang W et al. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog 2017; 13:e1006698 [CrossRef][PubMed]
    [Google Scholar]
  45. Rubnitz J, Subramani S. The minimum amount of homology required for homologous recombination in mammalian cells. Mol Cell Biol 1984; 4:2253–2258 [CrossRef][PubMed]
    [Google Scholar]
  46. Shang J, Ye G, Shi K, Wan Y, Luo C et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020; 581:221–224 [CrossRef][PubMed]
    [Google Scholar]
  47. Raj VS, Mou H, Smits SL, Dekkers DHW, Müller MA et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495:251–254 [CrossRef][PubMed]
    [Google Scholar]
  48. Zou L, Ruan F, Huang M, Liang L, Huang H et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020; 382:1177–1179 [CrossRef][PubMed]
    [Google Scholar]
  49. van den Brand JMA, Smits SL, Haagmans BL. Pathogenesis of Middle East respiratory syndrome coronavirus. J Pathol 2015; 235:175–184 [CrossRef][PubMed]
    [Google Scholar]
  50. Davison JM, Lickwar CR, Song L, Breton G, Crawford GE et al. Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor hepatocyte nuclear factor 4 alpha. Genome Res 2017; 27:1195–1206 [CrossRef][PubMed]
    [Google Scholar]
  51. Lan J, Ge J, Yu J, Shan S, Zhou H et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581:215–220 [CrossRef][PubMed]
    [Google Scholar]
  52. Wang N, Shi X, Jiang L, Zhang S, Wang D et al. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res 2013; 23:986–993 [CrossRef][PubMed]
    [Google Scholar]
  53. Shi J, Wen Z, Zhong G, Yang H, Wang C et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science 2020; 368:1016–1020 [CrossRef][PubMed]
    [Google Scholar]
  54. THC S, Brackman CJ, SM I, KWS T, PYT L et al. Infection of dogs with SARS-CoV-2. Nature 2020
    [Google Scholar]
  55. Baric RS, Fu K, Schaad MC, Stohlman SA. Establishing a genetic recombination map for murine coronavirus strain A59 complementation groups. Virology 1990; 177:646–656 [CrossRef][PubMed]
    [Google Scholar]
  56. Keck JG, Makino S, Soe LH, Fleming JO, Stohlman SA et al. RNA recombination of coronavirus. Adv Exp Med Biol 1987; 218:99–107 [CrossRef][PubMed]
    [Google Scholar]
  57. Lai MM, Baric RS, Makino S, Keck JG, Egbert J et al. Recombination between nonsegmented RNA genomes of murine coronaviruses. J Virol 1985; 56:449–456 [CrossRef][PubMed]
    [Google Scholar]
  58. Sawicki SG, Sawicki DL, Younker D, Meyer Y, Thiel V et al. Functional and genetic analysis of coronavirus replicase-transcriptase proteins. PLoS Pathog 2005; 1:e39 [CrossRef][PubMed]
    [Google Scholar]
  59. Almazán F, Dediego ML, Galán C, Escors D, Alvarez E et al. Construction of a severe acute respiratory syndrome coronavirus infectious cDNA clone and a replicon to study coronavirus RNA synthesis. J Virol 2006; 80:10900–10906 [CrossRef][PubMed]
    [Google Scholar]
  60. Keck JG, Soe LH, Makino S, Stohlman SA, Lai MM. RNA recombination of murine coronaviruses: recombination between fusion-positive mouse hepatitis virus A59 and fusion-negative mouse hepatitis virus 2. J Virol 1988; 62:1989–1998 [CrossRef][PubMed]
    [Google Scholar]
  61. Keck JG, Stohlman SA, Soe LH, Makino S, Lai MM. Multiple recombination sites at the 5'-end of murine coronavirus RNA. Virology 1987; 156:331–341 [CrossRef][PubMed]
    [Google Scholar]
  62. Zhang L, Homberger F, Spaan W, Luytjes W. Recombinant genomic RNA of coronavirus MHV-A59 after coreplication with a di RNA containing the MHV-RI spike gene. Virology 1997; 230:93–102 [CrossRef][PubMed]
    [Google Scholar]
  63. Zhang X, Liao CL, Lai MM. Coronavirus leader RNA regulates and initiates subgenomic mRNA transcription both in trans and in cis. J Virol 1994; 68:4738–4746 [CrossRef][PubMed]
    [Google Scholar]
  64. Sawicki SG, Sawicki DL, Siddell SG. A contemporary view of coronavirus transcription. J Virol 2007; 81:20–29 [CrossRef][PubMed]
    [Google Scholar]
  65. Sethna PB, Hofmann MA, Brian DA. Minus-strand copies of replicating coronavirus mRNAs contain antileaders. J Virol 1991; 65:320–325 [CrossRef][PubMed]
    [Google Scholar]
  66. Gribble J, Pruijssers AJ, Agostini ML, Daniels-A J, Chappell JD et al. The coronavirus proofreading exoribonuclease mediates extensive viral recombination BioArchive; 2020
  67. Lui P-Y, Wong L-YR, Fung C-L, Siu K-L, Yeung M-L et al. Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3. Emerg Microbes Infect 2016; 5:e391–9 [CrossRef][PubMed]
    [Google Scholar]
  68. Niemeyer D, Zillinger T, Muth D, Zielecki F, Horvath G et al. Middle East respiratory syndrome coronavirus accessory protein 4A is a type I interferon antagonist. J Virol 2013; 87:12489–12495 [CrossRef][PubMed]
    [Google Scholar]
  69. Siu K-L, Yeung ML, Kok K-H, Yuen K-S, Kew C et al. Middle east respiratory syndrome coronavirus 4A protein is a double-stranded RNA-binding protein that suppresses PACT-induced activation of RIG-I and MDA5 in the innate antiviral response. J Virol 2014; 88:4866–4876 [CrossRef][PubMed]
    [Google Scholar]
  70. Yang Y, Zhang L, Geng H, Deng Y, Huang B et al. The structural and accessory proteins M, ORF 4A, ORF 4B, and ORF 5 of middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell 2013; 4:951–961 [CrossRef][PubMed]
    [Google Scholar]
  71. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, Uhl S, Hoagland D et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181:1036–1045 [CrossRef][PubMed]
    [Google Scholar]
  72. Huang C, Liu WJ, Xu W, Jin T, Zhao Y et al. A Bat-Derived putative Cross-Family recombinant coronavirus with a reovirus gene. PLoS Pathog 2016; 12:e1005883 [CrossRef][PubMed]
    [Google Scholar]
  73. Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 2020; 526:135–140 [CrossRef][PubMed]
    [Google Scholar]
  74. Yeung M-L, Yao Y, Jia L, Chan JFW, Chan K-H et al. MERS coronavirus induces apoptosis in kidney and lung by upregulating Smad7 and FGF2. Nat Microbiol 2016; 1:16004 [CrossRef][PubMed]
    [Google Scholar]
  75. Alsaad KO, Hajeer AH, Al Balwi M, Al Moaiqel M, Al Oudah N et al. Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study. Histopathology 2018; 72:516–524 [CrossRef][PubMed]
    [Google Scholar]
  76. Cha R-H, Joh J-S, Jeong I, Lee JY, Shin H-S et al. Renal complications and their prognosis in Korean patients with middle East respiratory syndrome-coronavirus from the central MERS-CoV designated Hospital. J Korean Med Sci 2015; 30:1807–1814 [CrossRef][PubMed]
    [Google Scholar]
  77. Naicker S, Yang C-W, Hwang S-J, Liu B-C, Chen J-H et al. The novel coronavirus 2019 epidemic and kidneys. Kidney Int 2020; 97:824–828 [CrossRef][PubMed]
    [Google Scholar]
  78. Sanifer ML, Kee C, Cortese M, Triana S, Mukenhirn M et al. Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells BioArchive. BioArchive 2020
    [Google Scholar]
  79. Wang W, Xu Y, Gao R, Lu R, Han K et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020 [CrossRef]
    [Google Scholar]
  80. Wu Y, Guo C, Tang L, Hong Z, Zhou J et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol 2020; 5:434–435 [CrossRef][PubMed]
    [Google Scholar]
  81. Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J et al. SARS-CoV-2 productively infects human gut enterocytes. Science 2020; 369:50–54 [CrossRef][PubMed]
    [Google Scholar]
  82. Corman VM, Albarrak AM, Omrani AS, Albarrak MM, Farah ME et al. Viral shedding and antibody response in 37 patients with middle East respiratory syndrome coronavirus infection. Clin Infect Dis 2016; 62:477–483 [CrossRef][PubMed]
    [Google Scholar]
  83. Zhou J, Li C, Zhao G, Chu H, Wang D et al. Human intestinal tract serves as an alternative infection route for middle East respiratory syndrome coronavirus. Sci Adv 2017; 3:eaao4966 [CrossRef][PubMed]
    [Google Scholar]
  84. Crameri G, Durr PA, Klein R, Foord A, Yu M et al. Experimental infection and response to rechallenge of alpacas with middle East respiratory syndrome coronavirus. Emerg Infect Dis 2016; 22:1071–1074 [CrossRef][PubMed]
    [Google Scholar]
  85. Corman VM, Muth D, Niemeyer D, Drosten C. Hosts and sources of endemic human coronaviruses. Adv Virus Res 2018; 100:163–188 [CrossRef][PubMed]
    [Google Scholar]
  86. Raj VS, Farag EABA, Reusken CBEM, Lamers MM, Pas SD et al. Isolation of MERS coronavirus from a dromedary camel, Qatar, 2014. Emerg Infect Dis 2014; 20:1339–1342 [CrossRef][PubMed]
    [Google Scholar]
  87. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 2020; 20:533–534 [CrossRef][PubMed]
    [Google Scholar]
  88. WHO Emergencies preparedness, response WHO2020 [Available from:.
  89. Nasir JA, Speicher DJ, Kozak RA, Poinar HN, Miller MS et al. Rapid design of a bait capture platform for culture- and Amplification-Free next-generation sequencing of SARS-CoV-2. Preprints 2020
    [Google Scholar]
  90. Li B, HR S, Zhu Y, Yang XL, Anderson DE et al. Discovery of bat coronaviruses through surveillance and probe capture-based next-generation sequencing. mSphere 2020; 5:
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001491
Loading
/content/journal/jgv/10.1099/jgv.0.001491
Loading

Data & Media loading...

Supplements

Supplementary material 1

EXCEL
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error