Coronaviruses: An Overview of Their Replication and Pathogenesis

  • Anthony R. Fehr
  • Stanley PerlmanEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1282)


Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. Coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease in chickens to potentially lethal human respiratory infections. Here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and current prevention and treatment strategies. We also discuss the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV).

Key words

Nidovirales Coronavirus Positive-sense RNA viruses SARS-CoV MERS-CoV 


  1. 1.
    Zhao L, Jha BK, Wu A et al (2012) Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. Cell Host Microbe 11:607–616. doi: 10.1016/j.chom.2012.04.011 PubMedCentralPubMedGoogle Scholar
  2. 2.
    Barcena M, Oostergetel GT, Bartelink W et al (2009) Cryo-electron tomography of mouse hepatitis virus: insights into the structure of the coronavirion. Proc Natl Acad Sci U S A 106:582–587PubMedCentralPubMedGoogle Scholar
  3. 3.
    Neuman BW, Adair BD, Yoshioka C et al (2006) Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy. J Virol 80:7918–7928PubMedCentralPubMedGoogle Scholar
  4. 4.
    Beniac DR, Andonov A, Grudeski E et al (2006) Architecture of the SARS coronavirus prefusion spike. Nat Struct Mol Biol 13:751–752. doi: 10.1038/nsmb1123 PubMedGoogle Scholar
  5. 5.
    Delmas B, Laude H (1990) Assembly of coronavirus spike protein into trimers and its role in epitope expression. J Virol 64:5367–5375PubMedCentralPubMedGoogle Scholar
  6. 6.
    Bosch BJ, van der Zee R, de Haan CA et al (2003) The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol 77:8801–8811PubMedCentralPubMedGoogle Scholar
  7. 7.
    Collins AR, Knobler RL, Powell H et al (1982) Monoclonal antibodies to murine hepatitis virus-4 (strain JHM) define the viral glycoprotein responsible for attachment and cell–cell fusion. Virology 119:358–371PubMedGoogle Scholar
  8. 8.
    Abraham S, Kienzle TE, Lapps W et al (1990) Deduced sequence of the bovine coronavirus spike protein and identification of the internal proteolytic cleavage site. Virology 176:296–301PubMedGoogle Scholar
  9. 9.
    Luytjes W, Sturman LS, Bredenbeek PJ et al (1987) Primary structure of the glycoprotein E2 of coronavirus MHV-A59 and identification of the trypsin cleavage site. Virology 161:479–487PubMedGoogle Scholar
  10. 10.
    de Groot RJ, Luytjes W, Horzinek MC et al (1987) Evidence for a coiled-coil structure in the spike proteins of coronaviruses. J Mol Biol 196:963–966PubMedGoogle Scholar
  11. 11.
    Armstrong J, Niemann H, Smeekens S et al (1984) Sequence and topology of a model intracellular membrane protein, E1 glycoprotein, from a coronavirus. Nature 308:751–752PubMedGoogle Scholar
  12. 12.
    Nal B, Chan C, Kien F et al (2005) Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins S, M and E. J Gen Virol 86:1423–1434. doi: 10.1099/vir.0.80671-0 PubMedGoogle Scholar
  13. 13.
    Neuman BW, Kiss G, Kunding AH et al (2011) A structural analysis of M protein in coronavirus assembly and morphology. J Struct Biol 174:11–22. doi: 10.1016/j.jsb.2010.11.021 PubMedGoogle Scholar
  14. 14.
    Godet M, L’Haridon R, Vautherot JF et al (1992) TGEV corona virus ORF4 encodes a membrane protein that is incorporated into virions. Virology 188:666–675PubMedGoogle Scholar
  15. 15.
    DeDiego ML, Alvarez E, Almazan F et al (2007) A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. J Virol 81:1701–1713PubMedCentralPubMedGoogle Scholar
  16. 16.
    Nieto-Torres JL, Dediego ML, Verdia-Baguena C et al (2014) Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathog 10:e1004077. doi: 10.1371/journal.ppat.1004077 PubMedCentralPubMedGoogle Scholar
  17. 17.
    Chang CK, Sue SC, Yu TH et al (2006) Modular organization of SARS coronavirus nucleocapsid protein. J Biomed Sci 13:59–72. doi: 10.1007/s11373-005-9035-9 PubMedGoogle Scholar
  18. 18.
    Hurst KR, Koetzner CA, Masters PS (2009) Identification of in vivo-interacting domains of the murine coronavirus nucleocapsid protein. J Virol 83:7221–7234. doi: 10.1128/JVI.00440-09 PubMedCentralPubMedGoogle Scholar
  19. 19.
    Stohlman SA, Lai MM (1979) Phosphoproteins of murine hepatitis viruses. J Virol 32:672–675PubMedCentralPubMedGoogle Scholar
  20. 20.
    Stohlman SA, Baric RS, Nelson GN et al (1988) Specific interaction between coronavirus leader RNA and nucleocapsid protein. J Virol 62:4288–4295PubMedCentralPubMedGoogle Scholar
  21. 21.
    Molenkamp R, Spaan WJ (1997) Identification of a specific interaction between the coronavirus mouse hepatitis virus A59 nucleocapsid protein and packaging signal. Virology 239:78–86PubMedGoogle Scholar
  22. 22.
    Kuo L, Masters PS (2013) Functional analysis of the murine coronavirus genomic RNA packaging signal. J Virol 87:5182–5192. doi: 10.1128/JVI.00100-13 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Hurst KR, Koetzner CA, Masters PS (2013) Characterization of a critical interaction between the coronavirus nucleocapsid protein and nonstructural protein 3 of the viral replicase-transcriptase complex. J Virol 87:9159–9172. doi: 10.1128/JVI.01275-13 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Sturman LS, Holmes KV, Behnke J (1980) Isolation of coronavirus envelope glycoproteins and interaction with the viral nucleocapsid. J Virol 33:449–462PubMedCentralPubMedGoogle Scholar
  25. 25.
    Klausegger A, Strobl B, Regl G et al (1999) Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus. J Virol 73:3737–3743PubMedCentralPubMedGoogle Scholar
  26. 26.
    Cornelissen LA, Wierda CM, van der Meer FJ et al (1997) Hemagglutinin-esterase, a novel structural protein of torovirus. J Virol 71:5277–5286PubMedCentralPubMedGoogle Scholar
  27. 27.
    Kazi L, Lissenberg A, Watson R et al (2005) Expression of hemagglutinin esterase protein from recombinant mouse hepatitis virus enhances neurovirulence. J Virol 79:15064–15073PubMedCentralPubMedGoogle Scholar
  28. 28.
    Lissenberg A, Vrolijk MM, van Vliet AL et al (2005) Luxury at a cost? Recombinant mouse hepatitis viruses expressing the accessory hemagglutinin esterase protein display reduced fitness in vitro. J Virol 79:15054–15063PubMedCentralPubMedGoogle Scholar
  29. 29.
    Kubo H, Yamada YK, Taguchi F (1994) Localization of neutralizing epitopes and the receptor-binding site within the amino-terminal 330 amino acids of the murine coronavirus spike protein. J Virol 68:5403–5410PubMedCentralPubMedGoogle Scholar
  30. 30.
    Cheng PK, Wong DA, Tong LK et al (2004) Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Lancet 363:1699–1700PubMedGoogle Scholar
  31. 31.
    Belouzard S, Chu VC, Whittaker GR (2009) Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A 106:5871–5876. doi: 10.1073/pnas.0809524106 PubMedCentralPubMedGoogle Scholar
  32. 32.
    Baranov PV, Henderson CM, Anderson CB et al (2005) Programmed ribosomal frameshifting in decoding the SARS-CoV genome. Virology 332:498–510. doi: 10.1016/j.virol.2004.11.038 PubMedGoogle Scholar
  33. 33.
    Brierley I, Digard P, Inglis SC (1989) Characterization of an efficient coronavirus ribosomal frameshifting signal: requirement for an RNA pseudoknot. Cell 57:537–547PubMedGoogle Scholar
  34. 34.
    Araki K, Gangappa S, Dillehay DL et al (2010) Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation. J Exp Med 207:2355–2367PubMedCentralPubMedGoogle Scholar
  35. 35.
    Ziebuhr J, Snijder EJ, Gorbalenya AE (2000) Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 81:853–879PubMedGoogle Scholar
  36. 36.
    Mielech AM, Chen Y, Mesecar AD et al (2014) Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Res. doi: 10.1016/j.virusres.2014.01.025 PubMedGoogle Scholar
  37. 37.
    Snijder EJ, Bredenbeek PJ, Dobbe JC et al (2003) Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 331:991–1004PubMedGoogle Scholar
  38. 38.
    Sethna PB, Hofmann MA, Brian DA (1991) Minus-strand copies of replicating coronavirus mRNAs contain antileaders. J Virol 65:320–325PubMedCentralPubMedGoogle Scholar
  39. 39.
    Brown CG, Nixon KS, Senanayake SD et al (2007) An RNA stem-loop within the bovine coronavirus nsp1 coding region is a cis-acting element in defective interfering RNA replication. J Virol 81:7716–7724. doi: 10.1128/JVI.00549-07 PubMedCentralPubMedGoogle Scholar
  40. 40.
    Guan BJ, Wu HY, Brian DA (2011) An optimal cis-replication stem-loop IV in the 5′ untranslated region of the mouse coronavirus genome extends 16 nucleotides into open reading frame 1. J Virol 85:5593–5605. doi: 10.1128/JVI.00263-11 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Liu P, Li L, Keane SC et al (2009) Mouse hepatitis virus stem-loop 2 adopts a uYNMG(U)a-like tetraloop structure that is highly functionally tolerant of base substitutions. J Virol 83:12084–12093. doi: 10.1128/JVI.00915-09 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Raman S, Bouma P, Williams GD et al (2003) Stem-loop III in the 5′ untranslated region is a cis-acting element in bovine coronavirus defective interfering RNA replication. J Virol 77:6720–6730PubMedCentralPubMedGoogle Scholar
  43. 43.
    Liu Q, Johnson RF, Leibowitz JL (2001) Secondary structural elements within the 3′ untranslated region of mouse hepatitis virus strain JHM genomic RNA. J Virol 75:12105–12113. doi: 10.1128/JVI.75.24.12105-12113.2001 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Goebel SJ, Miller TB, Bennett CJ et al (2007) A hypervariable region within the 3′ cis-acting element of the murine coronavirus genome is nonessential for RNA synthesis but affects pathogenesis. J Virol 81:1274–1287. doi: 10.1128/JVI.00803-06 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Williams GD, Chang RY, Brian DA (1999) A phylogenetically conserved hairpin-type 3′ untranslated region pseudoknot functions in coronavirus RNA replication. J Virol 73:8349–8355PubMedCentralPubMedGoogle Scholar
  46. 46.
    Hsue B, Masters PS (1997) A bulged stem-loop structure in the 3′ untranslated region of the genome of the coronavirus mouse hepatitis virus is essential for replication. J Virol 71:7567–7578PubMedCentralPubMedGoogle Scholar
  47. 47.
    Hsue B, Hartshorne T, Masters PS (2000) Characterization of an essential RNA secondary structure in the 3′ untranslated region of the murine coronavirus genome. J Virol 74:6911–6921PubMedCentralPubMedGoogle Scholar
  48. 48.
    Sawicki SG, Sawicki DL, Siddell SG (2007) A contemporary view of coronavirus transcription. J Virol 81:20–29PubMedCentralPubMedGoogle Scholar
  49. 49.
    Bentley K, Keep SM, Armesto M et al (2013) Identification of a noncanonically transcribed subgenomic mRNA of infectious bronchitis virus and other gammacoronaviruses. J Virol 87:2128–2136. doi: 10.1128/JVI.02967-12 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Keck JG, Makino S, Soe LH et al (1987) RNA recombination of coronavirus. Adv Exp Med Biol 218:99–107PubMedGoogle Scholar
  51. 51.
    Lai MM, Baric RS, Makino S et al (1985) Recombination between nonsegmented RNA genomes of murine coronaviruses. J Virol 56:449–456PubMedCentralPubMedGoogle Scholar
  52. 52.
    Krijnse-Locker J, Ericsson M, Rottier PJM et al (1994) Characterization of the budding compartment of mouse hepatitis virus: evidence that transport from the RER to the Golgi complex requires only one vesicular transport step. J Cell Biol 124:55–70PubMedGoogle Scholar
  53. 53.
    Tooze J, Tooze S, Warren G (1984) Replication of coronavirus MHV-A59 in sac-cells: determination of the first site of budding of progeny virions. Eur J Cell Biol 33:281–293PubMedGoogle Scholar
  54. 54.
    de Haan CA, Rottier PJ (2005) Molecular interactions in the assembly of coronaviruses. Adv Virus Res 64:165–230PubMedGoogle Scholar
  55. 55.
    Bos EC, Luytjes W, van der Meulen HV et al (1996) The production of recombinant infectious DI-particles of a murine coronavirus in the absence of helper virus. Virology 218:52–60PubMedGoogle Scholar
  56. 56.
    Siu YL, Teoh KT, Lo J et al (2008) The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles. J Virol 82:11318–11330. doi: 10.1128/JVI.01052-08 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Raamsman MJ, Locker JK, de Hooge A et al (2000) Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. J Virol 74:2333–2342PubMedCentralPubMedGoogle Scholar
  58. 58.
    Corse E, Machamer CE (2000) Infectious bronchitis virus E protein is targeted to the Golgi complex and directs release of virus-like particles. J Virol 74:4319–4326PubMedCentralPubMedGoogle Scholar
  59. 59.
    Fischer F, Stegen CF, Masters PS et al (1998) Analysis of constructed E gene mutants of mouse hepatitis virus confirms a pivotal role for E protein in coronavirus assembly. J Virol 72:7885–7894PubMedCentralPubMedGoogle Scholar
  60. 60.
    Boscarino JA, Logan HL, Lacny JJ et al (2008) Envelope protein palmitoylations are crucial for murine coronavirus assembly. J Virol 82:2989–2999. doi: 10.1128/JVI.01906-07 PubMedCentralPubMedGoogle Scholar
  61. 61.
    Ye Y, Hogue BG (2007) Role of the coronavirus E viroporin protein transmembrane domain in virus assembly. J Virol 81:3597–3607. doi: 10.1128/JVI.01472-06 PubMedCentralPubMedGoogle Scholar
  62. 62.
    Hurst KR, Kuo L, Koetzner CA et al (2005) A major determinant for membrane protein interaction localizes to the carboxy-terminal domain of the mouse coronavirus nucleocapsid protein. J Virol 79:13285–13297PubMedCentralPubMedGoogle Scholar
  63. 63.
    Perlman S, Netland J (2009) Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7:439–450PubMedCentralPubMedGoogle Scholar
  64. 64.
    Mihindukulasuriya KA, Wu G, St LJ et al (2008) Identification of a novel coronavirus from a beluga whale by using a panviral microarray. J Virol 82:5084–5088PubMedCentralPubMedGoogle Scholar
  65. 65.
    He B, Zhang Y, Xu L et al (2014) Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in china. J Virol 88:7070–7082. doi: 10.1128/JVI.00631-14 PubMedCentralPubMedGoogle Scholar
  66. 66.
    Nga PT, Parquet Mdel C, Lauber C et al (2011) Discovery of the first insect nidovirus, a missing evolutionary link in the emergence of the largest RNA virus genomes. PLoS Pathog 7:e1002215. doi: 10.1371/journal.ppat.1002215 PubMedCentralPubMedGoogle Scholar
  67. 67.
    Lauber C, Ziebuhr J, Junglen S et al (2012) Mesoniviridae: a proposed new family in the order Nidovirales formed by a single species of mosquito-borne viruses. Arch Virol 157:1623–1628. doi: 10.1007/s00705-012-1295-x PubMedCentralPubMedGoogle Scholar
  68. 68.
    Levy GA, Liu M, Ding J et al (2000) Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis. Am J Pathol 156:1217–1225PubMedCentralPubMedGoogle Scholar
  69. 69.
    Lampert PW, Sims JK, Kniazeff AJ (1973) Mechanism of demyelination in JHM virus encephalomyelitis. Acta Neuropathol 24:76–85PubMedGoogle Scholar
  70. 70.
    Weiner LP (1973) Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus). Arch Neurol 28:298–303PubMedGoogle Scholar
  71. 71.
    Wu GF, Dandekar AA, Pewe L et al (2000) CD4 and CD8 T cells have redundant but not identical roles in virus-induced demyelination. J Immunol 165:2278–2286PubMedGoogle Scholar
  72. 72.
    Wang F, Stohlman SA, Fleming JO (1990) Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated. J Neuroimmunol 30:31–41PubMedGoogle Scholar
  73. 73.
    Wu GF, Perlman S (1999) Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus. J Virol 73:8771–8780PubMedCentralPubMedGoogle Scholar
  74. 74.
    McIntosh K, Becker WB, Chanock RM (1967) Growth in suckling-mouse brain of “IBV-like” viruses from patients with upper respiratory tract disease. Proc Natl Acad Sci U S A 58:2268–2273PubMedCentralPubMedGoogle Scholar
  75. 75.
    Bradburne AF, Bynoe ML, Tyrell DAJ (1967) Effects of a “new” human respiratory virus in volunteers. Br Med J 3:767–769PubMedCentralPubMedGoogle Scholar
  76. 76.
    Hamre D, Procknow JJ (1966) A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 121:190–193PubMedGoogle Scholar
  77. 77.
    Woo PC, Lau SK, Chu CM et al (2005) Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol 79:884–895PubMedCentralPubMedGoogle Scholar
  78. 78.
    van der Hoek L, Pyrc K, Jebbink MF et al (2004) Identification of a new human coronavirus. Nat Med 10:368–373PubMedGoogle Scholar
  79. 79.
    van der Hoek L, Sure K, Ihorst G et al (2005) Croup is associated with the novel coronavirus NL63. PLoS Med 2:e240PubMedCentralPubMedGoogle Scholar
  80. 80.
    Chibo D, Birch C (2006) Analysis of human coronavirus 229E spike and nucleoprotein genes demonstrates genetic drift between chronologically distinct strains. J Gen Virol 87:1203–1208PubMedGoogle Scholar
  81. 81.
    Vijgen L, Keyaerts E, Lemey P et al (2005) Circulation of genetically distinct contemporary human coronavirus OC43 strains. Virology 337:85–92PubMedGoogle Scholar
  82. 82.
    Guan Y, Zheng BJ, He YQ et al (2003) Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 302:276–278PubMedGoogle Scholar
  83. 83.
    Lau SK, Woo PC, Li KS et al (2005) Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc Natl Acad Sci U S A 102:14040–14045PubMedCentralPubMedGoogle Scholar
  84. 84.
    Li W, Shi Z, Yu M et al (2005) Bats are natural reservoirs of SARS-like coronaviruses. Science 310:676–679PubMedGoogle Scholar
  85. 85.
    Ge XY, Li JL, Yang XL et al (2013) Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503:535–538. doi: 10.1038/nature12711 PubMedGoogle Scholar
  86. 86.
    Peiris JS, Yuen KY, Osterhaus AD et al (2003) The severe acute respiratory syndrome. N Engl J Med 349:2431–2441PubMedGoogle Scholar
  87. 87.
    Peiris JS, Chu CM, Cheng VC et al (2003) Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361:1767–1772PubMedGoogle Scholar
  88. 88.
    Spiegel M, Schneider K, Weber F et al (2006) Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells. J Gen Virol 87:1953–1960PubMedGoogle Scholar
  89. 89.
    Law HK, Cheung CY, Ng HY et al (2005) Chemokine upregulation in SARS coronavirus infected human monocyte derived dendritic cells. Blood 106:2366–2376PubMedCentralPubMedGoogle Scholar
  90. 90.
    Lau YL, Peiris JSM (2005) Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol 17:404–410PubMedGoogle Scholar
  91. 91.
    Roberts A, Paddock C, Vogel L et al (2005) Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J Virol 79:5833–5838PubMedCentralPubMedGoogle Scholar
  92. 92.
    Zhao J, Zhao J, Perlman S (2010) T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice. J Virol 84:9318–9325PubMedCentralPubMedGoogle Scholar
  93. 93.
    Zhao J, Zhao J, Legge K et al (2011) Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest 121:4921–4930. doi: 10.1172/JCI59777 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Zaki AM, van Boheemen S, Bestebroer TM et al (2012) Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814–1820. doi: 10.1056/NEJMoa1211721 PubMedGoogle Scholar
  95. 95.
    van Boheemen S, de Graaf M, Lauber C et al (2012) Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3. doi:10.1128/mBio.00473-12Google Scholar
  96. 96.
    Meyer B, Muller MA, Corman VM et al (2014) Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg Infect Dis 20:552–559. doi: 10.3201/eid2004.131746 PubMedCentralPubMedGoogle Scholar
  97. 97.
    Eckerle I, Corman VM, Muller MA et al (2014) Replicative capacity of MERS coronavirus in livestock cell lines. Emerg Infect Dis 20:276–279. doi: 10.3201/eid2002.131182 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Memish ZA, Cotten M, Meyer B et al (2014) Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg Infect Dis 20:1012–1015. doi: 10.3201/eid2006.140402 PubMedCentralPubMedGoogle Scholar
  99. 99.
    Azhar EI, El-Kafrawy SA, Farraj SA et al (2014) Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med. doi: 10.1056/NEJMoa1401505 Google Scholar
  100. 100.
    Raj VS, Mou H, Smits SL et al (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254. doi: 10.1038/nature12005 PubMedGoogle Scholar
  101. 101.
    Zhao J, Li K, Wohlford-Lenane C et al (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970–4975. doi: 10.1073/pnas.1323279111 PubMedCentralPubMedGoogle Scholar
  102. 102.
    Emery SL, Erdman DD, Bowen MD et al (2004) Real-time reverse transcription-polymerase chain reaction assay for SARS-associated coronavirus. Emerg Infect Dis 10:311–316. doi: 10.3201/eid1002.030759 PubMedCentralPubMedGoogle Scholar
  103. 103.
    Gaunt ER, Hardie A, Claas EC et al (2010) Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol 48:2940–2947. doi: 10.1128/JCM.00636-10 PubMedCentralPubMedGoogle Scholar
  104. 104.
    Cinatl J, Morgenstern B, Bauer G et al (2003) Treatment of SARS with human interferons. Lancet 362:293–294PubMedGoogle Scholar
  105. 105.
    Stockman LJ, Bellamy R, Garner P (2006) SARS: systematic review of treatment effects. PLoS Med 3:e343PubMedCentralPubMedGoogle Scholar
  106. 106.
    Laude H, Van Reeth K, Pensaert M (1993) Porcine respiratory coronavirus: molecular features and virus-host interactions. Vet Res 24:125–150PubMedGoogle Scholar
  107. 107.
    Saif LJ (2004) Animal coronavirus vaccines: lessons for SARS. Dev Biol (Basel) 119:129–140Google Scholar
  108. 108.
    Wang L, Junker D, Collisson EW (1993) Evidence of natural recombination within the S1 gene of infectious bronchitis virus. Virology 192:710–716PubMedGoogle Scholar
  109. 109.
    Vennema H, de Groot RJ, Harbour DA et al (1990) Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J Virol 64:1407–1409PubMedCentralPubMedGoogle Scholar
  110. 110.
    Zust R, Cervantes-Barragan L, Kuri T et al (2007) Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines. PLoS Pathog 3:e109PubMedCentralPubMedGoogle Scholar
  111. 111.
    Netland J, DeDiego ML, Zhao J et al (2010) Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease. Virology 399:120–128. doi: 10.1016/j.virol.2010.01.004 PubMedCentralPubMedGoogle Scholar
  112. 112.
    de Haan CA, Volders H, Koetzner CA et al (2002) Coronaviruses maintain viability despite dramatic rearrangements of the strictly conserved genome organization. J Virol 76:12491–12502PubMedCentralPubMedGoogle Scholar
  113. 113.
    Yount B, Roberts RS, Lindesmith L et al (2006) Rewiring the severe acute respiratory syndrome coronavirus (SARS-CoV) transcription circuit: engineering a recombination-resistant genome. Proc Natl Acad Sci U S A 103:12546–12551PubMedCentralPubMedGoogle Scholar
  114. 114.
    Graham RL, Becker MM, Eckerle LD et al (2012) A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease. Nat Med 18:1820–1826. doi: 10.1038/nm.2972 PubMedCentralPubMedGoogle Scholar
  115. 115.
    Yeager CL, Ashmun RA, Williams RK et al (1992) Human aminopeptidase N is a receptor for human coronavirus 229E. Nature 357:420–422. doi: 10.1038/357420a0 PubMedGoogle Scholar
  116. 116.
    Hofmann H, Pyrc K, van der Hoek L et al (2005) Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc Natl Acad Sci U S A 102:7988–7993PubMedCentralPubMedGoogle Scholar
  117. 117.
    Delmas B, Gelfi J, L’Haridon R et al (1992) Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature 357:417–420. doi: 10.1038/357417a0 PubMedGoogle Scholar
  118. 118.
    Li BX, Ge JW, Li YJ (2007) Porcine aminopeptidase N is a functional receptor for the PEDV coronavirus. Virology 365:166–172. doi: 10.1016/j.virol.2007.03.031 PubMedGoogle Scholar
  119. 119.
    Tresnan DB, Levis R, Holmes KV (1996) Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I. J Virol 70:8669–8674PubMedCentralPubMedGoogle Scholar
  120. 120.
    Benbacer L, Kut E, Besnardeau L et al (1997) Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus. J Virol 71:734–737PubMedCentralPubMedGoogle Scholar
  121. 121.
    Nedellec P, Dveksler GS, Daniels E et al (1994) Bgp2, a new member of the carcinoembryonic antigen-related gene family, encodes an alternative receptor for mouse hepatitis viruses. J Virol 68:4525–4537PubMedCentralPubMedGoogle Scholar
  122. 122.
    Williams RK, Jiang GS, Holmes KV (1991) Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins. Proc Natl Acad Sci U S A 88:5533–5536PubMedCentralPubMedGoogle Scholar
  123. 123.
    Schultze B, Herrler G (1992) Bovine coronavirus uses N-acetyl-9-O-acetylneuraminic acid as a receptor determinant to initiate the infection of cultured cells. J Gen Virol 73(Pt 4):901–906PubMedGoogle Scholar
  124. 124.
    Li W, Moore MJ, Vasilieva N et al (2003) Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426:450–454PubMedGoogle Scholar
  125. 125.
    Huang C, Lokugamage KG, Rozovics JM et al (2011) Alphacoronavirus transmissible gastroenteritis virus nsp1 protein suppresses protein translation in mammalian cells and in cell-free HeLa cell extracts but not in rabbit reticulocyte lysate. J Virol 85:638–643. doi: 10.1128/JVI.01806-10 PubMedCentralPubMedGoogle Scholar
  126. 126.
    Kamitani W, Huang C, Narayanan K et al (2009) A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein. Nat Struct Mol Biol 16:1134–1140. doi: 10.1038/nsmb.1680 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Kamitani W, Narayanan K, Huang C et al (2006) Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc Natl Acad Sci U S A 103:12885–12890PubMedCentralPubMedGoogle Scholar
  128. 128.
    Tanaka T, Kamitani W, DeDiego ML et al (2012) Severe acute respiratory syndrome coronavirus nsp1 facilitates efficient propagation in cells through a specific translational shutoff of host mRNA. J Virol 86:11128–11137. doi: 10.1128/JVI.01700-12 PubMedCentralPubMedGoogle Scholar
  129. 129.
    Graham RL, Sims AC, Brockway SM et al (2005) The nsp2 replicase proteins of murine hepatitis virus and severe acute respiratory syndrome coronavirus are dispensable for viral replication. J Virol 79:13399–13411. doi: 10.1128/JVI.79.21.13399-13411.2005 PubMedCentralPubMedGoogle Scholar
  130. 130.
    Cornillez-Ty CT, Liao L, Yates JR 3rd et al (2009) Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J Virol 83:10314–10318. doi: 10.1128/JVI.00842-09 PubMedCentralPubMedGoogle Scholar
  131. 131.
    Chatterjee A, Johnson MA, Serrano P et al (2009) Nuclear magnetic resonance structure shows that the severe acute respiratory syndrome coronavirus-unique domain contains a macrodomain fold. J Virol 83:1823–1836PubMedCentralPubMedGoogle Scholar
  132. 132.
    Egloff MP, Malet H, Putics A et al (2006) Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J Virol 80:8493–8502. doi: 10.1128/JVI.00713-06 PubMedCentralPubMedGoogle Scholar
  133. 133.
    Eriksson KK, Cervantes-Barragan L, Ludewig B et al (2008) Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1″-phosphatase, a viral function conserved in the alpha-like supergroup. J Virol 82:12325–12334. doi: 10.1128/JVI.02082-08 PubMedCentralPubMedGoogle Scholar
  134. 134.
    Frieman M, Ratia K, Johnston RE et al (2009) Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol 83:6689–6705PubMedCentralPubMedGoogle Scholar
  135. 135.
    Neuman BW, Joseph JS, Saikatendu KS et al (2008) Proteomics analysis unravels the functional repertoire of coronavirus nonstructural protein 3. J Virol 82:5279–5294PubMedCentralPubMedGoogle Scholar
  136. 136.
    Serrano P, Johnson MA, Almeida MS et al (2007) Nuclear magnetic resonance structure of the N-terminal domain of nonstructural protein 3 from the severe acute respiratory syndrome coronavirus. J Virol 81:12049–12060PubMedCentralPubMedGoogle Scholar
  137. 137.
    Serrano P, Johnson MA, Chatterjee A et al (2009) Nuclear magnetic resonance structure of the nucleic acid-binding domain of severe acute respiratory syndrome coronavirus nonstructural protein 3. J Virol 83:12998–13008. doi: 10.1128/JVI.01253-09 PubMedCentralPubMedGoogle Scholar
  138. 138.
    Ziebuhr J, Thiel V, Gorbalenya AE (2001) The autocatalytic release of a putative RNA virus transcription factor from its polyprotein precursor involves two paralogous papain-like proteases that cleave the same peptide bond. J Biol Chem 276:33220–33232. doi: 10.1074/jbc.M104097200 PubMedGoogle Scholar
  139. 139.
    Clementz MA, Kanjanahaluethai A, O’Brien TE et al (2008) Mutation in murine coronavirus replication protein nsp4 alters assembly of double membrane vesicles. Virology 375:118–129PubMedCentralPubMedGoogle Scholar
  140. 140.
    Gadlage MJ, Sparks JS, Beachboard DC et al (2010) Murine hepatitis virus nonstructural protein 4 regulates virus-induced membrane modifications and replication complex function. J Virol 84:280–290. doi: 10.1128/JVI.01772-09 PubMedCentralPubMedGoogle Scholar
  141. 141.
    Lu Y, Lu X, Denison MR (1995) Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. J Virol 69:3554–3559PubMedCentralPubMedGoogle Scholar
  142. 142.
    Oostra M, Hagemeijer MC, van Gent M et al (2008) Topology and membrane anchoring of the coronavirus replication complex: not all hydrophobic domains of nsp3 and nsp6 are membrane spanning. J Virol 82:12392–12405PubMedCentralPubMedGoogle Scholar
  143. 143.
    Zhai Y, Sun F, Li X et al (2005) Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nat Struct Mol Biol 12:980–986PubMedGoogle Scholar
  144. 144.
    Imbert I, Guillemot JC, Bourhis JM et al (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J 25:4933–4942PubMedCentralPubMedGoogle Scholar
  145. 145.
    Egloff MP, Ferron F, Campanacci V et al (2004) The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc Natl Acad Sci U S A 101:3792–3796PubMedCentralPubMedGoogle Scholar
  146. 146.
    Bouvet M, Debarnot C, Imbert I et al (2010) In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog 6:e1000863. doi: 10.1371/journal.ppat.1000863 PubMedCentralPubMedGoogle Scholar
  147. 147.
    Decroly E, Debarnot C, Ferron F et al (2011) Crystal structure and functional analysis of the SARS-coronavirus RNA cap 2′-O-methyltransferase nsp10/nsp16 complex. PLoS Pathog 7:e1002059. doi: 10.1371/journal.ppat.1002059 PubMedCentralPubMedGoogle Scholar
  148. 148.
    Xu X, Liu Y, Weiss S et al (2003) Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design. Nucleic Acids Res 31:7117–7130PubMedCentralPubMedGoogle Scholar
  149. 149.
    Ivanov KA, Thiel V, Dobbe JC et al (2004) Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J Virol 78:5619–5632PubMedCentralPubMedGoogle Scholar
  150. 150.
    Ivanov KA, Ziebuhr J (2004) Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5′-triphosphatase activities. J Virol 78:7833–7838. doi: 10.1128/JVI.78.14.7833-7838.2004 PubMedCentralPubMedGoogle Scholar
  151. 151.
    Eckerle LD, Becker MM, Halpin RA et al (2010) Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog 6:e1000896. doi: 10.1371/journal.ppat.1000896 PubMedCentralPubMedGoogle Scholar
  152. 152.
    Eckerle LD, Lu X, Sperry SM et al (2007) High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J Virol 81:12135–12144PubMedCentralPubMedGoogle Scholar
  153. 153.
    Minskaia E, Hertzig T, Gorbalenya AE et al (2006) Discovery of an RNA virus 3′->5′ exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci U S A 103:5108–5113. doi: 10.1073/pnas.0508200103 PubMedCentralPubMedGoogle Scholar
  154. 154.
    Chen Y, Cai H, Pan J et al (2009) Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc Natl Acad Sci U S A 106:3484–3489. doi: 10.1073/pnas.0808790106 PubMedCentralPubMedGoogle Scholar
  155. 155.
    Bhardwaj K, Sun J, Holzenburg A et al (2006) RNA recognition and cleavage by the SARS coronavirus endoribonuclease. J Mol Biol 361:243–256. doi: 10.1016/j.jmb.2006.06.021 PubMedGoogle Scholar
  156. 156.
    Ivanov KA, Hertzig T, Rozanov M et al (2004) Major genetic marker of nidoviruses encodes a replicative endoribonuclease. Proc Natl Acad Sci U S A 101:12694–12699PubMedCentralPubMedGoogle Scholar
  157. 157.
    Decroly E, Imbert I, Coutard B et al (2008) Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2′O)-methyltransferase activity. J Virol 82:8071–8084PubMedCentralPubMedGoogle Scholar
  158. 158.
    Zust R, Cervantes-Barragan L, Habjan M et al (2011) Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol 12:137–143PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of MicrobiologyUniversity of Iowa Carver College of MedicineIowa CityUSA

Personalised recommendations