VOOZH about

URL: https://www.nature.com/articles/nrmicro2147?error=cookies_not_supported&code=083295e5-c3aa-463c-9fe4-ec290a089075

⇱ Coronaviruses post-SARS: update on replication and pathogenesis | Nature Reviews Microbiology

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Key Points

  • Coronaviruses are positive strand RNA viruses that cause disease in humans, and domestic and companion animals. They are most notorious for causing severe acute respiratory syndrome (SARS) outbreaks in 2002–2003. All coronaviruses follow the same basic strategy of replication.

  • All coronaviruses encode 15 or 16 replicase related proteins, 4 or 5 structural proteins and 1–8 group-specific or accessory proteins. Many of the replicase proteins are assembled into replication machinery in double-membrane vesicles (DMVs) and on a reticular network of membranes that are derived from the endoplasmic reticulum.

  • Coronaviruses are readily transmitted across species. This phenomenon was illustrated when the SARS-coronavirus crossed species from bats to intermediate hosts, such as palm civets, and then to humans. It also explains the large number of species, including humans, that are infected with viruses closely related to bovine coronavirus.

  • In many coronavirus infections, disease severity increases during virus clearance, suggesting that the host immune response is both protective and pathogenic. Furthermore, inhibition of specific aspects of the immune response results in less severe disease and less tissue destruction, without diminishing the kinetics of virus clearance.

  • Like all successful viruses, coronaviruses have evolved both passive and active mechanisms to evade the interferon response. Replication in DMVs may contribute to passive evasion of the innate immune response by making double-stranded RNA inaccessible to cellular sensors.

Abstract

Although coronaviruses were first identified nearly 60 years ago, they only received notoriety in 2003 when one of their members was identified as the aetiological agent of severe acute respiratory syndrome. Previously these viruses were known to be important agents of respiratory and enteric infections of domestic and companion animals and to cause approximately 15% of all cases of the common cold. This Review focuses on recent advances in our understanding of the mechanisms of coronavirus replication, interactions with the host immune response and disease pathogenesis. It also highlights the recent identification of numerous novel coronaviruses and the propensity of this virus family to cross species barriers.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Nidoviruses.
The alternative text for this image may have been generated using AI.
Figure 2: Structure of coronavirus genome and virion.
The alternative text for this image may have been generated using AI.
Figure 3: Mechanism of coronavirus replication and transcription.
The alternative text for this image may have been generated using AI.
Figure 4: Coronavirus-induced membrane alterations as platforms for viral replication.
The alternative text for this image may have been generated using AI.
Figure 5: Cross-species transmission of coronaviruses.
The alternative text for this image may have been generated using AI.
Figure 6: Inefficient activation of the type 1 interferon response, and immunopathological disease, in coronavirus infections.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

References

  1. Peiris, J. S., Guan, Y. & Yuen, K. Y. Severe acute respiratory syndrome. Nature Med. 10, S88–S97 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Barcena, M. et al. Cryo-electron tomography of mouse hepatitis virus: insights into the structure of the coronavirion. Proc. Natl Acad. Sci. USA 106, 582–587 (2009). This paper and Ref. 3 use novel methodologies to obtain detailed models of the structure of the intact coronavirion.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Neuman, B. W. et al. Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy. J. Virol. 80, 7918–7928 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Masters, P. S. The molecular biology of coronaviruses. Adv. Virus Res. 66, 193–292 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lissenberg, A. et al. Luxury at a cost? Recombinant mouse hepatitis viruses expressing the accessory hemagglutinin esterase protein display reduced fitness in vitro. J. Virol. 79, 15054–15063 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hemmila, E. et al. Ceacam1aβˆ’/βˆ’ mice are completely resistant to infection by murine coronavirus mouse hepatitis virus A59. J. Virol. 78, 10156–10165 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weiss, S. R. & Navas-Martin, S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol. Mol. Biol. Rev. 69, 635–664 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, W. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450–454 (2003). This is the first report identifying the SARS-CoV receptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, W. et al. The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2. Virology 367, 367–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Hofmann, H. et al. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl Acad. Sci. USA 102, 7988–7993 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuba, K. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Med. 11, 875–879 (2005). This report suggests that interactions between the SARS-CoV S protein and its receptor may contribute to disease progression, in addition to facilitating virus entry.

    Article  CAS  PubMed  Google Scholar 

  12. Imai, Y. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112–116 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ning, Q. et al. Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4Ξ±. J. Biol. Chem. 278, 15541–15549 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Zhao, X., Nicholls, J. M. & Chen, Y. G. Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-Ξ² signaling. J. Biol. Chem. 283, 3272–3280 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. DeDiego, M. L. et al. A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. J. Virol. 81, 1701–1713 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Kuo, L. & Masters, P. S. The small envelope protein E is not essential for murine coronavirus replication. J. Virol. 77, 4597–4608 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ortego, J., Ceriani, J. E., Patino, C., Plana, J. & Enjuanes, L. Absence of E protein arrests transmissible gastroenteritis coronavirus maturation in the secretory pathway. Virology 368, 296–308 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Madan, V., Garcia Mde, J., Sanz, M. A. & Carrasco, L. Viroporin activity of murine hepatitis virus E protein. FEBS Lett. 579, 3607–3612 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wilson, L., McKinlay, C., Gage, P. & Ewart, G. SARS coronavirus E protein forms cation-selective ion channels. Virology 330, 322–331 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Yount, B. et al. Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice. J. Virol. 79, 14909–14922 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ontiveros, E., Kuo, L., Masters, P. S. & Perlman, S. Inactivation of expression of gene 4 of mouse hepatitis virus strain JHM does not affect virulence in the murine CNS. Virology 290, 230–238 (2001).

    Article  CAS  Google Scholar 

  22. de Haan, C. A., Masters, P. S., Shen, X., Weiss, S. & Rottier, P. J. The group-specific murine coronavirus genes are not essential, but their deletion, by reverse genetics, is attenuating in the natural host. Virology 296, 177–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Li, W. et al. Bats are natural reservoirs of SARS-like coronaviruses. Science 310, 676–679 (2005). This paper and Ref. 80 show that SARS-CoV probably originated in bats.

    Article  CAS  PubMed  Google Scholar 

  24. Fischer, F., Peng, D., Hingley, S. T., Weiss, S. R. & Masters, P. S. The internal open reading frame within the nucleocapsid gene of mouse hepatitis virus encodes a structural protein that is not essential for viral replication. J. Virol. 71, 996–1003 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang, C., Peters, C. J. & Makino, S. Severe acute respiratory syndrome coronavirus accessory protein 6 is a virion-associated protein and is released from 6 protein-expressing cells. J. Virol. 81, 5423–5426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ito, N. et al. Severe acute respiratory syndrome coronavirus 3a protein is a viral structural protein. J. Virol. 79, 3182–3186 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schaecher, S. R., Mackenzie, J. M. & Pekosz, A. The ORF7b protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is expressed in virus-infected cells and incorporated into SARS-CoV particles. J. Virol. 81, 718–731 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Neuman, B. W. et al. Proteomics analysis unravels the functional repertoire of coronavirus nonstructural protein 3. J. Virol. 82, 5279–5294 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sawicki, S. G., Sawicki, D. L. & Siddell, S. G. A contemporary view of coronavirus transcription. J. Virol. 81, 20–29 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R. & Hilgenfeld, R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300, 1763–1767 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Zhai, Y. et al. Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nature Struct. Mol. Biol. 12, 980–986 (2005).

    Article  CAS  Google Scholar 

  32. Chatterjee, A. et al. Nuclear magnetic resonance structure shows that the severe acute respiratory syndrome coronavirus-unique domain contains a macrodomain fold. J. Virol. 83, 1823–1836 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Joseph, J. S. et al. Crystal structure of nonstructural protein 10 from the severe acute respiratory syndrome coronavirus reveals a novel fold with two zinc-binding motifs. J. Virol. 80, 7894–7901 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Joseph, J. S. et al. Crystal structure of a monomeric form of severe acute respiratory syndrome coronavirus endonuclease nsp15 suggests a role for hexamerization as an allosteric switch. J. Virol. 81, 6700–6708 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peti, W. et al. Structural genomics of the severe acute respiratory syndrome coronavirus: nuclear magnetic resonance structure of the protein nsP7. J. Virol. 79, 12905–12913 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Saikatendu, K. S. et al. Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1β€²'-phosphate dephosphorylation by a conserved domain of nsP3. Structure 13, 1665–1675 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Almeida, M. S., Johnson, M. A., Herrmann, T., Geralt, M. & Wuthrich, K. Novel Ξ² -barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein 1 from the severe acute respiratory syndrome coronavirus. J. Virol. 81, 3151–3161 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Serrano, P. et al. Nuclear magnetic resonance structure of the N-terminal domain of nonstructural protein 3 from the severe acute respiratory syndrome coronavirus. J. Virol. 81, 12049–12060 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ricagno, S. et al. Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family. Proc. Natl Acad. Sci. USA 103, 11892–11897 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Su, D. et al. Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10. J. Virol. 80, 7902–7908 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Snijder, E. J. et al. 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, 991–1004 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Imbert, I. et al. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 25, 4933–4942 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ratia, K. et al. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proc. Natl Acad. Sci. USA 103, 5717–5722 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Deming, D. J., Graham, R. L., Denison, M. R. & Baric, R. S. Processing of open reading frame 1a replicase proteins nsp7 to nsp10 in murine hepatitis virus strain A59 replication. J. Virol. 81, 10280–10291 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Egloff, M. P. et al. 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. USA 101, 3792–3796 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Donaldson, E. F., Sims, A. C., Graham, R. L., Denison, M. R. & Baric, R. S. Murine hepatitis virus replicase protein nsp10 is a critical regulator of viral RNA synthesis. J. Virol. 81, 6356–6368 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Eckerle, L. D., Lu, X., Sperry, S. M., Choi, L. & Denison, M. R. High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J. Virol. 81, 12135–12144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen, Y. et al. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl Acad. Sci. USA 10 Feb 2009 (doi:10.1073/pnas.0808790106).

  49. Ivanov, K. A. et al. Major genetic marker of nidoviruses encodes a replicative endoribonuclease. Proc. Natl Acad. Sci. USA 101, 12694–12699 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Decroly, E. et al. Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2β€²O)-methyltransferase activity. J. Virol. 82, 8071–8084 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Snijder, E. J. et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. J. Virol. 80, 5927–5940 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. de Haan, C. A. & Rottier, P. J. Molecular interactions in the assembly of coronaviruses. Adv. Virus Res. 64, 165–230 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Prentice, E., Jerome, W. G., Yoshimori, T., Mizushima, N. & Denison, M. R. Coronavirus replication complex formation utilizes components of cellular autophagy. J. Biol. Chem. 279, 10136–10141 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Zhao, Z. et al. Coronavirus replication does not require the autophagy gene ATG5. Autophagy 3, 581–585 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Bechill, J., Chen, Z., Brewer, J. W. & Baker, S. C. Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression. J. Virol. 82, 4492–4501 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Knoops, K. et al. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 6, e226 (2008). This is an elegant electron microscopic study that uses 3D imaging of SARS-CoV-infected cells to delineate the relationship between virus replication and virus-induced membranous changes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Snijder, E. J., van Tol, H., Roos, N. & Pedersen, K. W. Non-structural proteins 2 and 3 interact to modify host cell membranes during the formation of the arterivirus replication complex. J. Gen. Virol. 82, 985–994 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Clementz, M. A., Kanjanahaluethai, A., O'Brien, T. E. & Baker, S. C. Mutation in murine coronavirus replication protein nsp4 alters assembly of double membrane vesicles. Virology 375, 118–129 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Kanjanahaluethai, A., Chen, Z., Jukneliene, D. & Baker, S. C. Membrane topology of murine coronavirus replicase nonstructural protein 3. Virology 361, 391–401 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Oostra, M. et al. Topology and membrane anchoring of the coronavirus replication complex: Not all hydrophobic domains of nsp3 and nsp6 are membrane spanning. J. Virol. 82, 12392–12405 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Oostra, M. et al. Localization and membrane topology of coronavirus nonstructural protein 4: involvement of the early secretory pathway in replication. J. Virol. 81, 12323–12336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Garbino, J. et al. A prospective hospital-based study of the clinical impact of non-severe acute respiratory syndrome (Non-SARS)-related human coronavirus infection. Clin. Infect. Dis. 43, 1009–1015 (2006).

    Article  PubMed  Google Scholar 

  63. Gu, J. et al. Multiple organ infection and the pathogenesis of SARS. J. Exp. Med. 202, 415–424 (2005).

    Article  CAS  Google Scholar 

  64. Fouchier, R. A. et al. A previously undescribed coronavirus associated with respiratory disease in humans. Proc. Natl Acad. Sci. USA 101, 6212–6216 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. van der Hoek, L. et al. Identification of a new human coronavirus. Nature Med. 10, 368–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Woo, P. C. et al. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J. Virol. 79, 884–895 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pyrc, K. et al. Mosaic structure of human coronavirus NL63, one thousand years of evolution. J. Mol. Biol. 364, 964–973 (2006). This manuscript delineates molecular evolution of HCoV-229E and HCoV-NL63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. van der Hoek, L. et al. Croup is associated with the novel coronavirus NL63. PLoS Med. 2, e240 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Donaldson, E. F. et al. Systematic assembly of a full-length infectious clone of human coronavirus NL63. J. Virol. 82, 11948–11957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rottier, P. J., Nakamura, K., Schellen, P., Volders, H. & Haijema, B. J. Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein. J. Virol. 79, 14122–14130 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. de Groot-Mijnes, J. D., van Dun, J. M., van der Most, R. G. & de Groot, R. J. Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease. J. Virol. 79, 1036–1044 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vennema, H. et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J. Virol. 64, 1407–1409 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Guan, Y. et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 302, 276–278 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Riley, S. et al. Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science 300, 1961–1966 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Chinese, S. M. E. C. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science 303, 1666–1669 (2004).

    Article  CAS  Google Scholar 

  76. Song, H. D. et al. Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. Proc. Natl Acad. Sci. USA 102, 2430–2435 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li, W. et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 24, 1634–1643 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sheahan, T., Rockx, B., Donaldson, E., Corti, D. & Baric, R. Pathways of cross-species transmission of synthetically reconstructed zoonotic severe acute respiratory syndrome coronavirus. J. Virol. 82, 8721–8732 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Poon, L. L. et al. Identification of a novel coronavirus in bats. J. Virol. 79, 2001–2009 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lau, S. K. et al. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl Acad. Sci. USA 102, 14040–14045 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Leung, D. T. et al. Extremely low exposure of a community to severe acute respiratory syndrome coronavirus: false seropositivity due to use of bacterially derived antigens. J. Virol. 80, 8920–8928 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Becker, M. M. et al. Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. Proc. Natl Acad. Sci. USA 105, 19944–19949 (2008). This manuscript describes the engineering of a non-cultivable bat SARS-like coronavirus using synthetic DNA technology.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ren, W. et al. Difference in receptor usage between severe acute respiratory syndrome (SARS) coronavirus and SARS-like coronavirus of bat origin. J. Virol. 82, 1899–1907 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Vijgen, L. et al. Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. J. Virol. 79, 1595–1604 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Alekseev, K. P. et al. Bovine-like coronaviruses isolated from four species of captive wild ruminants are homologous to bovine coronaviruses based on complete genomic sequences. J. Virol. 82, 12422–12431 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Jin, L. et al. Analysis of the genome sequence of an alpaca coronavirus. Virology 365, 198–203 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lorusso, A. et al. Gain, preservation, and loss of a group 1a coronavirus accessory glycoprotein. J. Virol. 82, 10312–10317 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Woo, P. C. et al. Comparative analysis of twelve genomes of three novel group 2c and group 2d coronaviruses reveals unique group and subgroup features. J. Virol. 81, 1574–1585 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Dominguez, S. R., O'Shea, T. J., Oko, L. M. & Holmes, K. V. Detection of group 1 coronaviruses in bats in North America. Emerg. Infect. Dis. 13, 1295–1300 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gloza-Rausch, F. et al. Detection and prevalence patterns of group I coronaviruses in bats, northern Germany. Emerg. Infect. Dis. 14, 626–631 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tong, S. et al. Detection of novel SARS-like and other coronaviruses in bats from Kenya. Emerg. Infect. Dis. 15, 482–485 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Woo, P. C. et al. Comparative analysis of complete genome sequences of three novel avian coronaviruses reveals a novel group 3c coronavirus. J. Virol. 83, 908–917 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Dong, B. Q. et al. Detection of a novel and highly divergent coronavirus from asian leopard cats and Chinese ferret badgers in Southern China. J. Virol. 81, 6920–6926 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mihindukulasuriya, K. A., Wu, G., St Leger, J., Nordhausen, R. W. & Wang, D. Identification of a novel coronavirus from a beluga whale by using a panviral microarray. J. Virol. 82, 5084–5088 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Perlman, S. & Dandekar, A. A. Immunopathogenesis of coronavirus infections: implications for SARS. Nature Rev. Immunol. 5, 917–927 (2005).

    Article  CAS  Google Scholar 

  96. Bergmann, C. C., Lane, T. E. & Stohlman, S. A. Coronavirus infection of the central nervous system: host–virus stand-off. Nature Rev. Microbiol. 4, 121–132 (2006).

    Article  CAS  Google Scholar 

  97. Savarin, C., Bergmann, C. C., Hinton, D. R., Ransohoff, R. M. & Stohlman, S. A. Memory CD4+ T-cell-mediated protection from lethal coronavirus encephalomyelitis. J. Virol. 82, 12432–12440 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kim, T. S. & Perlman, S. Virus-specific antibody, in the absence of T cells, mediates demyelination in mice infected with a neurotropic coronavirus. Am. J. Pathol. 166, 801–809 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kim, T. S. & Perlman, S. Viral expression of CCL2 is sufficient to induce demyelination in RAG1βˆ’/βˆ’ mice infected with a neurotropic coronavirus. J. Virol. 79, 7113–7120 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Williamson, J. S. & Stohlman, S. A. Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells. J. Virol. 64, 4589–4592 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Anghelina, D., Pewe, L. & Perlman, S. Pathogenic role for virus-specific CD4 T cells in mice with coronavirus-induced acute encephalitis. Am. J. Pathol. 169, 209–222 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Deming, D. et al. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 3, e525 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Roberts, A. et al. A mouse-adapted SARS-Coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog. 3, e5 (2007). This is the first report showing that a mouse-adapted SARS-CoV causes a SARS-like illness in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Roberts, A. et al. Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J. Virol. 79, 5833–5838 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Versteeg, G. A., Bredenbeek, P. J., van den Worm, S. H. & Spaan, W. J. Group 2 coronaviruses prevent immediate early interferon induction by protection of viral RNA from host cell recognition. Virology 361, 18–26 (2007). This report and Ref. 106 are the first to suggest that coronaviruses are invisible to the host innate immune response in some cells.

    Article  CAS  PubMed  Google Scholar 

  106. Zhou, H. & Perlman, S. Mouse hepatitis virus does not induce beta interferon synthesis and does not inhibit its induction by double-stranded RNA. J. Virol. 81, 568–574 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Spiegel, M. et al. Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. J. Virol. 79, 2079–2086 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. He, R. et al. Activation of AP-1 signal transduction pathway by SARS coronavirus nucleocapsid protein. Biochem. Biophys. Res. Commun. 311, 870–876 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kopecky-Bromberg, S. A., Martinez-Sobrido, L., Frieman, M., Baric, R. A. & Palese, P. SARS coronavirus proteins Orf 3b, Orf 6, and nucleocapsid function as interferon antagonists. J. Virol. 81, 548–557 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ye, Y., Hauns, K., Langland, J. O., Jacobs, B. L. & Hogue, B. G. Mouse hepatitis coronavirus A59 nucleocapsid protein is a type I interferon antagonist. J. Virol. 81, 2554–2563 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Narayanan, K. et al. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells. J. Virol. 82, 4471–4479 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wathelet, M. G., Orr, M., Frieman, M. B. & Baric, R. S. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J. Virol. 81, 11620–11633 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zust, R. et al. Coronavirus non-structural protein 1 is a major pathogenicity factor: implications for the rational design of coronavirus vaccines. PLoS Pathog. 3, e109 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Frieman, M. et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 81, 9812–9824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hussain, S., Perlman, S. & Gallagher, T. M. Severe acute respiratory syndrome coronavirus protein 6 accelerates murine hepatitis virus infections by more than one mechanism. J. Virol. 82, 7212–7222 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhao, J. et al. Severe acute respiratory syndrome-CoV protein 6 is required for optimal replication. J. Virol. 83, 2368–2373 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kamitani, W. et al. Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation. Proc. Natl Acad. Sci. USA 103, 12885–12890 (2006). Describes a novel mechanism of viral protein-induced inhibition of host gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Devaraj, S. G. et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J. Biol. Chem. 282, 32208–32221 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Cameron, M. J. et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J. Virol. 81, 8692–8706 (2007). This report provides a careful description of the changes in cytokine and chemokine expression that occurred in patients during the 2002–2003 epidemic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rempel, J. D., Murray, S. J., Meisner, J. & Buchmeier, M. J. Differential regulation of innate and adaptive immune responses in viral encephalitis. Virology 318, 381–392 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Ireland, D. D., Stohlman, S. A., Hinton, D. R., Atkinson, R. & Bergmann, C. C. Type I interferons are essential in controlling neurotropic coronavirus infection irrespective of functional CD8 T cells. J. Virol. 82, 300–310 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Cervantes-Barragan, L. et al. Control of coronavirus infection through plasmacytoid dendritic cell-derived type I interferon. Blood 109, 1131–1137 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Roth-Cross, J. K., Bender, S. J. & Weiss, S. R. Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain macrophages/microglia. J. Virol. 82, 9829–9838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cervantes-Barragan, L. et al. Type I IFN-mediated protection of macrophages and dendritic cells secures control of murine coronavirus infection. J. Immunol. 182, 1099–1106 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. He, L. et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J. Pathol. 210, 288–297 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, C. K. et al. T cell responses to whole SARS coronavirus in humans. J. Immunol. 181, 5490–5500 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Gu, J. & Korteweg, C. Pathology and pathogenesis of severe acute respiratory syndrome. Am. J. Pathol. 170, 1136–1147 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chen, J. & Subbarao, K. The immunobiology of SARS. Annu. Rev. Immunol. 25, 443–472 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Subbarao, K. & Roberts, A. Is there an ideal animal model for SARS? Trends Microbiol. 14, 299–303 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. McCray, P. B. Jr et al. Lethal infection in K18-hACE2 mice infected with SARS-CoV. J. Virol. 81, 813–821 (2006). This paper and REF. 131 show that mice transgenic for the human SARS-CoV develop a lethal infection characterized by extensive infection of the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Tseng, C. T. et al. SARS coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 (hACE2) virus receptor. J. Virol. 81, 1162–1173 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Netland, J., Meyerholz, D. K., Moore, S., Cassell, M. & Perlman, S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82, 7264–7275 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lee, D. T. et al. Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study. Clin. Infect. Dis. 39, 1247–1249 (2004).

    Article  PubMed  Google Scholar 

  134. Xu, J. et al. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin. Infect. Dis. 41, 1089–1096 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Nagata, N. et al. Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice. Am. J. Pathol. 172, 1625–1637 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Nagata, N. et al. Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus. J. Virol. 81, 1848–1857 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. de Lang, A. et al. Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques. PLoS Pathog. 3, e112 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Baas, T. et al. Genomic analysis reveals age-dependent innate immune responses to severe acute respiratory syndrome coronavirus. J. Virol. 82, 9465–9476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Morahan, G., Balmer, L. & Monley, D. Establishment of β€œThe Gene Mine”: a resource for rapid identification of complex trait genes. Mamm. Genome 19, 390–393 (2008).

    Article  PubMed  Google Scholar 

  140. Stockman, L. J., Bellamy, R. & Garner, P. SARS: systematic review of treatment effects. PLoS Med. 3, e343 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gosert, R., Kanjanahaluethai, A., Egger, D., Bienz, K. & Baker, S. C. RNA replication of mouse hepatitis virus takes place at double-membrane vesicles. J. Virol. 76, 3697–3708 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Sims, A. C., Ostermann, J. & Denison, M. R. Mouse hepatitis virus replicase proteins associate with two distinct populations of intracellular membranes. J. Virol. 74, 5647–5654 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported in part by research (PO1 AI060699 and RO1 NS36592) and training (T32 AI007533) grants from the National Institutes of Health (USA).

Author information

Authors and Affiliations

  1. Department of Microbiology and Interdisciplinary Program in Immunology, University of Iowa, Iowa City, 52242, Iowa, USA

    Stanley Perlman & Jason Netland

Authors
  1. Stanley Perlman
  2. Jason Netland

Corresponding author

Correspondence to Stanley Perlman.

Related links

Related links

FURTHER INFORMATION

Stanley Perlman's homepage

Glossary

Prothrombinase

Molecule that cleaves thrombin, thereby initiating the coagulation cascade.

Primase

In the case of nsp8, an RNA-dependent RNA polymerase that produces RNA primers that are required for initiation of RNA synthesis by the main viral RNA polymerase, nsp12.

Double-membrane vesicle

A structure that is observed in electron micrographs of infected cells and that is thought to be the site of virus replication.

Collaborative cross mice

A panel of 1,000 recombinant inbred mouse strains derived from 8 genetically diverse founder strains. The crosses were designed for complex trait analysis and will be useful for identifying and establishing the role of host genes in SARS pathogenesis.

About this article

Cite this article

Perlman, S., Netland, J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7, 439–450 (2009). https://doi.org/10.1038/nrmicro2147

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrmicro2147

Search

Advanced search

Quick links

πŸ‘ Nature Briefing

Sign up for the Nature Briefing newsletter β€” what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing