Skip to main content
Springer Nature Link
Log in

Murine coronavirus neuropathogenesis: determinants of virulence

  • Review
  • Published:
Save article
View saved research
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Murine coronavirus, mouse hepatitis virus (MHV), causes various diseases depending on the strain and route of inoculation. Both the JHM and A59 strains, when inoculated intracranially or intranasally, are neurovirulent. Comparison of the highly virulent JHM isolate, JHM.SD, with less virulent JHM isolates and with A59 has been used to determine the mechanisms and genes responsible for high neuropathogenicity of MHV. The focus of this review is on the contributions of viral spread, replication, and innate and adaptive immunity to MHV neuropathogenesis. JHM.SD spreads more quickly among neurons than less neurovirulent MHVs, and is able to spread in the absence of the canonical MHV receptor, CEACAM1a. The observation that JHM.SD infects more cells and expresses more antigen, but produces less infectious virus per cell than A59, implies that efficient replication is not always a correlate of high neurovirulence. This is likely due to the unstable nature of the JHM.SD spike protein (S). JHM.SD induces a generally protective innate immune response; however, the strong neutrophil response may be more pathogenic than protective. In addition, JHM.SD induces only a minimal T-cell response, whereas the strong T-cell response and the concomitant interferon-γ (IFN-γ) induced by the less neurovirulent A59 is protective. Differences in the S and nucleocapsid (N) proteins between A59 and JHM.SD contribute to JHM.SD neuropathogenicity. The hemmagglutinin-esterase (HE) protein may enhance neuropathogenicity of some MHV isolates, but is unlikely a major contributor to the high neuroviruence of JHM.SD. Further data suggest that neither the internal (I) protein nor nonstructural proteins ns4, and ns2 are significant contributors to neurovirulence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from €37.37 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price includes VAT (Netherlands)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • Barnett EM, Perlman S (1993). The olfactory nerve and not the trigeminal nerve is the major site of CNS entry for mouse hepatitis virus, strain JHM. Virology194: 185–191.

    Article  CAS  PubMed  Google Scholar 

  • Bender SJ, Phillips JM, Scott EP, Weiss SR (2010). Murine coronavirus receptors are differentially expressed in the central nervous system and play virus strain-dependent roles in neuronal spread.J Virol 84: 11030–11044.

    Article  CAS  PubMed  Google Scholar 

  • Bender SJ, Weiss SR (2010). Pathogenesis of murine coronavirus in the central nervous system.J Neuroimmune Pharmacol 5: 336–354.

    Article  PubMed  Google Scholar 

  • Bergmann CC, Parra B, Hinton DR, Chandran R, Morrison M, Stohlman SA (2003). Perforin-mediated effector function within the central nervous system requires IFN-gamma-mediated MHC up-regulation.J Immunol 170: 3204–3213.

    CAS  PubMed  Google Scholar 

  • Cheever FS, Daniels JB, Pappenheimer AM, Baily OT (1949). A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. I. Isolation and biological properties of the virus.J ExpMed 90: 181–194.

    Article  CAS  Google Scholar 

  • Cowley TJ, Long SY, Weiss SR (2010). The murine coronavirus nucleocapsid gene is a determinant of virulence.J Virol 84: 1752–1763.

    Article  CAS  PubMed  Google Scholar 

  • De Albuquerque N, Baig E, Ma X, Zhang J, He W, Rowe A, Habal M, Liu M, Shalev I, Downey GP, Gorczynski R, Butany J, Leibowitz J, Weiss SR, McGilvray ID, Phillips MJ, Fish EN, Levy GA (2006). Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice.J Virol 80: 10382–10394.

    Article  PubMed  Google Scholar 

  • Dorries R (2001). The role of T-cell-mediated mechanisms in virus infections of the nervous system.Curr Top Microbiol Immunol 253: 219–245.

    CAS  PubMed  Google Scholar 

  • Eriksson KK, Cervantes-Barragan L, Ludewig B, Thiel V (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.

    Article  CAS  PubMed  Google Scholar 

  • Fazakerley JK, Parker SE, Bloom F, Buchmeier MJ (1992). The V5A13.1 envelope glycoprotein deletion mutant of mouse hepatitis virus type-4 is neuroattenuated by its reduced rate of spread in the central nervous system.Virol 187: 178–188.

    Article  CAS  Google Scholar 

  • Fischer F, Peng D, Hingley ST, Weiss SR, Masters PS (1997). 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.

    CAS  PubMed  Google Scholar 

  • Fishman PS, Gass JS, Swoveland PT, Lavi E, Highkin MK, Weiss SR (1985). Infection of the basal ganglia by a murine coronavirus.Science 229: 877–879.

    Article  CAS  PubMed  Google Scholar 

  • Gallagher TM, Buchmeier MJ (2001). Coronavirus spike proteins in viral entry and pathogenesis.Virology 279: 371–374.

    Article  CAS  PubMed  Google Scholar 

  • Gallagher TM, Buchmeier MJ, Perlman S (1992). Cell receptor-independent infection by a neurotropic murine coronavirus.Virology 191: 517–522.

    Article  CAS  PubMed  Google Scholar 

  • Gallagher TM, Parker SE, Buchmeier MJ (1990). Neutralization-resistant variants of a neurotropic coronavirus are generated by deletions within the amino-terminal half of the spike glycoprotein.J Virol 64: 731–741.

    CAS  PubMed  Google Scholar 

  • Gombold JL, Sutherland RM, Lavi E, Paterson Y, Weiss SR (1995). Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells.Microb Pathog 18:211–2211.

    Article  CAS  PubMed  Google Scholar 

  • Gorbalenya AE, Koonin EV, Lai MM (1991). Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha- and coronaviruses.FEBS Lett 288: 201–205.

    Article  CAS  PubMed  Google Scholar 

  • Haspel MV, Lampert PW, Oldstone MB (1978). Temperature-sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination.Proc Natl Acad Sci U S A 75: 4033–4036.

    Article  CAS  PubMed  Google Scholar 

  • Houtman JJ, Fleming JO (1996a). Dissociation of demyelination and viral clearance in congenitally immunodeficient mice infected with murine coronavirus JHM.J NeuroVirol 2: 101–110.

    Article  CAS  PubMed  Google Scholar 

  • Houtman JJ, Fleming JO (1996b). Pathogenesis of mouse hepatitis virus-induced demyelination.J NeuroVirol 2: 361–376.

    Article  CAS  PubMed  Google Scholar 

  • Iacono KT, Kazi L, Weiss SR (2006). Both spike and background genes contribute to murine coronavirus neurovirulence.J Virol 80: 6834–6843.

    Article  CAS  PubMed  Google Scholar 

  • Karman J, Ling C, Sandor M, Fabry Z (2004). Initiation of immune responses in brain is promoted by local dendritic cells.J Immunol 173: 2353–2361.

    CAS  PubMed  Google Scholar 

  • Kazi L, Lissenberg A, Watson R, de Groot RJ, Weiss SR (2005). Expression of hemagglutinin esterase protein from recombinant mouse hepatitis virus enhances neurovirulence.J Virol 79: 15064–15073.

    Article  CAS  PubMed  Google Scholar 

  • Knobler RL, Haspel MV, Oldstone MB (1981). Mouse hepatitis virus type 4 (JHM strains) induced fatal central nervous system disease. I. genetic control and murine neuron as the susceptible site of disease.J Exp Med 153: 832–843.

    Article  CAS  PubMed  Google Scholar 

  • Koetzner CA, Kuo L, Goebel SJ, Dean AB, Parker MM, Masters PS (2010). Accessory protein 5a is a major antagonist of the antiviral action of interferon against murine coronavirus.J Virol 84: 8262–8274.

    Article  CAS  PubMed  Google Scholar 

  • Krueger DK, Kelly SM, Lewicki DN, Ruffolo R, Gallagher TM (2001). Variations in disparate regions of the murine coronavirus spike protein impact the initiation of membrane fusion.J Virol 75: 2792–2802.

    Article  CAS  PubMed  Google Scholar 

  • LaMonica N, Banner LR, Morris VL, Lai MMC (1991). Localization of extensive deletions in the structural genes of two neurotropic variants of murine coronavirus JHM.Virology 182: 883–888.

    Article  CAS  Google Scholar 

  • Lampert PW, Sims JK, Kniazeff AJ (1973). Mechanism of demyelination in JHM virus encephalomyelitis.Acta Neurophathol (Berl) 24: 76–85.

    Article  CAS  Google Scholar 

  • Lavi E, Fishman PS, Highkin MK, Weiss SR (1988). Limbic encephalitis after inhalation of a murine coronavirus.Lab Invest 58: 31–36.

    CAS  PubMed  Google Scholar 

  • Lavi E, Gilden DH, Highkin MK, Weiss SR (1986). The organ tropism of mouse hepatitis virus A59 in mice is dependent on dose and route of inoculation.Lab Anim Sci 36: 130–135.

    CAS  PubMed  Google Scholar 

  • Lavi E, Gilden DH, Wroblewska Z, Rorke LB, Weiss SR (1984). Experimental demyelination produced by the A59 strain of mouse hepatitis virus.Neurology 34: 597–603.

    CAS  PubMed  Google Scholar 

  • Lin MT, Hinton DR, Marten NW, Bergmann CC, Stohlman SA (1999). Antibody prevents virus reactivation within the central nervous system.J Immunol 162: 7358–7368.

    CAS  PubMed  Google Scholar 

  • Lin MT, Stohlman SA, Hinton DR (1997). Mouse hepatitis virus is cleared from the central nervous systems of mice lacking perforin-mediated cytolysis.J Virol 71: 383–391.

    CAS  PubMed  Google Scholar 

  • Macnamara KC, Bender SJ, Chua MM, Watson R, Weiss SR (2008). Priming of CD8+ T cells during central nervous system infection with a murine coronavirus is strain-dependent.J Virol 82: 6150–6160.

    Article  CAS  PubMed  Google Scholar 

  • MacNamara KC, Chua MM, Phillips JJ, Weiss SR (2005). Contributions of the viral genetic background and a single amino acid substitution in an immunodominant CD8+ T-cell epitope to murine coronavirus neurovirulence.J Virol 79: 9108–9118.

    Article  CAS  PubMed  Google Scholar 

  • Marten NW, Stohlman SA, Bergmann CC (2001). MHV infection of the CNS: mechanisms of immune-mediated control.Viral Immunol 14: 1–18.

    Article  CAS  PubMed  Google Scholar 

  • Marten NW, Stohlman SA, Zhou J, Bergmann CC (2003). Kinetics of virus-specific CD8+-T-cell expansion and trafficking following central nervous system infection.J Virol 77: 2775–2778.

    Article  CAS  PubMed  Google Scholar 

  • Matsubara Y, Watanabe R, Taguchi F (1991). Neurovirulence of six different murine coronavirus JHMV variants for rats.Virus Res 20: 45–58.

    Article  CAS  PubMed  Google Scholar 

  • Matthews AE, Weiss SR, Shlomchik MJ, Hannum LG, Gombold JL, Paterson Y (2001). Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver.J Immunol 167: 5254–5263.

    CAS  PubMed  Google Scholar 

  • Miura TA, Travanty EA, Oko L, Bielefeldt-Ohmann H, Weiss SR, Beauchemin N, Holmes KV (2008). The spike glycoprotein of murine coronavirus MHV-JHM mediates receptor-independent infection and spread in the central nervous system of Ceacam1a-/- mice.J Virol 82: 755–763.

    Article  CAS  PubMed  Google Scholar 

  • Nakagaki K, Taguchi F (2005). Receptor-independent spread of a highly neurotropic murine coronavirus JHMV strain from initially infected microglial cells in mixed neural cultures.J Virol 79: 6102–6110.

    Article  CAS  PubMed  Google Scholar 

  • Navas S, Weiss SR (2003). Murine coronavirus-induced hepatitis: JHM genetic background eliminates A59 spike-determined hepatotropism.J Virol 77: 4972–4978.

    Article  CAS  PubMed  Google Scholar 

  • Ontiveros E, Kim TS, Gallagher TM, Perlman S (2003). Enhanced virulence mediated by the murine coronavirus, mouse hepatitis virus strain JHM, is associated with a glycine at residue 310 of the spike glycoprotein.J Virol 77: 10260–10269.

    Article  CAS  PubMed  Google Scholar 

  • Ontiveros E, Kuo L, Masters PS, Perlman S (2001). Inactivation of expression of gene 4 of mouse hepatitis virus strain JHM does not affect virulence in the murine CNS.Virology 289: 230–238.

    Article  CAS  PubMed  Google Scholar 

  • Parham D, Tereba A, Talbot PJ, Jackson DP, Morris VL (1986). Analysis of JHM central nervous system infections in rats.Arch Neurol 43: 702–708.

    CAS  PubMed  Google Scholar 

  • Parra B, Hinton DR, Marten NW, Bergmann CC, Lin MT, Yang CS, Stohlman SA (1999). IFN-gamma is required for viral clearance from central nervous system oligodendroglia.J Immunol 162: 1641–1647.

    CAS  PubMed  Google Scholar 

  • Parra B, Lin MT, Stohlman SA, Bergmann CC, Atkinson R, Hinton DR (2001). Contributions of Fas-Fas ligand interactions to the pathogenesis of mouse hepatitis virus in the central nervous system.J Virol 74: 2447–2450.

    Article  Google Scholar 

  • Pasick JM, Kalicharran K, Dales S (1994). Distribution and trafficking of JHM coronavirus structural proteins and virions in primary neurons and the OBL-21 neuronal cell line.J Virol 68: 2915–2928.

    CAS  PubMed  Google Scholar 

  • Perlman S, Jacobsen G, Afifi A (1989). Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves.Virology 170: 556–560.

    Article  CAS  PubMed  Google Scholar 

  • Perlman S, Schelper R, Bolger E, Ries D (1987). Late onset, symptomatic, demyelinating encephalomyelitis in mice infected with MHV-JHM in the presence of maternal antibody.Microb Pathog 2: 185–194.

    Article  CAS  PubMed  Google Scholar 

  • Perlman S, Sun N, Barnett EM (1995). Spread of MHV-JHM from nasal cavity to white matter of spinal cord. Transneuronal movement and involvement of astrocytes.Adv Exp Med Biol 380: 73–78.

    CAS  PubMed  Google Scholar 

  • Phillips JJ, Chua MM, Lavi E, Weiss SR (1999). Pathogenesis of chimeric MHV4/MHV-A59 recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence.J Virol 73: 7752–7760.

    CAS  PubMed  Google Scholar 

  • Phillips JJ, Chua MM, Rall GF, Weiss SR (2002). Murine coronavirus spike glycoprotein mediates degree of viral spread, inflammation, and virus-induced immunopathology in the central nervous system.Virology 301: 109–120.

    Article  CAS  PubMed  Google Scholar 

  • Putics A, Filipowicz W, Hall J, Gorbalenya AE, Ziebuhr J (2005). ADP-ribose-1′-monophosphatase: a conserved coronavirus enzyme that is dispensable for viral replication in tissue culture.J Virol 79: 12721–12731.

    Article  CAS  PubMed  Google Scholar 

  • Putics A, Gorbalenya AE, Ziebuhr J (2006). Identification of protease and ADP-ribose 1′-monophosphatase activities associated with transmissible gastroenteritis virus nonstructural protein 3.J Gen Virol 87: 651–656.

    Article  CAS  PubMed  Google Scholar 

  • Ramakrishna C, Bergmann CC, Holmes KV, Stohlman SA (2004). Expression of the mouse hepatitis virus receptor by central nervous system microglia.J Virol 78: 7828–7832.

    Article  CAS  PubMed  Google Scholar 

  • Rempel JD, Murray SJ, Meisner J, Buchmeier MJ (2004a). Differential regulation of innate and adaptive immune responses in viral encephalitis.Virology 318: 381–392.

    Article  CAS  PubMed  Google Scholar 

  • Rempel JD, Murray SJ, Meisner J, Buchmeier MJ (2004b). Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology.Virology 318: 45–54.

    Article  CAS  PubMed  Google Scholar 

  • Roth-Cross JK, Stokes H, Chang G, Chua MM, Thiel V, Weiss SR, Gorbalenya AE, Siddell SG (2009). Organ-specific attenuation of murine hepatitis virus strain A59 by replacement of catalytic residues in the putative viral cyclic phosphodiesterase ns2.J Virol 83: 3743–3753.

    Article  CAS  PubMed  Google Scholar 

  • Schwarz B, Routledge E, Siddell SG (1990). Murine coronavirus nonstructural protein ns2 is not essential for virus replication in transformed cells.J Virol 64: 4784–4791.

    CAS  PubMed  Google Scholar 

  • Scott EP, Branigan PJ, Del Vecchio AM, Weiss SR (2008). Chemokine expression during mouse hepatitis virus-induced encephalitis: contributions of the spike and background genes.J NeuroVirol 14: 5–16.

    Article  CAS  PubMed  Google Scholar 

  • Stevenson PG, Hawke S, Sloan DJ, Bangham CR (1997). The immunogenicity of intracerebral virus infection depends on anatomical site.J Virol 71: 145–151.

    CAS  PubMed  Google Scholar 

  • Stohlman SA, Bergmann CC, Lin MT, Cua DJ, Hinton DR (1998). CTL effector function within the central nervous system requires CD4+ T cells.J Immunol 160: 2896–2904.

    CAS  PubMed  Google Scholar 

  • Sun N, Perlman S (1995). Spread of a neurotropic coronavirus to spinal cord white matter via neurons and astrocytes.J Virol 69: 633–641.

    CAS  PubMed  Google Scholar 

  • Sussman MA, Shubin RA, Kyuwa S, Stohlman SA (1989). T-cell-mediated clearance of mouse hepatitis virus strain JHM from the central nervous system.J Virol 63: 3051–3061.

    CAS  PubMed  Google Scholar 

  • Sutherland RM, Chua MM, Lavi E, Weiss SR, Paterson Y (1997). CD4+ and CD8+ T cells are not major effectors of mouse hepatitis virus A59-induced demyelinating disease.J NeuroVirol 3: 225–228.

    Article  CAS  PubMed  Google Scholar 

  • Taguchi F, Matsuyama S, Saeki K (1999). Difference in Bgp-independent fusion activity among mouse hepatitis viruses.Arch Virol 144: 2041–2049.

    Article  CAS  PubMed  Google Scholar 

  • Taguchi F, Siddell SG, Wege H, ter Meulen V (1985). Characterization of a variant virus selected in rat brains after infection by a coronavirus mouse hepatitis virus JHM.J Virol 54: 429–435.

    CAS  PubMed  Google Scholar 

  • Tsai JC, Zelus BD, Holmes KV, Weiss SR (2003). The N-terminal domain of the murine coronavirus spike glycoprotein determines the CEACAM1 receptor specificity of the virus strain.J Virol 77: 841–850.

    Article  CAS  PubMed  Google Scholar 

  • Wang FI, Hinton DR, Gilmore W, Trousdale MD, Fleming JO (1992). Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination.Lab Invest 66: 744–754.

    CAS  PubMed  Google Scholar 

  • Weiner LP (1973). Pathogenesis of demyelination induced by a mouse hepatitis.Arch Neurol 28: 298–303.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yokomori K, Asanaka M, Stohlman SA, Makino S, Shubin RA, Gilmore W, Weiner LP, Wang FI, Lai MM (1995). Neuropathogenicity of mouse hepatitis virus JHM isolates differing in hemagglutinin-esterase protein expression.J NeuroVirol 1: 330–339.

    Article  CAS  PubMed  Google Scholar 

  • Yokomori K, Baker SC, Stohlman SA, Lai MM (1992). Hemagglutinin-esterase-specific monoclonal antibodies alter the neuropathogenicity of mouse hepatitis virus.J Virol 66: 2865–2874.

    CAS  PubMed  Google Scholar 

  • Yokomori K, Lai MM (1991). Mouse hepatitis virus S RNA sequence reveals that nonstructural proteins ns4 and ns5a are not essential for murine coronavirus replication.J Virol 65: 5605–5608.

    CAS  PubMed  Google Scholar 

  • Yokomori K, Stohlman SA, Lai MM (1993). The detection and characterization of multiple hemagglutinin-esterase (HE)-defective viruses in the mouse brain during subacute demyelination induced by mouse hepatitis virus.Virology 192: 170–178.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Stohlman SA, Atkinson R, Hinton DR, Marten NW (2002). Matrix metalloproteinase expression correlates with virulence following neurotropic mouse hepatitis virus infection.J Virol 76: 7374–7384.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Stohlman SA, Hinton DR, Marten NW (2003). Neutrophils promote mononuclear cell infiltration during viral-induced encephalitis.J Immunol 170: 3331–3336.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania School of Medicine, 36th Street and Hamilton Walk, 10104-6076, Philadelphia, PA, USA

    Timothy J Cowley & Susan R Weiss

Authors
  1. Timothy J Cowley
    View author publications

    Search author on:PubMed Google Scholar

  2. Susan R Weiss
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Susan R Weiss.

Additional information

This work was supported by NIH grants NS-54695 and AI-60021 to S.R.W. T.J.C. was partially supported in part by NIH training grant AI-07324.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cowley, T.J., Weiss, S.R. Murine coronavirus neuropathogenesis: determinants of virulence. Journal of NeuroVirology 16, 427–434 (2010). https://doi.org/10.1007/BF03210848

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue date:

  • DOI: https://doi.org/10.1007/BF03210848

Keywords