Induction of Demyelination by a Temperature-sensitive Mutant of the Coronavirus MHV-A59 is Associated with Restriction of Viral Replication in the Brain
The neurovirulence of eight temperature-sensitive (ts) mutants of mouse hepatitis virus strain A59 in 4-week-old BALB/c mice was investigated. Whereas a dose of 100 p.f.u. of wild-type virus killed mice within a week, a 1000-fold higher dose of ts mutants did not. Three ts mutants induced demyelinating disease in the central nervous system (CNS). The pathology of the demyelinating disease caused by one mutant, designated ts-342, was studied in detail. Pathological changes, starting 3 days post-inoculation (p.i.), were characterized by inflammation and demyelination in the CNS. Antibody responses directed against all virus-specific structural proteins were present at 7 days p.i. No virus particles were observed by electron microscopy at 14 days p.i. However, macrophages and lymphocytes were abundant in the areas of demyelination. The growth kinetics in vivo of wild-type virus, ts-342 and a revertant of ts-342 were compared. Wild-type virus and the revertant replicated rapidly in the brain and spread to the liver causing a lethal hepatitis. Ts-342, however, replicated to a much lesser extent within the brain and could not be detected in the blood or liver. The ts lesion in the genome of ts-342 seems, therefore, to determine the outcome of the infection.
BuchmeierM. J.,
LewickiH. A.,
TalbotP. J.,
KnoblerR. L.1984; Murine hepatitis virus-4 (strain JHM) induced neurologic disease is modulated in vivo by monoclonal antibody. Virology 132:261–270
DalzielR. G.,
LampertP. W.,
TalbotP. J.,
BuchmeierM. J.1986; Site specific alteration of murine hepatitis virus type-4 (MHV-4) peplomer glycoprotein E2 results in reduced neurovirulence. Journal of Virology 59:463–471
FlemingJ. O.,
TrousdaleM. D.,
El-ZaatariF. A. K.,
StohlmanS. A.,
WeinerL. P.1986; Pathogenicity of antigenic variants of murine coronavirus JHM selected with monoclonal antibodies. Journal of Virology 58:869–875
HaspelM. V.,
LampertP. W.,
OldstoneM. B. A.1978; Temperature-sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination. Proceedings of the National Academv of Sciences U.S.A.: 754033–4036
JohnsonG. D.,
NogueiraaraujoG. M. DE C.1981; A simple method of reducing the fading of immunofluorescence during microscopy. Journal of Immunological Methods 43:349–350
KesslerS. W.1975; Rapid isolation of antigens from cells with a staphylococcal protein A-antibody absorbent: parameters of the interaction of antibody-antigen complexes with protein A. Journal of Immunology 115:1617–1624
KnoblerR. L.,
HaspelM. V.1981; Mouse hepatitis virus type-4 (JHM strain)-induced fatal central nervous system disease. I. Genetic control and the murine neuron as the susceptible site of disease. Journal of Experimental Medicine 153:832–843
KnoblerR. L.,
TunisonL. A.,
LampertP. w.,
OldstoneM. B. A.1982; Selected mutants of mouse hepatitis virus type 4 (JHM strain) induce different CNS diseases. Pathobiology of disease induced by wild type and mutants ts8 and ts 15 in BALB/c and SJL/j mice. American Journal of Pathology 109:157–168
KoolenM. J. M.,
OsterhausA.D.M.E.,
Van SteenisG.,
HorzinekM. C.,
Van Der ZeijstB. A. M.1983; Temperature-sensitive mutants of mouse hepatitis virus strain A59: isolation, characterization and neuropathogenic properties. Virology 125:393–402
KoolenM. J. M.,
OsterhausA.D.M.E.,
SiebelinkK. H. J.,
HorzinekM. C.,
Van Der ZeijstB. A. M.1984; Monoclonal antibodies to the three classes of mouse hepatitis virus strain A59 proteins. Advances in Experimental Medical Biology 173:115–116
KoolenM. J. M.,
HuygenP. L. M.,
CalafatJ.,
Van Der ZeijstB. A. M.1985; Virus-induced central positional nystagmus in mice. Acta oto-laryngologica 100:172–179
LaviL.,
GildenD. H.,
HighkinM. K.,
WeissS. R.1984a; Persistence of mouse hepatitis virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybridization. Journal of Virology 51:563–566
RottierP. J. M.,
SpaanW. J. M.,
HorzinekM. C.,
Van Der ZeijstB. A. M.1981a; Translation of three mouse hepatitis virus strain A59 subgenomic RNAs in Xenopus laevis oocytes. Journal of Virology 38:20–26
RottierP. J. M.,
HorzinekM. C.,
Van Der ZeijstB. A. M.1981b; Viral protein synthesis in mouse hepatitis virus strain A59-infected cells: effect of tunicamycin. Journal of Virology 40:350–357
SiddellS. G.,
AndersonR.,
CavanaghD.,
FujiwaraK.,
KlenkH. D.,
MacNaughtonM. R.,
PensaertM.,
StohlmanS. A.,
SturmanL.,
Van Der ZeijstB. A. M.1983; Coronaviridae. Intervirology 20:181–189
SorensenO.,
PercyD.,
DalesS.1980; In vivo and in vitro models of demyelinating disease. III. JHM virus infection of rats. Archives of Neurology 37:478–484
SturmanL. S.1977; Characterization of corona virus. I. Structural proteins: effects of preparative conditions on the migration of protein in polyacrylamide gels. Virology 77:637–649
Van BerloM. F.,
WolswijkG.,
CalafatJ.,
KoolenM. J. M.,
HorzinekM. C.1986; Restricted replication of coronavirus MHV-A59 in primary mouse brain astrocytes correlates with reduced pathogenicity. Journal of Virology 58:426–433
WatanabeR.,
WegeH.,
Ter Meulenv.1983; Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis. Nature; London: 305150–153
Induction of Demyelination by a Temperature-sensitive Mutant of the Coronavirus MHV-A59 is Associated with Restriction of Viral Replication in the Brain