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1、Coronavirus Induction of Class I Major Histocompatibility Complex Expression in Murine Astrocytes Is Virus Strain Specific By Wendy Gilmore,* Jorge Correale,* and Leslie P. Weiner*r From the Departments of *Neurology and $Microbiology, University of Southern California School of Mecine, Los Angeles,
2、 California 90033 Summary Neurotropic strains of mouse hepatitis viruses (MHV) such as MHV-A59 (A59) and MHV-4 (JHMV) cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. They are widely used as models of human demyelinating diseases such as multiple s
3、clerosis (MS), in which immune mechanisms are thought to participate in the development of lesions in the central nervous system (CNS). The effects of MHV infection on target cell functions in the CNS are not well understood, but A59 has been shown to induce the expression of MHC class I molecules i
4、n glial cells after in vivo and in vitro infection. Changes in class I expression in infected cells may contribute to the immunopathogenesis of MHV infection in the CNS. In this communication, a large panel of MHV strains was tested for their ability to stimulate class I expression in primary astroc
5、ytes in vitro. The data show that the more hepatotropic strains, such as MHV-A59, MHV-1, MHV-2, MHV-3, MHV-D, MHV-K, and MHV-NuU, were potent inducers of class I expression in astrocytes during acute infection, measured by radioimmunoassay. The K b molecule was preferentially expressed over D b. By
6、contrast, JHMV and several viral strains derived from it did not stimulate the expression of class I molecules. Assays of virus infectivity indicated that the class I-inducing activity did not correlate with the ability of the individual viral strain to replicate in astrocytes. However, exposure of
7、the viruses or the supernatants from infected astrocytes to ultraviolet light abolished the class I-inducing activity, indicating that infectious virus is required for class I expression. These data also suggest that class I expression was induced directly by virus infection, and not by the secretio
8、n of a soluble substance into the medium by infected astrocytes. Finally, analyses of A59/JHMV recombinant viral strains suggest that class I-inducing activity resides in one of the A59 structural genes. M ouse hepatitis viruses (MHV) 1 are members of the Coronaviridae, which cause gastrointestinal,
9、 neurolog- ical, and respiratory diseases in a wide variety of mammalian species (1-7). Although some MHV strains, such as A59 and MHV-3, can cause both gastrointestinal and neurological dis- ease in mice and rats, many tend to induce pathology that is restricted to either system, prompting their cl
10、assification as hepatotropic or neurotropic. There has been considerable interest in the study of the more neurotropic strains of MHV, such as JHMV and A59, because of their ability to produce demyelinating lesions that resemble the demyelinating plaques observed in the human neurological disease, m
11、ultiple scle- rosis (MS). In addition, MHV and human coronavirus iso- 1 Abbreviations used in thispaper: CNS, central nervous system; GFAP, glial fibrillary acidic protein; i.c., intracerebral; M, membrane; MHV, mouse hepatitis virus; m.o.i., multiplicity of infection; MS, multiple sclerosis; N, nuc
12、leocapsid; p.i., post infection; S, spike; VSV, vesicular stomatitis virus. 1013 lates are capable of inducing demyelination in primates (8), and coronavirus RNA and antigen have been detected in demyelinating lesions in the brains of MS patients (9, 10). As Coronaviridae, all MHV strains are envelo
13、ped viruses that contain a single-stranded, positive-sense ILNA genome of 31-kb that is expressed as 7 or 8 mRNAs encoding both structural and nonstructural proteins (11). The structural pro- teins have been well characterized, and include the nucleo- capsid (N) protein, which interacts with the vir
14、al RNA, and two envelope glycoproteins, the spike (S) and membrane (M) proteins. The S protein forms the virion surface spikes and is responsible for binding the cellular MHV receptor, inducing cell-to-cell fusion and providing a target for neutralizing an- tibodies. It is the least conserved of the
15、 structural proteins among the MHV strains (12-16). M interacts with the N protein-R.NA comply, and may be involved in virus assembly. It is the most conserved structural protein among the MHV. A third envelope glycoprotein, hemagglutinin-esterase (HE), has been identified in MHV-S and several JHMV
16、isolates, J. Exp. Med. ?9 The Rockefeller University Press ?9 0022-1007/94/09/1013/11 $2.00 Volume 180 September 1994 1013-1023 on March 7, 2015jem.rupress.orgDownloaded from Published September 1, 1994 and may participate in the pathogenesis of JHMV infection in the central nervous system (CNS) (11, 17). Nonstructural proteins include an RNA-dependent RNA polymerase, and three additional proteins that do not appear to be required for viral replication, but whose functions and biologi