Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system

Gombold, James L.; Weiss, Susan R.

doi:10.1016/0882-4010(92)90015-g

Cited by 27 publications

(21 citation statements)

References 32 publications

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“…It has been shown that during an MHV-induced chronic demyelination in the CNS of mice, several inflammatory molecules, such as interleukin 1␤ (IL-1␤), tumor necrosis factor, IL-6, type 2 nitric oxide synthase (53), cytokine response gene 2, RANTES, and macrophage-inflammatory protein 1␤, or their mRNAs are detected (33). Upregulation of MHC class I mRNA and antigen expression has been observed in MHV-infected animals (25,36). The fact that HCoV-OC43 and MHV belong to the same antigenic group (32) is consistent with the possibility that this human virus could act similarly to its murine counterpart in the CNS of its host.…”

Section: Vol 74 2000supporting

confidence: 65%

Neuroinvasion by Human Respiratory Coronaviruses

Arbour

Day

Newcombe

et al. 2000

J Virol

472

482

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Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by patches of demyelination and infiltration of inflammatory cells (21). The etiology of this disabling diseasehas not yet been determined, but both genetic factors, such as genes encoding human leukocyte antigens, T-cell receptors, and myelin basic protein (MBP) (18,19,26), and environmental factors such as viruses have been implicated (31). At least four human demyelinating diseases have a known viral etiology: subacute sclerosing panencephalitis as a late complication of measles virus infection of childhood (35), progressive multifocal leukoencephalopathy caused by the JC papovavirus (57), encephalopathy and myelopathy (neuro-AIDS) caused by human immunodeficiency virus (43), and human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (28). Over the last decades, several viruses have been associated with MS, based on detection of virions, viral nucleic acids, or viral proteins in CNS or the presence of antiviral antibodies in serum and/or cerebrospinal fluid. A confirmed association with MS is awaited but may involve more than one virus.Several studies have associated human coronaviruses (HCoV) with MS. Coronavirus-like particles were detected in autopsied brain tissue from an MS patient (56). Two coronaviruses that are molecularly related to murine neurotropic coronaviruses were isolated from brain material obtained at autopsy from two MS patients (9). Intrathecal anti-HCoV antibody synthesis indicative of a CNS infection was reported in MS patients (45). HCoV RNA was detected in MS patient brains (37, 51) and in cerebrospinal fluid of MS and other neurological disease (OND) patients (15). Coronavirus antigens were also detected in MS patient brains (37). Moreover, we have shown that HCoV can infect human astrocytes and microglia in primary cultures (8) and can acutely and persistently infect immortalized human glial cells (4, 5). Thus, accumulating evidence suggests that these viruses, first isolated as pathogens of the respiratory tract and now associated with up to one-third of human common colds (39), might be neurotropic, neuroinvasive, and neurovirulent in humans, as is the case for their murine counterpart, the coronavirus mouse hepatitis virus (MHV). Interestingly, upper respiratory infections of viral origin were shown to be an important trigger of MS attacks (2,40,48). Moreover, coronavirus seasonal patterns fit the observed occurrence of MS exacerbations (48).MHV-induced demyelinating disease involving coronaviruses is used as an animal model for elucidating the complex pathogenesis of MS. As for MS, MHV pathogenesis is multifactorial (27). Its outcome is influenced by genetics of the host and virus, dose and route of inoculation, and host age and immunological status at the time of infection (58). Neurotropic MHV strains could invade the CNS following an intranasal inoculation in mice (34) and could also gain access to the CNS via the hematogenous and/or lymphatic systems in mice (7) and i...

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Section: Vol 74 2000supporting

confidence: 65%

Neuroinvasion by Human Respiratory Coronaviruses

Arbour

Day

Newcombe

et al. 2000

J Virol

472

482

View full text Add to dashboard Cite

show abstract

“…Mouse hepatitis virus (MHV) is a neurotropic murine coronavirus that has been used in numerous studies of viral neurovirulence and the mechanism of virus-mediated demyelination in the central nervous system (Fleming et al, 1993;Gilmore et al, 1994;Gombold et al, 1995;Gombold and Weiss, 1992;Hingley et al, 1994;Houtman and Fleming, 1996;Lavi et al, 1984Lavi et al, , 1988Wang et al, 1990;Watanabe et al, 1983;Weiner, 1973). Like all coronaviruses, MHV strain A59 possesses a large (31 kb) single-stranded, positive-sense RNA genome (Lee et al, 1991;Pachuk et al, 1989) that is associated with the viral nucleocapsid protein (Sturman et al, 1980) inside a host cell-derived membrane.…”

Section: Introductionmentioning

confidence: 99%

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

2000

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The spike glycoprotein of mouse hepatitis virus strain A59 mediates the early events leading to infection of cells, including fusion of the viral and cellular membranes. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail. In this study, we examined the role of these carboxyl-terminal domains in spike-mediated membrane fusion. We show that the cytoplasmic tail is not required for fusion but has the capacity to enhance membrane fusion activity. Chimeric spike protein mutants containing substitutions of the entire transmembrane anchor and cys domain with the herpes simplex virus type 1 glycoprotein D (gD-1) anchor demonstrated that fusion activity requires the presence of the A59 membrane-spanning domain and the portion of the cys domain that lies upstream of the cytoplasmic tail. The cys domain is a required element since its deletion from the wild-type spike protein abrogates fusion activity. However, addition of the cys domain to fusion-defective chimeric proteins was unable to restore fusion activity. Thus, the cys domain is necessary but is not sufficient to complement the gD-1 anchor and allow for membrane fusion. Site-specific mutations of conserved cysteine residues in the cys domain markedly reduce membrane fusion, which further supports the conclusion that this region is crucial for spike function. The results indicate that the carboxyl-terminus of the spike transmembrane anchor contains at least two distinct domains, both of which are necessary for full membrane fusion.

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“…MHV infection of the CNS induces enhanced expression of MHC class I antigens on brain cells in vitro and in vivo [15][16][17][18][19]. However, the significance of MHC induction in mHV infection is still not clear.…”

Section: Introductionmentioning

confidence: 99%

Cellular Reservoirs for Coronavirus Infection of the Brain in β<sub>2</sub>-Microglobulin Knockout Mice

Lavi¹,

Sarma²,

Weiss

1999

Pathobiology

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Mouse hepatitis virus (MHV) A59 infection which causes acute encephalitis, hepatitis, and chronic demyelination, is one of the experimental models for multiple sclerosis. Previous studies showed that lethal infection of β₂-microglobulin ‘knockout’ (β₂M(–/–)) mice required 500-fold less virus and viral clearance was delayed as compared to infection of immunocompetent C57Bl/6 (B6) mice. To investigate the mechanism of the increased susceptibility of β₂M(–/–) mice to MHV-A59, we studied organ pathology and the distribution of viral antigen and RNA during acute and chronic infection. A59-infected β₂M(–/–) mice were more susceptible to acute encephalitis and hepatitis, but did not have increased susceptibility to demyelination. Viral antigen and RNA distribution in the brain was increased in microglia, lymphocytes, and small vessel endothelial cells while the distribution in neurons and glia was similar in β₂M(–/–) mice and B6 mice. Acute hepatitis and thymus cortical hypoplasia in β₂M(–/–) mice were delayed in onset but pathologic changes in these organs were similar to those in B6 mice. The low rate of demyelination in β₂M(–/–) mice was consistent with the low dose of the virus given. A less neurotropic virus MHV-2, caused increased parenchymal inflammation in β₂M(–/–) mice, but without demyelination. Thus, CD8+ cells were important for viral clearance from endothelial cells, microglia and inflammatory cells, but not from neuronal and glial cells. In addition, CD8+ cells played a role in preventing the spread of encephalitis.

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Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system

Cited by 27 publications

References 32 publications

Neuroinvasion by Human Respiratory Coronaviruses

Neuroinvasion by Human Respiratory Coronaviruses

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

Cellular Reservoirs for Coronavirus Infection of the Brain in β<sub>2</sub>-Microglobulin Knockout Mice

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