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REVIEWS M i if ti ur ne coronavlrus n ec on a paradigm for virus induced demyelinating disease Thomas E Lane and Michael J Buchmeier C urrent hypotheses to ex plain the etiology and pathogenesis of demyel inating diseases in humans in clude the idea that an infectious agent encountered early in life may prime or trigger a disease process that manifests later in life as white matter demyelin ationL Although epidemiologi cal evidence points to an infec tious etiology a single agent has never been linked convinc ingly with human diseases such as multiple sclerosis MS a chronic central nervous system A variety of neurological diseases in humans including multiple sderosis MS have been postulated to have a viral etiology The use of animal models provides insights into potential mechanism s involved in the disease process The murine coronavirus induced demyelinating disease in rodents is one such model for demyelinating disease in humans T E Lane and M J Buchmeier are in the Dept of Neuropharmacology The Scripps Research Institute 0666 N Torrey Pines Rd La Jolla CA 92037 USA tel 1 619 784 7056 fax 1 619 784 7369 e mail buchm scripps edu CNS disease that is characterized by multifocal in flammatory loci and myelin destruction2 L Animal models of virus induced demyelination have provided useful paradigms to study the demyelinating process Coronaviruses constitute a large group of positive stranded RNA viruses that are associated with a wide variety of respiratory gastrointestinal and neurologi cal diseases in animals and humans 4 s Although the majority of coronavirus infections of humans are asso ciated with upper respiratory tract infections several laboratories have attempted to correlate inflammatory neurological disease with coronaviral infection and re cent reports have demonstrated the presence of corona virus RNA and antigens in demyelinating plaque le sions in the brains of MS patients 6 7 Furthermore increased levels of antibodies against coronavirus have been detected in MS patients as compared with con trol patients s and a murine coronavirus mouse hepa titis virus MHV which had previously been thought only to infect mice has recently been shown to replicate and cause demyelination in the CNS of nonhuman primates 9 At this time however there is no conclu sive evidence that any human neurological disease let alone MS occurs as a result of human coronavirus in fection Certainly other viruses including herpes sim plex virus type 1 HSV 1 1 measles 11 and human T cell leukemia virus type i HTLV 1 12 have been suggested to be associated etiologically with MS Ref 13 How ever the accumulated data suggest that the human coronaviruses are capable of infecting both the human and nonhuman primate CNS Given the existing ex perimental evidence for murine coronavirus involve ment in virus induced CNS disease in rodents the possibility that the human coro naviruses are capable of causing a similar encephalomyelitis in humans remains open Clearly the results indicate that the host range and potential to cause dis ease by coronaviruses are more complex than appreciated pre viously and reinforce the need for a better understanding of the biology of human and mouse coronaviruses 9 The murine coronaviruses are capable of causing a vari ety of diseases in mice such as hepatitis and gastroenteritis 4 Infection of rodents with neuroadapted strains of MHV results in acute encephalitis and white matter demyelination 4 5 There are several similarities be tween MHV induced demyelination and MS which make this a good laboratory model for studying the underlying mechanisms of the MS disease process Table 1 14 161 1 genetic susceptibility appears to play a prominent role in the development of MS in humans while the genetic background of rodents which de termines susceptibility and immune response is of cru cial importance in MHV induced demyelination3 14 17 2 MS patients often experience cyclic periods of ex acerbation followed by remission 3 18 and MHV infected Table 1 Comparison of pathological events in multiple sclerosis MS and coronavirus demyelination Multiple sclerosis Coronavirus Infectious agent suggested by Viral trigger epidemiology Genetic susceptibility Multifocal white matter lesions Exacerbation of disease symptoms Myelin stripping NOS 2 expression IFN 7 IL 1 TNF o Genetic susceptibility Multifocal white matter lesions Subacute acute and chronic stages Myelin stripping NOS 2 expression IFN 7 IL 1 TNF c Abbreviations IL 1 interleukin 1 IFN 7 interferon 7 NOS 2 nitric oxide synthase TNF c tumor necrosis factor Copyright 1997 Elsevier Science Ltd All rights reserved 0966 842X 97f 17 00 PlI S0966 842X 96 10075 5 TRENDS IN MI R I 1 L Y 9 vo 5 No 1 JANU RY 1997 REVIEWS q Fig 1 Light micrograph showing a coronal section of spinal cord of mouse infected 32 days earlier with a demyelinating variant of mouse hepatitis virus MHV Two large foci of white matter demyelin ation are evident in the ventral funiculi and adjacent to the ventral median fissure The section is stained with luxol fast blue Scale bar lO0 m rodents go through progressive stages of subacute acute and chronic disease accompanied by demyelination and remyelination s ls s and 3 in terms of neuropathology MS patients and MHV infected mice display multi focal white matter lesions accompanied by myelin strip ping3 5 15 18 2 in both cases immune mechanisms are thought to participate in the disease The cytokines TNF x tumor necrosis factor 00 IFNq interferon 7 and IL 1 interleukin 1 as well as the enzyme inducible nitric oxide synthase NOS 2 which is responsible for high level output of the free radical nitric oxide NO have all been found to be localized to white matter plaques in humans with MS and MHV infected mice experiencing demyelinating disease2 2 It should be emphasized that in addition to the mu rine coronavirus model of demyelination there are a number of other excellent animal models for MS such as the Theiler s murine encephalomyelitis virus TMEV system and the experimental allergic encephalomyelitis EAE model in mice and rats 27 This brief review will concentrate on the MHV rodent system and its use as a model for human demyelinating disease Background MHV is an enveloped virus containing a 32 kb single stranded RNA genome that replicates exclusively in the cytoplasm of infected cells 2s Virus replication occurs via a viral RNA dependent RNA polymerase translated from open reading frame one of the genomic RNA The three predominant structural proteins identified in MHV are the nucleocapsid protein N 60 kDa which is as sociated with the RNA genome the membrane pro tein M 25 kDa and the spike pro tein S 180 kDa 8 2s The S protein assembles into a trimeric peplomer which exhibits a characteristic mor phology described as a lollipop like spike extending 20 nm from the surface of the virion 4 In ad dition a hemaglutinin esterase pro tein HE 65 kDa is expressed by some strains of MHV Refs 4 28 The S protein is an important determinant of MHV biology and pathogenesis 4 5 14 16 2 29 Functions associated with the S protein in clude binding to host cell recep tors induction of fusion of viral envelope with cell membrane dur ing entry and induction of cell fusion syncytium formation 28 Williams et al 3 have shown that the S protein recognizes a cellular receptor MHV R which is a mouse biliary glycoprotein BGP A and a member of the murine carcinoembryonic antigen CEA family of glycoproteins The MHV R is found predominantly in the brush border of the small intestine and liver and is nearly un detectable in the brain Recently Chen et al have reported a pregnancy specific glycoprotein member of the CEA family which is expressed in the brains of C57B1 6 mice and serves as a receptor for various strains of MHV As with many viruses the outcome of infection with MHV depends upon a variety of different factors such as host and viral genetics and the dose and route of inoculation For example intranasal i n and intra cranial i c infection of susceptible strains of mice such as BALB c and C57B1 6 with wild type MHV MHV JHM results in a rapid and fatal encephalo myelitis that is accompanied by gray matter involve ment with infection of neurons oligodendrocytes and astrocytes and extensive damage to large areas of the olfactory and limbic system 14 15 The small percentage of mice that survive the initial bout of acute encepha lomyelitis may develop a chronic demyelinating dis ease that is characterized by extensive white matter involvement and episodes of demyelination Fig 1 14 15 The mice may also develop a hindlimb paralysis with some animals even developing tetraplegia In contrast infection of SJL J mice with MHV JHM does not re sult in either an acute encephalitis or demyelination The difference in genetic susceptibility between BALB c and SJL J to MHV JHM is based on polymorphism in the BGP gene and is reflected in the sensitivity of neurons and macrophages to the virus 32 33 A number of different attentuated strains of MHV have been developed from the wild type virus MHV JHM through the use of either monoclonal antibodies raised against the S protein 29 34 temperature sensitive mutants 3s or long term passage in cell culture 36 Mice TRt l s IN M C ROmOIO 10 Vol 5 No I JANt ARY 1997 REVIEWS infected with these neuroattenuated strains generally do not develop fatal encephalitis but may develop neuro logical disease that is characterized by mononuclear infiltration into the brain and spinal cord as well as chronic demyelination 14 16 37 Neuroattentuated strains of MHV tend to spread very slowly through the CNS with little neuronal infection and the majority of in fected cells being gila It has been postulated that the slow rate of spread of certain neuroattenuated strains of MHV allows the intervention of the host immune response and thus the elimination of the bulk of in fecting virus 37 Immune response and demyelination The immune response to MHV infection of the CNS plays a critical role in contributing to the pathogenesis of demyelination Infection of Lewis rats with MHV JHM results in the development of acute encephalo myelitis and chronic demyelinating disease At the onset of clinical symptoms for example hindlimb paralysis lymphocytes both CD4 and CD8 T cells enter the brain However when the animals conva lesce the number of infiltrating T cells drops to the levels seen before the occurrence of symptoms suggesting that the T cells are participating in the disease process3L Gamma irradiation of MHV infected mice results in higher titers of virus compared with non irradiated control mice but irradiated animals do not develop demyelination Adoptive transfer of MHV immune splenocytes restores demyelination to the infected irradiated mice 39 Thy 1 cells appear to be essential for the restoration of demyelination indicating a role for T cells in the disease process These data suggest that MHV induced demyelination is immunologically mediated A recent study by Houtman and Fleming 4 has used several strains of congenitally immunodeficient mice to discriminate between the role of the immune response in the clearance of infectious virus and in the develop ment of demyelinating disease Intracranial inoculation of a neuroattenuated MHV variant into immunocom petent C57B1 6 mice results in clearance of infectious virus and robust demyelination By contrast virus infected severe combined immunodeficient SCID mice did not clear the virus and did not develop demyelin ation before dying 12 days postinfection Demyelination with incomplete clearance of infectious virus was also observed in MHV JHM infected nude mice Adoptive transfer of immune splenocytes from C57B1 6 mice but not from nude mice to SCID mice results in clear ance of infectious virus and demyelination These studies substantiate an immunological basis for demyelination in MHV infected mice and further more suggest that elements of the immune system that are required for demyelination are distinct from those required for clearance of infectious virus The fact that nude mice were unable to clear virus yet developed de myelinating disease suggests that conventionally edu cated T cells are not an essential component for de myelination The authors suggest that the 78 subset of T cells natural killer cells as well as cytokines may participate in the demyelinating process 4 It is also important to consider the major histocom patibility complex MHC class I and II antigens in de myelination following infection by MHV of resident cells of the CNS Previous studies involving MHV in duction of MHC antigens on glial cells have been con troversial Infection of primary astrocytes results in an increase in class I expression although this appears to be dependent upon both the MHV strain and the gen etic background of the rodent414L Recent work by Gilmore et al 42 demonstrates that persistent infection of astrocytes by MHV results in an inhibition of class I expression Sun etal 2s report no expression of class I or II antigen by astrocytes in chronically infected mice ex periencing demyelinating disease Rather inflamma tory macrophage and microglia appear to be the pre dominant cell type expressing these antigens 2s The role of MHC class I in demyelination remains complex in light of recent reports indicating that demyelination can occur in MHV infected mice that lack either stable expression of the MHC class I molecule 4 or functional CD8 T cells 44 Expression of MHC class II has been shown to be important in dictating the susceptibility of demyelin ating disease to other animal models such as TMEV Ref 45 and EAE Ref 46 Furthermore infection of astrocytes from MHV susceptible Lewis rats with MHV JHM results in induction of MHC class II on the surface of the cell whereas no similar increase was observed in astrocytes from disease resistant Brown Norway rats 47 48 However mice deficient in class II expression express robust demyelination following in fection with MHV JHM Ref 40 Therefore it may be possible that other genes in addition to or distinct from MHC class I and II may control the outcome of demyelination The question of whether MHV infection generates autoimmune T cells which contribute to Y 11 vo 5 N I l JANUAP Y 1997 REVIEWS Box 1 Potential mechanisms of demyelination induced by mouse hepatitis virus MHV Virus persistence Disrupts oligodendrocyte function In astrocytes results in chronic NOS 2 nitric oxide synthase TN F c tumor necrosis factor x and IL 6 interleukin 6 expression and glial toxicity Persistent viral antigens expressed in glial cells target chronic immune response to white matter Molecular mimicry Virus infection primes immune response to crossreact with myelin antigens such as myelin basic protein MBP and proteolipid protein PLP Infectious virus can be isolated from mice suffering from demyelinating disease if the animals are infected at the suckling stage and nursed by immunized dams 5s s6 An elegant study by Pewe et al 7 demonstrates that virus persisting in the brain and spinal cords of mice suffering from chronic but not acute demyelinating disease undergoes changes within the hypervariable region of the S gene which has previously been defined as a CD8 T cell epitope These data suggest that these viral variants escape from cytotoxic T lymphocyte CTL recognition which then allows for enhanced viral replication within the CNS and the development of clinical disease 57 Adami et al s2 investigated coronaviral persistence by examining viral sequences from the brains of mice from 0 42 days postinfection with a neuroattenuated variant of MHV Although infectious virus was not de tected in the brain beyond 13 days postinfection viral RNA was easily detected by reverse transcription polymerase chain reaction RT PCR amplification Se quence analysis of the cloned PCR products revealed that multiple point and deletion mutations had oc curred many of which were concentrated in both the S and N sequences Greater than 65 of the nucleotide changes observed resulted in amino acid changes sug gesting that a strong selective pressure exists within the CNS Many of the mutations and deletions reported in the S sequence were concentrated in the hypervariable domain originally described by Parker et al s3 and con tinued by Banner and Lai 54 These findings suggest that a diverse population of RNA quasi species many of which are likely to be defective persist within the CNS The consequences of this type of infection may con tribute to the pathogenesis of chronic demyelination by perturbing normal cellular function or if the RNAs are translationally active by chronically stimulating the immune system s3 Table 2 Host factors that may contribute to virus induced demyelination Host factor Pathology TNF z IFN 7 IL 3 IL 4 IL 6 NOS 2 Recruitment of inflammatory cells to CNS Direct toxicity to oligodendrocytes Induction of neuronal apoptosis T cell activation Induction of the major histocompatibility complex MHC and the receptor for the Fc domain of immunoglobulin Macrophage microglial activation T cell proliferation T cell proliferation Enhancement of antibody response Direct toxicity to oligodendrocytes Nitric oxide production Toxicity to oligodendrocytes Abbreviations CNS central nervous system IL 3 interleukin 3 IL 4 interleukin 4 IL 6 interleukin 6 IFN y interferon 7 TNF x tumor necrosis factor x NOS 2 nitric oxide synthase Mechanism s of chronic demyelinating disease A variety of different mechanisms have been postu lated to contribute to MHV induced disease Box 1 As discussed above the pathological basis for disease depends on a variety of factors including the system being studied i e mouse versus rat the age and gen etic background of the rodent and the dose and strain of virus being used Direct lysis of oligodendrocytes the cells responsible for myelin production and mainte nance in the brain by MHV during the acute phase of infection has been suggested to be responsible for acute demyelinating lesions in the CNS Refs 19 20 35 The mechanism s responsible for demyelination in chronically infected animals is less understood Al though MHV infects glia such as astrocytes and oligo dendrocytes readily in vitro and in vivo recent work by Perlman and Reis s8 has shown that astrocytes are the cells that harbor the virus within the brains and spinal cords of infected animals suffering from chronic disease Moreover histological evidence suggests that MHV infected astrocytes are activated as measured by increased staining for glial fibrillary acidic protein GFAP 2s These observations are interesting because astrocytes are closely associated with oligodendrocytes and are required by the oligodendrocyte for normal cellular function Therefore any perturbation of astrocyte function and or production of toxic factors for example cytokines and NO may have dramatic effects on the surround ing microenvironment and may contribute potentially to demyelination 25 Table 2 Sun et al 25 have measured increased stain ing for the cytokines TNF ot IL 1 3 and IL 6 as well as NOS 2 in the spinal cords of mice chronically infected with MHV and con taining demyelinating lesions Although as sociated with areas of viral infection and demyelination the activated astrocytes were generally not infected with virus Both NO and TNF ot have been shown to be toxic to oligodendrocytes s9 61 In the murine EAE model inhibition of NOS 2 activity amelio rates demyelination suggesting a contribu tory role for NO in the demyelinating pro cess 62 Furthermore recent work by Boullerne et al 63 suggests that NO may be involved in MS demyelination Sun et al 25 speculate that production of these factors may contribute TRENL S IN MI R BIOt C Y 12 v 5 No 1 JANUARY 1997 REVIEWS to the demyelinating process However there is some controversy as to the role TNF has in the disease pro cess Stohlman et al 64 have reported that administration of antibodies against TNF ct does not ameliorate either MHV induc