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Further observations on subacute sclerosing encephalitis in adult hamsters: the effects of intranasal infections with Langat virus, measles virus and SSPE-measles virus.

Passage by i.c. inoculations of suckling hamsters enhanced the virulence for adult hamsters of Langat virus (TP21), neurotropic strain of measles virus (HNT) and SSPE-measles virus (HBS), not only for i.c. infections but also for intranasal instillations. The various viral strains passaged in hamsters showed a great similarity of behaviour including the ability of producing in a proportion of apparently unaffected survivors a subacute sclerosing encephalitis, leading to atrophy of parts of the brain especially the rhinencephalon. When large groups of animals were used for transmission experiments it became obvious that within one week after intranasal exposure, all the hamsters either died or became clinically affected, or did not show signs of disease but developed acute inflammatory brain lessions. tlater on, between 2-6 weeks following inoculations only 90% of hamsters were affected with either overt signs of disease or subacute brain lesions, suggesting that in about 10% of hamsters the initial infection did not progress further and that in these animals the early brain lesions disappeared. Passage levels, irrespective of the virus used, did not influence the total numbers of infected hamsters but showed a significant effect on the mortality in TP21 and HNT infections where the number of dead and clinically affected increased in the higher passes. In these higher passes the number of survivors with subacute brain lesions decreased. In SSPE-measles virus the number of clinically affected hamsters and those surviving but developing brain lesions remained constant throughout. Vacuolated neurons were present in the brains of hamsters that survived one of the above 3 viral infections. They were seen beginning from 6 weeks after infection only in animals that developed subacute sclerosing lesions and were most commonly found in the amygdaloid nuclei and in the pyriform cortex. There was a dramatic increase in the number of brains with vacuolated neurons in hamsters infected with the high viral passes; however, in the 36th hamster passage of TP21 no vacuolated neurons were present but the total number of survivors was small, the majority had no brain lesions and none had subacute sclerosing changes.

Age Factors↗

SLAM (CDw150) is a cellular receptor for measles virus.

Measles virus continues to be a major killer of children, claiming roughly one million lives a year. Measles virus infection causes profound immunosuppression, which makes measles patients susceptible to secondary infections accounting for high morbidity and mortality. The Edmonston strain of measles virus, and vaccine strains derived from it, use as a cellular receptor human CD46 (refs 3, 4), which is expressed on all nucleated cells; however, most clinical isolates of measles virus cannot use CD46 as a receptor. Here we show that human SLAM (signalling lymphocyte-activation molecule; also known as CDw150), a recently discovered membrane glycoprotein expressed on some T and B cells, is a cellular receptor for measles virus, including the Edmonston strain. Transfection with a human SLAM complementary DNA enables non-susceptible cell lines to bind measles virus, support measles virus replication and develop cytopathic effects. The distribution of SLAM on various cell lines is consistent with their susceptibility to clinical isolates of measles virus. The identification of SLAM as a receptor for measles virus opens the way to a better understanding of the pathogenesis of measles virus infection, especially the immunosuppression induced by measles virus.

Animals↗

Virology of measles virus.

Measles virus is the prototypic member of the Morbillivirus genus of the family Paramyxoviridae. The viral genomic RNA is single-stranded, nonsegmented, and of negative polarity and encodes six major structural proteins. The two viral transmembrane glycoproteins, the hemagglutinin and fusion proteins, are both required for virus-host cell membrane fusion, while attachment to host cells is mediated by the hemagglutinin. The human CD46 molecule has been identified as a cellular receptor for measles virus. Antibodies raised against either viral glycoprotein neutralize measles virus in vitro and protect against infection. Although measles virus remains a single serotype (monotypic), nucleotide sequence analyses have identified distinct lineages among recent wild type isolates. These genetic changes were manifested by detectable antigenic variation between vaccine and wild type viruses and at some point may influence strategies for control, elimination, and eventual eradication of measles virus.

Animals↗

Effect of undiluted passage on the polypeptides of measles virus.

Measles virus induces a large polypeptide (L; mol. wt. 180 K), a large glycopolypeptide (H; mol. wt. 80 K), a nucleocapsid associated polypeptide (P; mol. wt. 70 K), a nucleocapsid polypeptide (N; mol. wt. 60 K), a second glycopolypeptide (F0; mol. wt. 60 K), a matrix or membrane polypeptide (M; mol. wt. 37 K) and a small polypeptide (S; mol. wt. 15 K). The second glycopolypeptide (F0) appears to be cleaved in purified measles virus. Defective interfering particles accumulate during passage of measles virus leading to a decrease in the amounts of virus-specific protein synthesized in infected cells. Even in the best preparations of purified measles virus, host proteins are always detected and these become more predominant in preparations with low infectivity.

Carcinoma, Squamous Cell↗

Stimulation of prostaglandin E production by rat synovium induced by intraarticular injection of measles virus.

Measles virus was injected into the joints of rats. Prostaglandin E in organ cultures of synovial tissue removed from injected joints was evaluated. A 9-fold increase of prostaglandin E concentration was found in cultures of synovial membranes from joints injected with measles virus as compared to controls. Histologic examination revealed inflammation in the synovial membranes of joints injected with virus. We suggest that prostaglandin E may mediate joint inflammation induced by measles virus.

Animals↗

CD46, a primate-specific receptor for measles virus.

Measles virus normally infects only primate cells. The receptor for measles virus has recently been shown to be the complement regulator CD46, also known as membrane cofactor protein. Transfection of rodent cells with human CD46 renders them susceptible to the virus, suggesting that transgenic animals may prove useful for testing antiviral agents and vaccines.

Amino Acid Sequence↗

Modulation of immune functions by measles virus.

Measles virus remains among the most potent global pathogens killing more than 1 million children annually. A profound suppression of general immune functions occurs during and for weeks after the acute disease, which favors secondary infections. In contrast, virus-specific immune responses are efficiently generated, mediate viral control and clearance and confer a long-lasting immunity. Because they sense pathogen-associated molecular patterns, and subsequently initiate and shape adaptive immune responses, professional antigen-presenting cells (APC) such as dendritic cells are likely to play a key role in the induction and quality of the virus-specific immune response. Key features of immune suppression associated with measles virus, however, are compatible with interference with APC maturation and function and subsequent qualitative and quantitative alterations of T cell activation.

Antigen-Presenting Cells↗

A review of measles virus.

Measles virus is an epidemic disease with a worldwide distribution. Since the development of the live attenuated vaccine, the incidence of reported measles cases has declined by greater than 99% in the United States. Measles causes a systemic illness manifested by a characteristic prodrome and pathognomonic rash. Although usually a self-limited disease, measles can cause severe complications, especially in adults and the immunocompromised. We discuss a vaccination schedule for preschool and school-aged children. Recent research has demonstrated clinical benefit in patients with severe measles virus infections that are treated with ribavirin and vitamin A supplementation.

Humans↗

Are human herpes viruses or measles virus associated with esophageal achalasia?

In order to test the hypothesis that esophageal achalasia may be due to neurotropic viral damage to the esophageal myenteric plexus, esophageal tissue with or without achalasia was analyzed by polymerase chain reaction for the presence of human herpes virus DNA or measles virus RNA. The DNA and RNA were extracted from the esophageal muscle of 12 patients with achalasia and six patients with upper esophageal carcinoma. Peripheral blood mononuclear cells from eight adult volunteers and two samples of umbilical blood mononuclear cells were also used as controls. PCR amplification with a pair of primers specific for herpes simplex type 1 and 2 viruses identified 92-bp fragments in nearly all specimens, including those without achalasia. Each 92-bp fragment was confirmed to be identical to a single herpes simplex virus sequence by automated DNA sequence analysis. No amplification for five other herpes viruses or measles virus was detected. Therefore, a specific viral etiology for achalasia was not identified in this study.

Adult↗

Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus.

Human plasmacytoid dendritic cells (PDC) are key sentinels alerting both innate and adaptive immune responses through production of huge amounts of alpha/beta interferon (IFN). IFN induction in PDC is triggered by outside-in signal transduction pathways through Toll-like receptor 7 (TLR7) and TLR9 as well as by recognition of cytosolic virus-specific patterns. TLR7 and TLR9 ligands include single-stranded RNA and CpG-rich DNA, respectively, as well as synthetic derivatives thereof which are being evaluated as therapeutic immune modulators promoting Th1 immune responses. Here, we identify the first viruses able to block IFN production by PDC. Both TLR-dependent and -independent IFN responses are abolished in human PDC infected with clinical isolates of respiratory syncytial virus (RSV), RSV strain A2, and measles virus Schwarz, in contrast to RSV strain Long, which we previously identified as a potent IFN inducer in human PDC (Hornung et al., J. Immunol. 173:5935-5943, 2004). Notably, IFN synthesis of PDC activated by the TLR7 and TLR9 agonists resiquimod (R848) and CpG oligodeoxynucleotide 2216 is switched off by subsequent infection by RSV A2 and measles virus. The capacity of RSV and measles virus of human PDC to shut down IFN production should contribute to the characteristic features of these viruses, such as Th2-biased immune pathology, immune suppression, and superinfection.

Dendritic Cells↗

Cell surface activation of the alternative complement pathway by the fusion protein of measles virus.

Measles virus (MV)-infected cells are activators of the alternative human complement pathway, resulting in high deposition of C3b on the cell surface. Activation was observed independent of whether CD46 was used as a cellular receptor and did not correlate with CD46 down-regulation. The virus itself was an activator of the alternative pathway and was covered by C3b/C3bi, resulting in some loss in infectivity without loss of virus binding to target cells. The cell surface expression of MV fusion (F), but not haemagglutinin, envelope protein resulted in complement activation of the Factor B-dependent alternative pathway in a dose-dependent manner and F-C3b complexes were formed. The underlying activation mechanism was not related to any decrease in cell surface expression of the complement regulators CD46 and CD55. The C3b/C3bi coating of MV-infected cells and virus should ensure enhanced targeting of MV antigens to the immune system, through binding to complement receptors.

Animals↗

Multiple isoforms of CD46 (membrane cofactor protein) serve as receptors for measles virus.

Measles virus (MV) causes a productive infection in humans and certain simian hosts. Rodent cells such as Chinese hamster ovary (CHO) and murine cell lines normally resist MV infection. Human CD46, or membrane cofactor protein, a complement regulatory protein, recently has been reported as the cellular receptor for MV. Multiple isoforms of the CD46 protein exist; four of these isoforms are commonly expressed on human cells. Expression of each of the four isoforms in CHO cells followed by exposure to MV led to the appearance of viral proteins within the cells and on the cell surface as detected by immunofluorescence. Syncytium formation also was observed in the cultures. CHO cells expressing any of the four isoforms and exposed to MV formed infectious centers when plated on Vero cell monolayers, indicating that the cells can transmit virus to uninfected cells. The murine cell line MC57 expressing the BC1 isoform of CD46 also stained positively for MV antigens and was positive in the infectious center assay after exposure to MV. Treatment of CD46-expressing cells with antibody to human CD46 inhibited MV binding in a dose-dependent manner. These observations indicate that any of the four primary isoforms of CD46 are able to serve as a receptor for MV.

Amino Acid Sequence↗

[Cellular tropism and adaptation of the measles virus].

Measles virus (MV) is a member of the genus Morbillivirus in the family Paramyxoviridae. Clinical isolates of MV use signaling lymphocyte activating molecule (SLAM) as a cellular receptor. SLAM is mainly expressed on immune cells such as immature thymocytes, activated lymphocytes and mature dendritic cells. This distribution of SLAM can account for the lymphotropism of MV. On the other hand, laboratory strains of MV use CD46 as an alternative receptor, through amino acid change(s) in the receptor binding hemagglutinin protein. Recently, several reports imply the existence of the cellular receptor(s) other than SLAM and CD46. In this review, we discuss the receptor usage of MV and its adaptation to cultured cells.

Adaptation, Biological↗

The measles virus.

Measles is one of widely spread virus infections that is a major cause of deaths in some tropical areas. The measles virus is a member of the genus of Morbillivirus of the family of Paramyxoviridae. The virions contain six polypeptides, including one glycoprotein; two of them are surface proteins that possess hemagglutinating and hemolytic activities, one of them is polymerase. Replication of the measles virus is similar to that of other Paramyxoviruses. Besides the acute infection for measles virus a persistent infection is characteristic that affects central nervous system and inner organs. Molecular mechanisms of it were studied and the results are discussed to explain the pathogenesis of subacute sclerosing panencephalitis, systemic lupus erythematosus and other diseases in which measles or measles-like virus may be involved.

Animals↗

CD46- and CD150-independent endothelial cell infection with wild-type measles viruses.

Measles virus (MV) infects endothelial cells of the skin, the brain and other organs during acute or persistent infections. Endothelial cells are supposed to play an important role in virus spread from the blood stream to surrounding tissues. CD46 and CD150 (signalling lymphocytic activation molecule, SLAM) have been described as cellular receptors for certain MV strains. We found that human umbilical vein and brain microvascular endothelial cells (HUVECs and HBMECs) were CD46-positive, but did not express SLAM. Wild-type MV strains, which do not use CD46 as a receptor at the surface of transfected Chinese hamster ovary cells, infected HUVECs and HBMECs to varying extents in a strain-dependent way. This infection was not inhibited by antibodies to CD46. These data suggest the presence of an additional unidentified receptor for MV uptake and spread in human endothelial cells.

Antigens, CD↗

Isolation and immunological characterization of the nucleocapsid and membrane proteins of measles virus.

Measles virus nucleoprotein (NP) and matrix (M) components were purified by two different procedures. Antigens were prepared by sedimenting material from 1% Cutscum extracts of infected cells into the interphase between 65 and 40% sucrose and further fractionation of the interphase material in a linear CsCl gradient, density range 1.20 to 1.33 g/ml. NP components contaminated with some M material and cellular actin banded at 1.30 to 1.32 g/ml, but at the low density range of 1.20 to 1.22 g/ml pure M component was demonstrable. Partially denatured antigens were obtained by elution of the 60K NP and 36K M polypeptides after SDS-polyacrylamide slab gel electrophoresis. Rabbit hyperimmune sera were prepared against both purified antigens and isolated polypeptides. All sera reacted only with homologous antigen except the antiserum against NP components isolated from CsCl gradients, which also contained antibodies to the M component. Antibodies against NP antigen stained both intranuclear inclusions and cytoplasmic material in immune fluorescence tests. In contrast, antisera against M antigen only stained the cytoplasm. Since intranuclear nucleocapsids are smooth, whereas intracytoplasmic nucleocapsids are 'fuzzy', this may infer that the fuzziness, at least in part, is caused by M antigen adhering to nucleocapsid components.

Capsid↗

Inhibitors of measles virus.

Measles virus (MV) infections have been almost eradicated in some industrialized nations. However, MV continues to cause severe disease and mortality in the world and is responsible for clusters of exogenous-borne disease in essentially disease-free countries. Because of the ebb and flow of immunization campaigns, especially in the poverty-stricken and war-torn Third World, and the ominous potential for severe disease and mortality, it is vital that research for discovery of therapeutic countermeasures should continue. To that end, a number of compounds have been evaluated for efficacy in vitro and in animal models, and several therapeutic modalities have been tested in the clinic. The only current therapies used in the clinic include ribavirin administered orally or intravenously, alone or in combination with immune serum globulin; these therapies have demonstrated variable efficacy. Therefore, drug discovery efforts have been launched to supplement the existing treatments for MV infections. Antisense molecules, adenosine and guanosine nucleosides, including ring-expanded 'fat' nucleoside analogues, brassinosteroids, coumarins, peptide inhibitors, modulators of cholesterol synthesis and a variety of natural products have been screened for efficacy and toxicity both in vitro and in animals. However, none of these agents has gone into human clinical trials and most will not merit further development due to toxicity concerns and/or low potency. Thus, further research is needed to develop more potent and less toxic drugs that could be used for treating MV infections to supplement the existing MV vaccine campaigns.

Animals↗