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Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.

ABSTRACT: Mumps virus is highly neurotropic and, prior to widespread vaccination programs, was the major cause of viral meningitis in the United States. Nonetheless, the genetic basis of mumps virus neurotropism and neurovirulence was until recently not understood, largely due to the lack of an animal model. Here, nonneurovirulent (Jeryl Lynn vaccine) and highly neurovirulent (88-1961 wild type) mumps virus strains were passaged in human neural cells or in chicken fibroblast cells with the goal of neuroadapting or neuroattenuating the viruses, respectively. When tested in our rat neurovirulence assay against the respective parental strains, a Jeryl Lynn virus variant with an enhanced propensity for replication (neurotropism) and damage (neurovirulence) in the brain and an 88-1961 wild-type virus variant with decreased neurotropic and neurovirulent properties were recovered. To determine the molecular basis for the observed differences in neurovirulence and neuroattenuation, the complete genomes of the parental strains and their variants were fully sequenced. A comparison at the nucleotide level associated three amino acid changes with enhanced neurovirulence of the neuroadapted vaccine strain: one each in the nucleoprotein, matrix protein, and polymerase and three amino acid changes with reduced neurovirulence of the neuroattenuated wild-type strain: one each in the fusion protein, hemagglutinin-neuraminidase protein, and polymerase. The potential role of these amino acid changes in neurotropism, neurovirulence, and neuroattenuation is discussed.

SUBMITTER: Rubin SA

PROVIDER: S-EPMC229304 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

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Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.

Rubin Steven A SA Amexis Georgios G Pletnikov Mikhail M Li Zongqi Z Vanderzanden Jacqueline J Mauldin Jeremy J Sauder Christian C Malik Tahir T Chumakov Konstantin K Carbone Kathryn M KM

Journal of virology 20031101 21

Mumps virus is highly neurotropic and, prior to widespread vaccination programs, was the major cause of viral meningitis in the United States. Nonetheless, the genetic basis of mumps virus neurotropism and neurovirulence was until recently not understood, largely due to the lack of an animal model. Here, nonneurovirulent (Jeryl Lynn vaccine) and highly neurovirulent (88-1961 wild type) mumps virus strains were passaged in human neural cells or in chicken fibroblast cells with the goal of neuroad ...[more]

PMID: 14557647

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Project description:Venezuelan equine encephalitis virus (VEEV) is an alphavirus in the family Togaviridae. VEEV causes a bi-phasic illness in mice where primary replication in lymphoid organs is followed by entry into the central nervous system (CNS). The CNS phase of infection is marked by encephalitis and large scale neuronal death ultimately resulting in death. Molecular determinants of VEEV neurovirulence are not well understood. In this study, host gene expression response to highly neurovirulent VEEV (V3000 strain) infection was compared with that of a partially neurovirulent VEEV (V3034 strain) to identify host factors associated with VEEV neurovirulence.Whole genome microarrays were performed to identify the significantly modulated genes. Microarray observations were classified into three categories i.e., genes that were similarly modulated against both V3000 and V3034 infections, and genes that were uniquely modulated in infection with V3034 or V3000. Histologic sections of spleen and brain were evaluated by hematoxylin and eosin stains from all the mice.V3000 infection induced a greater degree of pathology in both the spleen and brain tissue of infected mice compared to V3034 infection. Genes commonly modulated in the spleens after V3000 or V3034 infection were associated with innate immune responses, inflammation and antigen presentation, however, V3000 induced a gene response profile that suggests a stronger inflammatory and apoptotic response compared to V3034. In the brain, both the strains of VEEV induced an innate immune response reflected by an upregulation of the genes involved in antigen presentation, interferon response, and inflammation. Similar to the spleen, V3000 was found to induce a stronger inflammatory response than V3034 in terms of induction of pro-inflammatory genes and associated pathways. Ccl2, Ccl5, Ccl6, and Ly6 were uniquely upregulated in V3000 infected mouse brains and correlated with the extensive inflammation observed in the brain.The common gene profile identified from V3000 and V3034 exposure can help in understanding a generalized host response to VEEV infection. Inflammatory genes that were uniquely identified in mouse brains with V3000 infection will help in better understanding the lethal neurovirulence of VEEV. Future studies are needed to explore the roles played by the genes identified in VEEV induced encephalitis.

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Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.

Publications

Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.

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