Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibodies to the envelope proteins (E) of the 17D vaccine strain of yellow fever virus (17D YF) and to dengue 2 virus were examined for their ability to confer passive protection against lethal 17D YF encephalitis in mice. All 13 IgG anti-17D YF antibodies, regardless of neutralizing capacity, conferred solid protection when given in a relatively high dose prior to intracerebral inoculation of virus. Three antibodies with high in vitro neutralizing titres were all protective at a low dose as were several non-neutralizing antibodies. One flavivirus group-reactive antibody to dengue 2 virus conferred similar protection at low dose. Protection was also observed when antibodies were given several days after virus inoculation when peak infectious virus titres and histopathological evidence of infection were present in brains. The ability of a non-neutralizing antibody to protect could not be attributed to complement-dependent lysis of virus-infected cells and did not correlate with avidity or with proximity of its binding site to a critical neutralizing epitope of the E protein. Some antibodies, characterized as non-neutralizing by plaque reduction assay on Vero cells, inhibited the growth of virus in a mouse neuroblastoma cell line, suggesting one possible mechanism of protection. These results may be relevant to the design of prospective flavivirus vaccines and support the possibility of conferring broadened protection among flaviviruses by stimulating the antibody response to appropriate epitopes of the E protein.
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PMID:Lethal 17D yellow fever encephalitis in mice. I. Passive protection by monoclonal antibodies to the envelope proteins of 17D yellow fever and dengue 2 viruses. 394 85

The protective capacity of antiviral antibodies has generally been considered to depend on their interactions with structural components of the virion. Here we report protection against lethal 17D yellow fever virus (YF) encephalitis of mice by passive administration of nonneutralizing monoclonal antibodies to a 17D YF-specified nonstructural glycoprotein, gp48, and by active immunization with purified gp48. Among five anti-gp48 monoclonal antibodies tested, two with high titer complement-fixing (CF) activity were protective, whereas three antibodies with little or no CF activity were not. The ability of antibodies to protect correlated with their ability to promote complement-mediated cytolysis (CMC) of 51Cr-labeled 17D YF-infected mouse neuroblastoma (Neuro 2a) cells. Purified gp48, prepared from lysates of 17D YF-infected Vero cells by immunoaffinity chromatography, was shown to bear both YF type-specific and flavivirus group-reactive determinants in a solid phase radioimmunoassay. Immunization of mice with purified gp48 resulted in solid protection in the absence of detectable anti-virion antibody, measured by neutralization and radioimmunoprecipitation assays. The results are consistent with plasma membrane expression of gp48 and susceptibility of 17D YF-infected neural cells to CMC, a possible mechanism of host defense in 17D YF encephalitis. Protection provided by immunization with gp48, which bears a group-reactive determinant and is highly conserved among flaviviruses, may have implications in regard to flavivirus vaccine design.
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PMID:Protection against 17D yellow fever encephalitis in mice by passive transfer of monoclonal antibodies to the nonstructural glycoprotein gp48 and by active immunization with gp48. 403 1

Serial passage of yellow fever 17D virus (YF5.2iv, derived from an infectious molecular clone) on mouse neuroblastoma (NB41A3) cells established a persistent noncytopathic infection associated with a variant virus. This virus (NB15a) was dramatically reduced in plaque formation and exhibited impaired replication kinetics on all cell lines examined compared to the parental virus. Nucleotide sequence analysis of NB15a revealed a substitution in domain III of the envelope (E) protein at residue 360, where an aspartic acid residue was replaced by glycine. Single mutations were also found within the NS2A and NS3 proteins. Engineering of YF5.2iv virus to contain the E(360) substitution yielded a virus (G360 mutant) whose plaque size and growth efficiency in cell culture resembled those of NB15a. Compared with YF5.2iv, both NB15a and G360 were markedly restricted for spread through Vero cell monolayers and mildly restricted in C6/36 cells. On NB41A3 cells, spread of the viruses was similar, but all three were generally inefficient compared with spread in other cell lines. Compared to YF5.2iv virus, NB15a was uniformly impaired in its ability to penetrate different cell lines, but a difference in cell surface binding was detected only on NB41A3 cells, where NB15a appeared less efficient. Despite its small plaque size, impaired growth, and decreased penetration efficiency, NB15a did not differ from YF5.2iv in mouse neurovirulence testing, based on mortality rates and average survival times after intracerebral inoculation of young adult mice. The data indicate that persistence of yellow fever virus in NB41A3 cells is associated with a mutation in the receptor binding domain of the E protein that impairs the virus entry process in cell culture. However, the phenotypic changes which occur in the virus as a result of the persistent infection in vitro do not correlate with attenuation during pathogenesis in the mouse central nervous system.
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PMID:Neuroblastoma cell-adapted yellow fever 17D virus: characterization of a viral variant associated with persistent infection and decreased virus spread. 1202 51

The induction of apoptotic cell death is a prominent cytopathic effect of dengue (DEN) viruses. One of the key questions to be addressed is which viral components induce apoptosis in DEN virus-infected cells. This study investigated whether the small membrane (M) protein was involved in the induction of apoptosis by DEN virus. This was addressed by using a series of enhanced green fluorescent protein-fused DEN proteins. Evidence is provided that intracellular production of the M ectodomains (residues M-1 to M-40) of all four DEN serotypes triggered apoptosis in host cells such as mouse neuroblastoma Neuro 2a and human hepatoma HepG2 cells. The M ectodomains of the wild-type strains of Japanese encephalitis, West Nile and yellow fever viruses also had proapoptotic properties. The export of the M ectodomain from the Golgi apparatus to the plasma membrane appeared to be essential for the initiation of apoptosis. The study found that anti-apoptosis protein Bcl-2 protected HepG2 cells against the death-promoting activity of the DEN M ectodomain. This suggests that the M ectodomain exerts its cytotoxic effects by activating a mitochondrial apoptotic pathway. The cytotoxicity of the DEN M ectodomain reflected the intrinsic proapoptotic properties of the nine carboxy-terminal amino acids (residues M-32 to M-40) designated ApoptoM: Residue M-36 was unique in that it modulated the death-promoting activity of the M ectodomain. Defining the ApoptoM-activated signalling pathways leading to apoptosis will provide the basis for studying how the M protein might play a key role in the fate of the flavivirus-infected cells.
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PMID:Dengue virus M protein contains a proapoptotic sequence referred to as ApoptoM. 1367 13

A yellow fever (YFV) 17D virus variant, which causes persistent infection of mouse neuroblastoma cells associated with defective cell penetration and small plaque size, yielded plaque-revertant viruses from cells transfected with viral transcripts encoding the adaptive mutation (Gly360 in the E protein). Reconstruction of a plaque-purified revertant which contained Gly360 and additional substitutions (Asn for Lys303 and Val for Ala261) yielded a virus whose infectious center size, growth efficiency, and cell penetration rate similar to the parental YF5.2iv virus, whereas viruses with Asn303 or Val261 alone with Gly360 yielded either a small-plaque virus or a parental revertant. These data indicate that the YFV E protein is subject to suppression of mutations in domain III that are deleterious for viral entry and spread by a second-site mutation in domain II. Position 261 lies within the hydrophobic ligand-binding pocket at the domain I-II interface, a site believed to be involved in the hinge-like conformational change of domain II during activation of membrane fusion-activity. Results of this study provide genetic data consistent with findings on flavivirus structure and implicate domain III in functions beyond simply cell surface attachment.
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PMID:Yellow fever 17D virus: pseudo-revertant suppression of defective virus penetration and spread by mutations in domains II and III of the E protein. 1532 96

Persistent infection of mouse neuroblastoma NB41A3 cells with yellow fever 17D virus generates viral variants which exhibit defective cell penetration, poor cell-to-cell spread, small plaque size and reduced growth efficiency, caused by substitution of glycine for aspartic acid or glutamic acid at positions 360 and 362 in the envelope protein. These positions occur within a charge cluster, Asp360-Asp361-Glu362, located in domain III, near its interface with domain I. To characterize further the molecular basis for the variant phenotype, a series of mutant viruses containing substitutions at position 360, 361 and 362, were studied for effects on the cell culture properties typical of the neuroblastoma-adapted variant. Most substitutions at position 360 gave rise to viruses that were very defective in cell penetration, growth efficiency and cell-to-cell spread, whereas substitution with glutamic acid yielded a virus indistinguishable from parental yellow fever 17D. Substitution with lysine was not tolerated and substitution with asparagine resulted in frequent wild-type revertants. A glycine residue was not tolerated at position 361, but substitution at 362 yielded a small plaque virus, similar to the effect of substitution at position 360. These data indicate that the yellow fever virus E protein contains a locus within domain III where a negative-charge cluster is important for optimal function of this domain in virus-cell interactions beyond the stage of virus attachment. Modelling predictions suggest that the mutations alter the local properties of the loop within domain III, and may compromise interactions of this domain with an adjacent region of domain I during conformational changes that occur in the E protein in association with virus entry.
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PMID:Neuroblastoma cell-adapted yellow fever virus: mutagenesis of the E protein locus involved in persistent infection and its effects on virus penetration and spread. 1565 61

Zika virus (ZIKV) is an emerging mosquito-borne pathogen representing a global health concern. It has been linked to fetal microcephaly and other birth defects and neurological disorders in adults. Sanofi Pasteur has engaged in the development of an inactivated ZIKV vaccine, as well as a live chimeric vaccine candidate ChimeriVax-Zika (CYZ) that could become a preferred vaccine depending on future ZIKV epidemiology. This report focuses on the CYZ candidate that was constructed by replacing the pre-membrane and envelope (prM-E) genes in the genome of live attenuated yellow fever 17D vaccine virus (YF 17D) with those from ZIKV yielding a viable CYZ chimeric virus. The replication rate of CYZ in the Vero cell substrate was increased by using a hybrid YF 17D-ZIKV signal sequence for the prM protein. CYZ was highly attenuated both in mice and in human in vitro models (human neuroblastoma and neuronal progenitor cells), without the need for additional attenuating modifications. It exhibited significantly reduced viral loads in organs compared to a wild-type ZIKV and a complete lack of neuroinvasion following inoculation of immunodeficient A129 mice. A single dose of CYZ elicited high titers of ZIKV-specific neutralizing antibodies in both immunocompetent and A129 mice and protected animals from ZIKV challenge. The data indicate that CYZ is a promising vaccine candidate against ZIKV.
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PMID:Chimeric yellow fever 17D-Zika virus (ChimeriVax-Zika) as a live-attenuated Zika virus vaccine. 3018 50