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Leslie L. Barton - One of the best experts on this subject based on the ideXlab platform.
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congenital Lymphocytic Choriomeningitis virus infection spectrum of disease
Annals of Neurology, 2007Co-Authors: Daniel J Bonthius, Leslie L. Barton, Rhonda Wright, Brian S Tseng, Elysa J Marco, Bahri Karacay, Paul D LarsenAbstract:Objective Lymphocytic Choriomeningitis virus (LCMV) is a human pathogen and an emerging neuroteratogen. When the infection occurs during pregnancy, the virus can target and damage the fetal brain and retina. We examined the spectrum of clinical presentations, neuroimaging findings, and clinical outcomes of children with congenital LCMV infection. Methods Twenty children with serologically confirmed congenital LCMV infection were identified. The children underwent neuroimaging studies and were followed prospectively for up to 11 years. Results All children with congenital LCMV infection had chorioretinitis and structural brain anomalies. However, the presenting clinical signs, severity of vision disturbance, nature and location of neuropathology, and character and severity of brain dysfunction varied substantially among cases. Neuroimaging abnormalities included microencephaly, periventricular calcifications, ventriculomegaly, pachygyria, cerebellar hypoplasia, porencephalic cysts, periventricular cysts, and hydrocephalus. The combination of microencephaly and periventricular calcifications was the most common neuroimaging abnormality, and all children with this combination had profound mental retardation, epilepsy, and cerebral palsy. However, others had less severe neuroimaging abnormalities and better outcomes. Some children had isolated cerebellar hypoplasia, with jitteriness as their presenting sign and ataxia as their principal long-term neurological dysfunction. Interpretation Congenital LCMV infection can have diverse presenting signs, neuroimaging abnormalities, and clinical outcomes. In the companion article to this study, we utilize an animal model to show that the clinical and pathological diversity in congenital LCMV infection is likely due to differences in the gestational timing of infection. Ann Neurol 2007
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Lymphocytic Choriomeningitis virus: emerging fetal teratogen.
American journal of obstetrics and gynecology, 2002Co-Authors: Leslie L. Barton, Marilyn B. Mets, Cynthia L. BeauchampAbstract:Lymphocytic Choriomeningitis virus (LCMV), a rodent-borne arenavirus, is an often undiagnosed human fetal teratogen. We describe a neonate born with hydrocephalus and chorioretinitis after maternal second-trimester symptomatic LCMV infection. Previously reported affected infants are reviewed. We strongly suggest that obstetricians counsel their pregnant patients regarding the potential hazard that contact with infected pet, laboratory, and household mice and hamsters poses to pregnant women and their unborn children.
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congenital Lymphocytic Choriomeningitis virus infection decade of rediscovery
Clinical Infectious Diseases, 2001Co-Authors: Leslie L. Barton, Marilyn B. MetsAbstract:Lymphocytic Choriomeningitis virus (LCMV) is an underdiagnosed fetal teratogen. This diagnosis should be considered for infants and children with unexplained hydrocephalus, micro- or macrocephaly, intracranial calcifications, chorioretinitis, and nonimmune hydrops. The immunofluorescent antibody test is the only reasonable, commercially available, screening diagnostic tool. The differential diagnosis of congenital LCMV infection includes toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, enteroviruses, human parvovirus B12, and syphilis. The infection has also been misdiagnosed as various neurologic, ophthalmologic, and chromosomal syndromes. Further research, to determine the prevalence of this infection in human and rodent populations, and prospective studies, to delineate the clinical spectrum of congenital infection, are needed. The public and members of the medical profession should be made aware of the hazard that wild, pet, and laboratory rodents pose to pregnant women.
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congenital Lymphocytic Choriomeningitis virus infection decade of rediscovery
Clinical Infectious Diseases, 2001Co-Authors: Leslie L. Barton, Marilyn B. MetsAbstract:Lymphocytic Choriomeningitis virus (LCMV) is an underdiagnosed fetal teratogen. This diagnosis should be considered for infants and children with unexplained hydrocephalus, micro- or macrocephaly, intracranial calcifications, chorioretinitis, and nonimmune hydrops. The immunofluorescent antibody test is the only reasonable, commercially available, screening diagnostic tool. The differential diagnosis of congenital LCMV infection includes toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, enteroviruses, human parvovirus B19 [corrected], and syphilis. The infection has also been misdiagnosed as various neurologic, ophthalmologic, and chromosomal syndromes. Further research, to determine the prevalence of this infection in human and rodent populations, and prospective studies, to delineate the clinical spectrum of congenital infection, are needed. The public and members of the medical profession should be made aware of the hazard that wild, pet, and laboratory rodents pose to pregnant women.
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Lymphocytic Choriomeningitis virus: reemerging central nervous system pathogen.
Pediatrics, 2000Co-Authors: Leslie L. Barton, N. Joanne HyndmanAbstract:Lymphocytic Choriomeningitis virus (LCMV), a human zoonosis caused by a rodent-borne arenavirus, has been associated with both postnatal and intrauterine human disease. Infection in man is acquired after inhalation, ingestion, or direct contact with virus found in the urine, feces, and saliva of infected mice, hamsters, and guinea pigs. Congenital LCMV infection is a significant, often unrecognized cause of chorioretinitis, hydrocephalus, microcephaly or macrocephaly, and mental retardation. Acquired LCMV infection, asymptomatic in approximately one third of individuals, is productive of central nervous system manifestations in one half of the remaining cases. Aseptic meningitis or meningoencephalitis are the predominant syndromes, although transverse myelitis, a Guillain-Barre-type syndrome, as well as transient and permanent acquired hydrocephalus have also been reported. Fatalities are rare. We report a patient with meningoencephalitis attributable to LCMV and discuss the spectrum of central nervous system disease, newer diagnostic modalities, and preventive strategies. Lymphocytic Choriomeningitis virus, aseptic meningitis, meningoencephalitis, zoonosis, hydrocephalus, arenavirus.
Marilyn B. Mets - One of the best experts on this subject based on the ideXlab platform.
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Congenital Lymphocytic Choriomeningitis virus-an underdiagnosed fetal teratogen.
Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 2017Co-Authors: Michael Kinori, Hal R. Schwartzstein, Janice Lasky Zeid, Sudhi P. Kurup, Marilyn B. MetsAbstract:Congenital Lymphocytic Choriomeningitis virus (LCMV) infection is associated with high mortality and morbidity. Although the number of cases reported in the literature has been increasing, it might still be clinically an underdiagnosed human fetal teratogen. We report 2 more cases of serologically proven congenital LCMV infection. One case presented with Aicardi-like syndrome features. Since congenital LCMV infection may mimic Aicardi syndrome, serologic testing should be considered in the workup of patients with Aicardi syndrome to rule out LCMV infection.
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Lymphocytic Choriomeningitis virus: emerging fetal teratogen.
American journal of obstetrics and gynecology, 2002Co-Authors: Leslie L. Barton, Marilyn B. Mets, Cynthia L. BeauchampAbstract:Lymphocytic Choriomeningitis virus (LCMV), a rodent-borne arenavirus, is an often undiagnosed human fetal teratogen. We describe a neonate born with hydrocephalus and chorioretinitis after maternal second-trimester symptomatic LCMV infection. Previously reported affected infants are reviewed. We strongly suggest that obstetricians counsel their pregnant patients regarding the potential hazard that contact with infected pet, laboratory, and household mice and hamsters poses to pregnant women and their unborn children.
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congenital Lymphocytic Choriomeningitis virus infection decade of rediscovery
Clinical Infectious Diseases, 2001Co-Authors: Leslie L. Barton, Marilyn B. MetsAbstract:Lymphocytic Choriomeningitis virus (LCMV) is an underdiagnosed fetal teratogen. This diagnosis should be considered for infants and children with unexplained hydrocephalus, micro- or macrocephaly, intracranial calcifications, chorioretinitis, and nonimmune hydrops. The immunofluorescent antibody test is the only reasonable, commercially available, screening diagnostic tool. The differential diagnosis of congenital LCMV infection includes toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, enteroviruses, human parvovirus B12, and syphilis. The infection has also been misdiagnosed as various neurologic, ophthalmologic, and chromosomal syndromes. Further research, to determine the prevalence of this infection in human and rodent populations, and prospective studies, to delineate the clinical spectrum of congenital infection, are needed. The public and members of the medical profession should be made aware of the hazard that wild, pet, and laboratory rodents pose to pregnant women.
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congenital Lymphocytic Choriomeningitis virus infection decade of rediscovery
Clinical Infectious Diseases, 2001Co-Authors: Leslie L. Barton, Marilyn B. MetsAbstract:Lymphocytic Choriomeningitis virus (LCMV) is an underdiagnosed fetal teratogen. This diagnosis should be considered for infants and children with unexplained hydrocephalus, micro- or macrocephaly, intracranial calcifications, chorioretinitis, and nonimmune hydrops. The immunofluorescent antibody test is the only reasonable, commercially available, screening diagnostic tool. The differential diagnosis of congenital LCMV infection includes toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, enteroviruses, human parvovirus B19 [corrected], and syphilis. The infection has also been misdiagnosed as various neurologic, ophthalmologic, and chromosomal syndromes. Further research, to determine the prevalence of this infection in human and rodent populations, and prospective studies, to delineate the clinical spectrum of congenital infection, are needed. The public and members of the medical profession should be made aware of the hazard that wild, pet, and laboratory rodents pose to pregnant women.
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Lymphocytic Choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis.
American journal of ophthalmology, 2000Co-Authors: Marilyn B. Mets, Leslie L. Barton, Ali S. Khan, Thomas G. KsiazekAbstract:Abstract PURPOSE: To elucidate the role and clinical spectrum of congenital Lymphocytic Choriomeningitis virus infection as a cause of chorioretinopathy, congenital hydrocephalus, and macrocephaly or microcephaly in the United States. METHODS: We performed complete ophthalmologic surveys of all residents at Misericordia, a home for the severely mentally retarded in Chicago, and prospectively evaluated all patients with chorioretinitis or chorioretinal scars during a 36-month period at Children's Memorial Hospital, also located in Chicago. Sera for patients demonstrating chorioretinal scars (a sign of intrauterine infection) were tested for Toxoplasma gondii , rubella virus, cytomegalovirus, and herpes simplex virus and Lymphocytic Choriomeningitis virus antibodies. RESULTS: Four of 95 patients examined at the home had chorioretinal scars, and two of these patients had normal T. gondii , rubella virus, cytomegalovirus, and herpes simplex virus titers and dramatically elevated titers for Lymphocytic Choriomeningitis virus. Three of 14 cases of chorioretinitis at the hospital had normal T. gondii , rubella virus, cytomegalovirus, and herpes sim-plex virus titers and elevated Lymphocytic Choriomeningitis virus antibody titers. (A fourth case, diagnosed in 1996, was reported 2 years ago.) CONCLUSIONS: Lymphocytic Choriomeningitis virus was responsible for visual loss in two of four children secondary to chorioretinitis in a population of severely retarded children. The six new cases of Lymphocytic Choriomeningitis virus chorioretinitis identified in these two populations over the last 3 years, compared with the total number ever reported in the United States (10 cases), suggests that Lymphocytic Choriomeningitis virus may be a more common cause of congenital chorioretinitis than previously believed. Because its consequences for visual and psychomotor development are devastating, we conclude that the workup for congenital chorioretinitis should include Lymphocytic Choriomeningitis virus serology, especially if T. gondii , rubella virus, cytomegalovirus, and herpes simplex virus titers are negative.
Thomas G. Ksiazek - One of the best experts on this subject based on the ideXlab platform.
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High Diversity and Ancient Common Ancestry of Lymphocytic Choriomeningitis Virus
2013Co-Authors: Cesar G. Albariño, James A. Comer, Bobbie R. Erickson, Gustavo Palacios, Marina L. Khristova, Serena A. Carroll, Jeffrey Hui, Thomas Briese, Kirsten St. George, Thomas G. KsiazekAbstract:Lymphocytic Choriomeningitis virus (LCMV) is the prototype of the family Arenaviridae. LCMV can be associated with severe disease in humans, and its global distribution refl ects the broad dispersion of the primary rodent reservoir, the house mouse (Mus musculus). Recent interest in the natural history of the virus has been stimulated by increasing recognition of LCMV infections during pregnancy, and in clusters of LCMV-associated fatal illness among tissue transplant recipients. Despite its public health importance, little is known regarding the genetic diversity or distribution of virus variants. Genomic analysis of 29 LCMV strains collected from a variety of geographic and temporal sources showed these viruses to be highly diverse. Several distinct lineages exist, but there is little correlation with time or place of isolation. Bayesian analysis estimates the most recent common ancestor to be 1,000–5,000 years old, and this long history is consistent with complex phylogeographic relationships of the extant virus isolates. The rodent-borne arenaviruses (family Arenaviridae) are enveloped viruses with bisegmented RNA genomes that include several causative agents of hemorrhagic fevers in the New World and Africa (1). The large (L) genome RNA segment encodes the virus polymerase L and the Z protein, whereas the small (S) genome RNA segment encodes the nucleocapsid protein (NP) and glycoprotein precursor (GPC). The prototypic arenavirus, Lymphocytic Choriomeningitis virus (LCMV), is distributed worldwid
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High diversity and ancient common ancestry of Lymphocytic Choriomeningitis virus.
Emerging infectious diseases, 2010Co-Authors: Cesar G. Albariño, James A. Comer, Bobbie R. Erickson, Gustavo Palacios, Marina L. Khristova, Serena A. Carroll, Jeffrey Hui, Thomas Briese, Kirsten St. George, Thomas G. KsiazekAbstract:Lymphocytic Choriomeningitis virus (LCMV) is the prototype of the family Arenaviridae. LCMV can be associated with severe disease in humans, and its global distribution reflects the broad dispersion of the primary rodent reservoir, the house mouse (Mus musculus). Recent interest in the natural history of the virus has been stimulated by increasing recognition of LCMV infections during pregnancy, and in clusters of LCMV-associated fatal illness among tissue transplant recipients. Despite its public health importance, little is known regarding the genetic diversity or distribution of virus variants. Genomic analysis of 29 LCMV strains collected from a variety of geographic and temporal sources showed these viruses to be highly diverse. Several distinct lineages exist, but there is little correlation with time or place of isolation. Bayesian analysis estimates the most recent common ancestor to be 1,000–5,000 years old, and this long history is consistent with complex phylogeographic relationships of the extant virus isolates.
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Congenital Lymphocytic Choriomeningitis virus: an underdiagnosed cause of neonatal hydrocephalus.
The Pediatric infectious disease journal, 2006Co-Authors: Danica Jenine Schulte, Thomas G. Ksiazek, James A. Comer, Bobbie R. Erickson, Pierre E. Rollin, Stuart T. Nichol, Deborah LehmanAbstract:We report a case of congenital hydrocephalus caused by Lymphocytic Choriomeningitis virus with severe neurologic sequelae, including hydrocephalus, chorioretinitis, blindness and developmental delay. This is the first report of Lymphocytic Choriomeningitis virus isolation in the cerebrospinal fluid of a congenitally infected infant.
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Lymphocytic Choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis.
American journal of ophthalmology, 2000Co-Authors: Marilyn B. Mets, Leslie L. Barton, Ali S. Khan, Thomas G. KsiazekAbstract:Abstract PURPOSE: To elucidate the role and clinical spectrum of congenital Lymphocytic Choriomeningitis virus infection as a cause of chorioretinopathy, congenital hydrocephalus, and macrocephaly or microcephaly in the United States. METHODS: We performed complete ophthalmologic surveys of all residents at Misericordia, a home for the severely mentally retarded in Chicago, and prospectively evaluated all patients with chorioretinitis or chorioretinal scars during a 36-month period at Children's Memorial Hospital, also located in Chicago. Sera for patients demonstrating chorioretinal scars (a sign of intrauterine infection) were tested for Toxoplasma gondii , rubella virus, cytomegalovirus, and herpes simplex virus and Lymphocytic Choriomeningitis virus antibodies. RESULTS: Four of 95 patients examined at the home had chorioretinal scars, and two of these patients had normal T. gondii , rubella virus, cytomegalovirus, and herpes simplex virus titers and dramatically elevated titers for Lymphocytic Choriomeningitis virus. Three of 14 cases of chorioretinitis at the hospital had normal T. gondii , rubella virus, cytomegalovirus, and herpes sim-plex virus titers and elevated Lymphocytic Choriomeningitis virus antibody titers. (A fourth case, diagnosed in 1996, was reported 2 years ago.) CONCLUSIONS: Lymphocytic Choriomeningitis virus was responsible for visual loss in two of four children secondary to chorioretinitis in a population of severely retarded children. The six new cases of Lymphocytic Choriomeningitis virus chorioretinitis identified in these two populations over the last 3 years, compared with the total number ever reported in the United States (10 cases), suggests that Lymphocytic Choriomeningitis virus may be a more common cause of congenital chorioretinitis than previously believed. Because its consequences for visual and psychomotor development are devastating, we conclude that the workup for congenital chorioretinitis should include Lymphocytic Choriomeningitis virus serology, especially if T. gondii , rubella virus, cytomegalovirus, and herpes simplex virus titers are negative.
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congenital Lymphocytic Choriomeningitis virus syndrome a disease that mimics congenital toxoplasmosis or cytomegalovirus infection
Pediatrics, 1997Co-Authors: Rhonda Wright, Thomas G. Ksiazek, Daniel J Bonthius, Daniel Johnson, Mark Neumann, Pierre Rollin, Ronald V Keech, Patrick W Hitchon, Charles Grose, William E BellAbstract:Objective. To describe the clinical characteristics of intrauterine infection with Lymphocytic Choriomeningitis (LCM) virus, an uncommonly recognized cause of congenital viral infection. Patients. Three infants born in the midwestern United States in 1994 and 1995 with clinical features and serologic studies consistent with congenital LCM virus infection and cases of congenital infection identified by review of the medical literature between 1955 and 1996. Results. Twenty-six infants with serologically confirmed congenital LCM virus infection were identified. Twenty-two infants were products of term gestations, and birth weights ranged from 2384 to 4400 g (median, 3520 g). Ocular abnormalities, macrocephaly, or microcephaly were the most commonly identified neonatal features. Twenty-one infants (88%) had chorioretinopathy, 10 (43%) had macrocephaly (head circumference >90th percentile) at birth, and 3 (13%) were microcephalic (head circumference Conclusions. These cases suggest that congenital LCM virus infection could be an underrecognized cause of congenital infection among infants born in the United States. Because of the clinical similarities of these congenital infections, cases of congenital LCM virus infection can be confused with infections with cytomegalovirus or Toxoplasma gondii.
Juan Carlos De La Torre - One of the best experts on this subject based on the ideXlab platform.
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expanded potential for recombinant trisegmented Lymphocytic Choriomeningitis viruses protein production antibody production and in vivo assessment of biological function of genes of interest
Journal of Virology, 2011Co-Authors: Daniel L. Popkin, Juan Carlos De La Torre, Sébastien Emonet, John R Teijaro, Andrew M Lee, Hanna Lewicki, Michael B. A. OldstoneAbstract:The recombinant engineering of trisegmented Lymphocytic Choriomeningitis virus (LCMV) to express two genes of interest was recently reported. We used this technology to efficiently express green fluorescent protein (GFP) and the immunoregulatory gene product interleukin-10 (IL-10) in vitro, assess IL-10 function in vivo during viral meningitis, and generate specific, robust monoclonal antibody responses to IL-10. Tripartite viruses were attenuated in wild-type and TLR7(-/-) mice. However, IFNAR1(-/-) mice sustained systemic viral replication when 2 nucleotide substitutions from a persistent LCMV variant were present. These findings demonstrate the utility of tripartite LCMV in vitro and in vivo to study genes in the context of a well-defined model system.
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use of single cycle infectious Lymphocytic Choriomeningitis virus to study hemorrhagic fever arenaviruses
Journal of Virology, 2011Co-Authors: W Shanaka W I Rodrigo, Juan Carlos De La Torre, Luis MartinezsobridoAbstract:Several arenaviruses, chiefly Lassa virus (LASV) and Junin virus in West Africa and Argentina, respectively, cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and significant mortality. The investigation of antiviral strategies to combat HF arenaviruses is hampered by the requirement of biosafety level 4 (BSL-4) facilities to work with these viruses. These biosafety hurdles could be overcome by the use of recombinant single-cycle infectious arenaviruses. To explore this concept, we have developed a recombinant Lymphocytic Choriomeningitis virus (LCMV) (rLCMVΔGP/GFP) where we replaced the viral glycoprotein (GP) with the green fluorescent protein (GFP). We generated high titers of GP-pseudotyped rLCMVΔGP/GFP via genetic trans complementation using stable cell lines that constitutively express LCMV or LASV GPs. Replication of these GP-pseudotyped rLCMVΔGP/GFP viruses was restricted to GP-expressing cell lines. This system allowed us to rapidly and reliably characterize and quantify the neutralization activities of serum antibodies against LCMV and LASV within a BSL-2 facility. The sensitivity of the GFP-based microneutralization assay we developed was similar to that obtained with a conventionally used focus reduction neutralization (FRNT) assay. Using GP-pseudotyped rLCMVΔGP/GFP, we have also obtained evidence supporting the feasibility of this approach to identify and evaluate candidate antiviral drugs against HF arenaviruses without the need of BSL-4 laboratories.
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Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus
Journal of Virology, 2006Co-Authors: Luis Martínez-sobrido, Elina I. Zuniga, Debralee Rosario, Adolfo García-sastre, Juan Carlos De La TorreAbstract:The prototypic arenavirus Lymphocytic Choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-beta) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in the Arenaviridae family. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.
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mechanisms for Lymphocytic Choriomeningitis virus glycoprotein cleavage transport and incorporation into virions
Virology, 2003Co-Authors: Stefan Kunz, Juan Carlos De La Torre, Kurt H Edelmann, Robert Gorney, Michael B. A. OldstoneAbstract:The glycoprotein (GP) of Lymphocytic Choriomeningitis virus (LCMV) serves as virus attachment protein to its receptor on host cells and is a key determinant for cell tropism, pathogenesis, and epidemiology of the virus. The GP of LCMV is posttranslationally cleaved by the subtilase SKI-1/S1P into two subunits, the peripheral GP1, which is implicated in receptor binding, and the transmembrane GP2 that is structurally similar to the fusion active membrane proximal portions of the glycoproteins of other enveloped viruses. The present study shows that cleavage by SKI-1/S1P is not required for cell surface expression of LCMVGP on infected cells but is essential for its incorporation into virions and for the production of infectious virus particles. In absence of SKI-1/S1P cleavage, cell-to-cell propagation of the virus was markedly reduced. Further, proteolytic processing of LCMVGP depends on the presence of a cluster of basic amino acids at the C-terminus of the cytoplasmic domain of GP2, a structural motif that is conserved in Old World arenaviruses. The effect of the truncation of the cytoplasmic tail on cleavage suggests a structural interdependence between the cytoplasmic domain and the ectodomains of LCMVGP.
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recombinant Lymphocytic Choriomeningitis virus expressing vesicular stomatitis virus glycoprotein
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Daniel D Pinschewer, Mar Perez, Ana B Sanchez, Juan Carlos De La TorreAbstract:A recombinant S segment RNA (Sr) of the prototypic arenavirus Lymphocytic Choriomeningitis virus (LCMV) where the glycoprotein of vesicular stomatitis virus (VSVG) was substituted for the glycoprotein of LCMV (LCMV-GP) was produced intracellularly from cDNA under the control of a polymerase I promoter. Coexpression of the LCMV proteins NP and L allowed expression of VSVG from Sr. Infection of transfected cells with WT LCMV (LCMVwt) resulted in reassortment of the L segment of LCMVwt with the Sr at low frequency. Isolation of recombinant LCMV (rLCMV) expressing VSVG (rLCMV/VSVG) was achieved by selection against LCMVwt by using a cell line deficient in the cellular protease S1P. This approach was based on the finding that processing of LCMV-GP by S1P was required for virus infectivity. Characterization of protein and RNA expression of rLCMV/VSVG in infected cells confirmed the expected virus genome organization. rLCMV/VSVG caused syncytium formation in cultured cells and grew to approximately 100-fold lower titers than WT virus but, like the parent virus, it persisted in neonatally infected mice without clinical signs of disease.
Michael B. A. Oldstone - One of the best experts on this subject based on the ideXlab platform.
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a unique variant of Lymphocytic Choriomeningitis virus that induces pheromone binding protein mup critical role for ctl
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Brian C Ware, John H Elder, Brian M Sullivan, Stephanie Lavergne, Brett S Marro, Toru Egashira, Kevin P Campbell, Michael B. A. OldstoneAbstract:Lymphocytic Choriomeningitis virus (LCMV) WE variant 2.2 (v2.2) generated a high level of the major mouse urinary protein: MUP. Mice infected with LCMV WE v54, which differed from v2.2 by a single amino acid in the viral glycoprotein, failed to generate MUP above baseline levels found in uninfected controls. Variant 54 bound at 2.5 logs higher affinity to the LCMV receptor α-dystroglycan (α-DG) than v2.2 and entered α-DG-expressing but not α-DG-null cells. Variant 2.2 infected both α-DG-null or -expressing cells. Variant 54 infected more dendritic cells, generated a negligible CD8 T cell response, and caused a persistent infection, while v2.2 generated cytotoxic T lymphocytes (CTLs) and cleared virus within 10 days. By 20 days postinfection and through the 80-day observation period, significantly higher amounts of MUP were found in v2.2-infected mice. Production of MUP was dependent on virus-specific CTL as deletion of such cells aborted MUP production. Furthermore, MUP production was not elevated in v2.2 persistently infected mice unless virus was cleared following transfer of virus-specific CTL.
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expanded potential for recombinant trisegmented Lymphocytic Choriomeningitis viruses protein production antibody production and in vivo assessment of biological function of genes of interest
Journal of Virology, 2011Co-Authors: Daniel L. Popkin, Juan Carlos De La Torre, Sébastien Emonet, John R Teijaro, Andrew M Lee, Hanna Lewicki, Michael B. A. OldstoneAbstract:The recombinant engineering of trisegmented Lymphocytic Choriomeningitis virus (LCMV) to express two genes of interest was recently reported. We used this technology to efficiently express green fluorescent protein (GFP) and the immunoregulatory gene product interleukin-10 (IL-10) in vitro, assess IL-10 function in vivo during viral meningitis, and generate specific, robust monoclonal antibody responses to IL-10. Tripartite viruses were attenuated in wild-type and TLR7(-/-) mice. However, IFNAR1(-/-) mice sustained systemic viral replication when 2 nucleotide substitutions from a persistent LCMV variant were present. These findings demonstrate the utility of tripartite LCMV in vitro and in vivo to study genes in the context of a well-defined model system.
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mechanisms for Lymphocytic Choriomeningitis virus glycoprotein cleavage transport and incorporation into virions
Virology, 2003Co-Authors: Stefan Kunz, Juan Carlos De La Torre, Kurt H Edelmann, Robert Gorney, Michael B. A. OldstoneAbstract:The glycoprotein (GP) of Lymphocytic Choriomeningitis virus (LCMV) serves as virus attachment protein to its receptor on host cells and is a key determinant for cell tropism, pathogenesis, and epidemiology of the virus. The GP of LCMV is posttranslationally cleaved by the subtilase SKI-1/S1P into two subunits, the peripheral GP1, which is implicated in receptor binding, and the transmembrane GP2 that is structurally similar to the fusion active membrane proximal portions of the glycoproteins of other enveloped viruses. The present study shows that cleavage by SKI-1/S1P is not required for cell surface expression of LCMVGP on infected cells but is essential for its incorporation into virions and for the production of infectious virus particles. In absence of SKI-1/S1P cleavage, cell-to-cell propagation of the virus was markedly reduced. Further, proteolytic processing of LCMVGP depends on the presence of a cluster of basic amino acids at the C-terminus of the cytoplasmic domain of GP2, a structural motif that is conserved in Old World arenaviruses. The effect of the truncation of the cytoplasmic tail on cleavage suggests a structural interdependence between the cytoplasmic domain and the ectodomains of LCMVGP.
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Biology and Pathogenesis of Lymphocytic Choriomeningitis Virus Infection
Current topics in microbiology and immunology, 2002Co-Authors: Michael B. A. OldstoneAbstract:The strength of the Lymphocytic Choriomeningitis virus (LCMV) model rests on the following five foundations. First, the virus in vivo in its natural host, the mouse, or in vitro in cultured cells is non-cytolytic. This quality allows clear separation of effects caused by the virus from those caused by the host immune system. Consequently, the host cell control of viral infection as opposed to how virus interacts with cells to distort their functions without killing them can be decoded. Second, reactions to LCMV infection can encompass a widely diverse range of immune responses (Fig. 1). Usually when immunocompetent adult mice are injected with LCMV, they generate a marked immune response to eliminate the infectious agent. Although their innate responses include the production of interferon (IFN), macrophages and natural killer (NK) cells (Muller et al. 1994; see reviews Buchmeier et al. 1980; Borrow and Oldstone 1997; see chapter by Biron et al., this volume), it is the adoptive immune response — primarily the virus-specific CD8+ CTL response — that is responsible for virus clearance.
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identification of alpha dystroglycan as a receptor for Lymphocytic Choriomeningitis virus and lassa fever virus
Science, 1998Co-Authors: Wei Cao, Persephone Borrow, Hiroki Yamada, Michael D. Henry, Stuart T. Nichol, John H Elder, Eugene V Ravkov, Richard W Compans, Michael B. A. OldstoneAbstract:A peripheral membrane protein that is interactive with Lymphocytic Choriomeningitis virus (LCMV) was purified from cells permissive to infection. Tryptic peptides from this protein were determined to be alpha-dystroglycan (alpha-DG). Several strains of LCMV and other arenaviruses, including Lassa fever virus (LFV), Oliveros, and Mobala, bound to purified alpha-DG protein. Soluble alpha-DG blocked both LCMV and LFV infection. Cells bearing a null mutation of the gene encoding DG were resistant to LCMV infection, and reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Thus, alpha-DG is a cellular receptor for both LCMV and LFV.
