Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Callitrichid hepatitis (CH) is a highly fatal, rodent-borne zoonosis of New World primates (family Callitrichidae) caused by lymphocytic choriomeningitis virus (LCMV). It is unclear whether virulence in Callitrichidae is associated with specific genetic or phylogenetic markers of the virus as only a partial S RNA sequence of a single CH-associated isolate is known. In a period of 10 months, three pygmy marmosets (Cebuella pygmaea) and one Goeldi's monkey (Callimico goeldii) died from CH in a German zoo. LCMV was most likely transmitted by wild mice. Infection was associated with characteristic histopathological lesions in liver, brain, and lymphoid tissue. Virus sequences from all callitrichids and a captured mouse were > or =99.2% identical. LCMV strains from a pygmy marmoset and the Goeldi's monkey were isolated in cell culture and the 3.4-kb S RNA was completely sequenced. Both strains differed considerably in their genetic and phylogenetic characteristics from known LCMV strains, including the previously described CH-associated strain. These data show that CH is widespread and can be caused by distantly related LCMV strains.
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PMID:First outbreak of callitrichid hepatitis in Germany: genetic characterization of the causative lymphocytic choriomeningitis virus strains. 1138 20

Antiviral roles of natural killer (NK) cell subsets were examined in C57BL/6 mice infected with murine cytomegalovirus (MCMV) and other viruses, including lymphocytic choriomeningitis virus (LCMV), vaccinia virus (VV), and mouse hepatitis virus (MHV). Each virus vigorously induced an NK cell infiltrate into the peritoneal cavity and liver, causing some redistributions of NK cell subsets defined by monoclonal antibody (mAb) directed against Ly49A, C/I, D, and G2. Striking results were seen with a mAb (1F8) reactive with the positively signaling molecule Ly49H, present in MCMV-resistant C57BL/6 mice. mAb 1F8 also stains Ly49 C and I, but exclusion of those reactivities with mAb 5E6, which recognizes Ly49 C and I, indicated that Ly49H(+) cells infiltrated the peritoneal cavity and liver and were particularly effective at synthesizing interferon gamma. Depletion of 1F8(+) but not 5E6(+) cells in vivo by mAb injections enhanced MCMV titers by 20-1,000-fold in the spleen and approximately fivefold in the liver. Titers of LCMV or VV were not enhanced. These anti-MCMV effects were attributed to prototypical NK1.1(+)CD3(-) NK cells and not to NK1.1(+)CD3(+) "NK/T" cells. This is the first evidence that control of a virus infection in vivo is mediated by a distinct NK cell subset.
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PMID:Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. 1143 70

Cytotoxic T lymphocytes (CTL) play a major role in the recovery from primary viral infections and the accompanying tissue injuries. However, it is unclear to what extent the two main cytolytic pathways, perforin-granzyme A and B exocytosis and Fas ligand (FasL)-Fas interaction, contribute to these processes. Here we have employed mouse strains with either spontaneous mutations or targeted gene defects in one or more components of either of the two cytolytic pathways to analyze the molecular basis of viral clearance and induction of hepatitis during lymphocytic choriomeningitis virus infection. Our results reveal that viral clearance is solely dependent on perforin but that virus-induced liver damage only occurs when both the FasL/Fas and the perforin pathways, including granzymes A and B, are simultaneously activated. The finding that development of hepatitis but not viral clearance is dependent on the concomitant activation of FasL-Fas and perforin-granzymes may be helpful in designing novel strategies to prevent hepatic failures during viral infections.
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PMID:Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. 1150 23

The cellular promyelocytic leukemia protein (PML) associates with the proteins of several viruses and in some cases reduces viral propagation in cell culture. To examine the role of PML in vivo, we compared immune responses and virus loads of PML-deficient and control mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). PML(-/-) mice exhibited accelerated primary footpad swelling reactions to very-low-dose LCMV, higher swelling peaks upon high-dose inoculation, and higher viral loads in the early phase of systemic LCMV infection. T-cell-mediated hepatitis and consequent mortality upon infection with a hepatotropic LCMV strain required 10- to 100-times-lower inocula despite normal cytotoxic T-lymphocyte reactivity in PML(-/-) mice. Furthermore, PML deficiency rendered mice 10 times more susceptible to lethal immunopathology upon intracerebral LCMV inoculation. Accordingly, 10-times-lower VSV inocula elicited specific neutralizing-antibody responses, a replication-based effect not observed with inactivated virus or after immunization with recombinant VSV glycoprotein. These in vivo observations corroborated our results showing more virus production in PML(-/-) fibroblasts. Thus, PML is a contributor to innate immunity, defining host susceptibility to viral infections and to immunopathology.
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PMID:Effects of promyelocytic leukemia protein on virus-host balance. 1190 21

Arenaviruses can cause hemorrhagic fever and death in primates and guinea pigs, but these viruses are not highly pathogenic for most rodent carriers. In the United States, arenaviruses precipitated outbreaks of hepatitis in captive monkeys, and they present an emerging health threat in the tropical areas of Africa and South America. We describe infection of rhesus macaques with the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), using the WE strain that has been known to cause both encephalopathy and multifocal hemorrhage. Five macaques were inoculated: two by the intravenous (i.v.) and three by the intragastric (i.g.) route. Whereas the two i.v.-inoculated monkeys developed signs and lesions consistent with fatal hemorrhagic fever, the i.g.-inoculated monkeys had an attenuated infection with no disease. Pathological signs of the primate i.v. infection differ significantly from guinea pig arenavirus infections and make this a superior model for human viral hemorrhagic disease.
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PMID:Hemorrhagic fever occurs after intravenous, but not after intragastric, inoculation of rhesus macaques with lymphocytic choriomeningitis virus. 1199 78

Previous work has shown that stimulation of APCs via CD40 strongly influences the outcome of a CD8 T cell response. In this study, we examined the effect of CD40 ligation on peripheral tolerance induction of self-reactive CD8 T cells in an adoptive transfer model. Naive CD8 T cells from TCR-transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus were tolerized when transferred into H8-tg mice expressing the gp33 epitope under the control of a MHC class I promoter. However, if the H8 recipient mice were treated with agonistic anti-CD40 Abs, TCR-tg cells vigorously proliferated, and induced destruction of lymphoid organs and hepatitis. Break of peripheral tolerance induction was B cell independent and did not require CD28/B7 interactions. These findings provide further in vivo evidence for the crucial role of the activation state of the APC in peripheral tolerance induction and suggest the need for caution in systemically activating APC via CD40 ligation in the presence of self-reactive T cells.
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PMID:CD40 ligation in the presence of self-reactive CD8 T cells leads to severe immunopathology. 1199 66

Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2(b) background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.
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PMID:DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis. 1239 Dec

In this study, we develop a mathematical model for analysis of the compartmental aspects and immunopathology of lymphocytic choriomeningitis virus (LCMV) infection in mice. We used sets of original and published data on systemic (extrasplenic) virus distribution to estimate the parameters of virus growth and elimination for spleen and other anatomical compartments, such as the liver, kidney, thymus and lung as well as transfer rates between blood and the above organs. A mathematical model quantitatively integrating the virus distribution kinetics in the host, the specific cytotoxic T lymphocyte (CTL) response in spleen and the re-circulation of effector CTL between spleen, blood and liver is advanced to describe the CTL-mediated immunopathology (hepatitis) in mice infected with LCMV. For intravenous and "peripheral" routes of infection we examine the severity of the liver disease, as a function of the virus dose and the host's immune status characterized by the numbers of precursor and/or cytolytic effector CTL. The model is used to predict the efficacy of protection against virus persistence and disease in a localized viral infection as a function of the composition of CTL population. The modelling analysis suggests quantitative demands to CTL memory for maximal protection against a wide range of doses of infection with a primarily peripheral site of virus replication without the risk of favoring immunopathology. It specifies objectives for CTL vaccination to ensure virus elimination with minimal immunopathology vs. vaccination for disease.
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PMID:Modelling the dynamics of LCMV infection in mice: II. Compartmental structure and immunopathology. 1264 13

CTL escape mutations have been identified in several chronic infections, including mice infected with mouse hepatitis virus strain JHM. One outstanding question in understanding CTL escape is whether a CD8 T cell response to two or more immunodominant CTL epitopes would prevent CTL escape. Although CTL escape at multiple epitopes seems intuitively unlikely, CTL escape at multiple CD8 T cell epitopes has been documented in some chronically infected individual animals. To resolve this apparent contradiction, we engineered a recombinant variant of JHM that expressed the well-characterized gp33 epitope of lymphocytic choriomeningitis virus, an epitope with high functional avidity. The results show that the presence of a host response to this second epitope protected mice against CTL escape at the immunodominant JHM-specific CD8 T cell epitope, the persistence of infectious virus, and the development of clinical disease.
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PMID:Protection against CTL escape and clinical disease in a murine model of virus persistence. 1290 5

Both CD4(+) and CD8(+) T cells are required for clearance of the murine coronavirus mouse hepatitis virus (MHV) during acute infection. We investigated the effects of an epitope-specific CD8(+) T-cell response on acute infection of MHV, strain A59, in the murine CNS. Mice with CD8(+) T cells specific for gp33-41 (an H-2D(b)-restricted CD8(+) T-cell epitope derived from lymphocytic choriomeningitis glycoprotein) were infected with a recombinant MHV-A59, also expressing gp33-41, as a fusion protein with enhanced green fluorescent protein (EGFP). By 5 days postinfection, these mice showed significantly (approximately 20-fold) lower titers of infectious virus in the brain compared to control mice. Furthermore mice with gp33-41-specific CD8(+) cells exhibited much reduced levels of viral antigen in the brain as measured by immunohistochemistry using an antibody directed against viral nucleocapsid. More than 90% of the viruses recovered from brain lysates of such protected mice, at 5 days postinfection, had lost the ability to express EGFP and had deletions in their genomes encompassing EGFP and gp33-41. In addition, genomes of viruses from about half the plaques that retained the EGFP gene had mutations within the gp33-41 epitope. On the other hand, gp33-41-specific cells failed to protect perforin-deficient mice from infection by the recombinant MHV expressing gp33, indicating that perforin-mediated mechanisms were needed. Virus recovered from perforin-deficient mice did not exhibit loss of EGFP expression and the gp33-41 epitope. These observations suggest that the cytotoxic T-cell response to gp33-41 exerts a strong immune pressure that quickly selects epitope escape mutants to gp33-41.
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PMID:Effects of an epitope-specific CD8+ T-cell response on murine coronavirus central nervous system disease: protection from virus replication and antigen spread and selection of epitope escape mutants. 1472 70


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