Association of mouse fibrinogen-like protein with murine hepatitis virus-induced prothrombinase activity

Parr, Rebecca D.; Fung, Laisum; Reneker, Jeffrey; Myers-Mason, Nancy; Leibowitz, Julian L.; Levy, Gary

doi:10.1128/jvi.69.8.5033-5038.1995

Cited by 70 publications

(48 citation statements)

References 27 publications

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“…No difference in expression of fgl-2 mRNA was detected between A59-DE-HE-and A59-DE-CAT-infected mice (data not shown). Histologic examination of the livers did not reveal coagulopathy typically induced by MHV-3 infection (Parr et al 1995).…”

Section: Fig 3ðcontinuedmentioning

confidence: 79%

“…To determine if the activation of the mouse fibrinogen-like protein (fgl-2) gene was associated with the fulminent hepatitis induced by ic infection with the A59-DE-CAT virus, as has been shown to be the case in the hepatitis induced by MHV-3 (Parr et al 1995), livers were examined for the presence of fgl-2 gene mRNA by RT±PCR. No difference in expression of fgl-2 mRNA was detected between A59-DE-HE-and A59-DE-CAT-infected mice (data not shown).…”

Section: Fig 3ðcontinuedmentioning

confidence: 99%

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Expression of Hemagglutinin/Esterase by a Mouse Hepatitis Virus Coronavirus Defective–Interfering RNA Alters Viral Pathogenesis

et al. 1998

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A defective-interfering (DI) RNA of mouse hepatitis virus (MHV) was developed as a vector for expressing MHV hemagglutinin/esterase (HE) protein. The virus containing an expressed HE protein (A59-DE-HE) was generated by infecting cells with MHV-A59, which does not express HE, and transfecting the in vitro-transcribed DI RNA containing the HE gene. A similar virus (A59-DE-CAT) expressing the chloramphenicol acetyltransferase (CAT) was used as a control. These viruses were inoculated intracerebrally into mice, and the role of the HE protein in viral pathogenesis was evaluated. Results showed that all mice infected with parental A59 or A59-DE-CAT succumbed to infection by 9 days postinfection (p.i.), demonstrating that inclusion of the DI did not by itself alter pathogenesis. In contrast, 60% of mice infected with A59-DE-HE survived infection. HE- or CAT-specific subgenomic mRNAs were detected in the brains at days 1 and 2 p.i. but not later, indicating that the genes in the DI vector were expressed only in the early stage of viral infection. No significant difference in virus titer or viral antigen expression in brains was observed between A59-DE-HE- and A59-DE-CAT-infected mice, suggesting that virus replication in brain was not affected by the expression of HE. However, at day 3 p.i. there was a slight increase in the extent of inflammatory cell infiltration in the brains of the A59-DE-HE-infected mice. Surprisingly, virus titers in the livers of A59-DE-HE-infected mice were 3 log10 lower than that of the A59-DE-CAT-infected mice at day 6 p.i. Also, substantially less necrosis and viral antigen were detected in the livers of the A59-DE-HE-infected mice. This may account for the reduced mortality of these mice. The possible contribution of the host immune system to this difference in pathogenesis was analyzed by comparing the expression of four cytokines. Results showed that both tumor necrosis factor-alpha and interleukin-6 mRNAs increased in the brains of the A59-DE-HE-infected mice at day 2 p.i., whereas interferon-gamma and interleukin-1 alpha mRNAs were similar between A59-DE-HE- and A59-DE-CAT-infected mice. These data suggest that the transient expression of HE protein enhances an early innate immune response, possibly contributing to the eventual clearance of virus from the liver. This study indicates the feasibility of the DI expression system for studying roles of viral proteins during MHV infection.

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Section: Fig 3ðcontinuedmentioning

confidence: 79%

Section: Fig 3ðcontinuedmentioning

confidence: 99%

Expression of Hemagglutinin/Esterase by a Mouse Hepatitis Virus Coronavirus Defective–Interfering RNA Alters Viral Pathogenesis

et al. 1998

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“…3 Especially important is that MHV-3 infection in susceptible BALB/cJ mice causes the de novo synthesis of a unique procoagulant fgl2 prothrombinase by macrophages. 2 The murine fgl2 gene has been cloned, sequenced, and characterized in this laboratory. 2,4,14,15 Recent sequential studies showed that the development of fulminant viral hepatitis always followed the same pattern: initiation by viral-induced up-regulation of the fgl2 prothrombinase…”

Section: Discussionmentioning

confidence: 99%

“…The 225 amino acids at the carboxyl end corresponds to the well-conserved fibrinogen-related domain. 2 The five potential glycosylation sites are conserved in the mouse and human proteins. A cDNA of HFGL2, encompassing the entire coding region, was cloned into pcDNA3.1-His and expressed as a fusion protein (phfgl2his) in CHO cells ( Figure 3B).…”

Section: Isolation and Characterization Of Hfgl2mentioning

confidence: 99%

“…A novel murine cDNA fgl2, encoding a protein with prothrombinase-like activity, was previously cloned in our laboratory. 2 The sequence of the cDNA was essentially identical to a previously described sequence corresponding to a gene encoding a mouse fibrinogen-like protein, originally described as a cytotoxic T-cell-specific gene. When the cDNA containing the entire coding region was expressed in RAW 264.7 cells, a prothrombinase activity was detected by both a one-stage clotting assay and cleavage of 125 I-labeled prothrombin.…”

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Molecular and Functional Analysis of the Human Prothrombinase Gene (HFGL2) and Its Role in Viral Hepatitis

Levy¹,

Liu²,

Ding³

et al. 2000

The American Journal of Pathology

107

116

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In the present studies, we report the cloning and structural characterization of the HFGL2 gene and its functional role in human fulminant hepatitis. The HFGL2 gene is approximately 7 kb in length with 2 exons. The putative promoter contains cis element consensus sequences that strongly suggest the inducibility of its expression. From the nucleotide sequence of the human gene, a 439-amino acid long protein is predicted. The overall identity between the murine fgl2 and hfgl2 coded proteins is over 70%. About 225 amino acids at the carboxyl end of these molecules are almost 90% identical, and correspond to a well-conserved fibrinogen-related domain. Both HFGL2 and FGL2 encode a type II transmembrane protein with a predicted catalytic domain toward the amino terminus of the protein. Transient transfection of Chinese hamster ovary (CHO) cells with a fulllength cDNA of HFGL2 coding region resulted in high levels of prothrombinase activity. Livers from 8 patients transplanted for fulminant viral hepatitis were examined for extent of necrosis, inflammation, fibrin deposition, and HFGL2 induction. In situ hybridization showed positive staining of macrophages in areas of active hepatocellular necrosis. Fibrin stained positively in these areas and was confirmed by electron microscopy. These studies define a unique prothrombinase gene (HFGL2) and implicate its importance in the pathogenesis of fulminant viral hepatitis. The majority of individuals who develop acute viral hepatitis recover completely, and only a small fraction, less than one tenth of 1%, develop fulminant hepatic failure; why this occurs is not known.1 The fulminant form of the disease occurs at all ages of life and is not specific for any one viral type. The hallmark of the condition is the extreme rapidity of the necroinflammatory process resulting in widespread or total hepatocellular necrosis in weeks or even days; any satisfactory explanation must explain this rapid progression.A novel murine cDNA fgl2, encoding a protein with prothrombinase-like activity, was previously cloned in our laboratory.2 The sequence of the cDNA was essentially identical to a previously described sequence corresponding to a gene encoding a mouse fibrinogen-like protein, originally described as a cytotoxic T-cell-specific gene. When the cDNA containing the entire coding region was expressed in RAW 264.7 cells, a prothrombinase activity was detected by both a one-stage clotting assay and cleavage of 125 I-labeled prothrombin. Using a model of fulminant viral hepatitis, we demonstrated a causal relationship between the induction of fgl2 prothrombinase and the mortality of murine hepatitis virus infection (MHV-3). 3 We demonstrated that after MHV-3 infection in susceptible mice, mRNA transcripts of fgl2 were seen in macrophages and endothelial cells in the liver followed by fibrin deposition and liver necrosis. 4 The infusion of high-titered monoclonal antibodies to fgl2 prevented the coagulation disturbance, the hepatic necrosis, and mortality associated with MHV-3 infection. 5H...

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The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis

et al. 2008

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Association of mouse fibrinogen-like protein with murine hepatitis virus-induced prothrombinase activity

Cited by 70 publications

References 27 publications

Expression of Hemagglutinin/Esterase by a Mouse Hepatitis Virus Coronavirus Defective–Interfering RNA Alters Viral Pathogenesis

Expression of Hemagglutinin/Esterase by a Mouse Hepatitis Virus Coronavirus Defective–Interfering RNA Alters Viral Pathogenesis

Molecular and Functional Analysis of the Human Prothrombinase Gene (HFGL2) and Its Role in Viral Hepatitis

The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis

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