Pattern of disease after murine hepatitis virus strain 3 infection correlates with macrophage activation and not viral replication

Pope, Melissa; Rotstein, Ori D.; Cole, Edward; Sinclair, S.; Parr, Rebecca D.; Cruz, B; Fingerote, R. J.; Chung, Stephen W.; Gorczynski, Reg; Fung, Laisum

doi:10.1128/jvi.69.9.5252-5260.1995

Cited by 40 publications

(31 citation statements)

References 56 publications

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“…5 Indeed, it is not the viral load that determines the occurrence of massive necrosis but the viral induced up-regulation of the fgl2 gene which initiates the pathological process. 5,18 Although, treatment with neutralizing antibodies to the fgl2 gene abrogates the disease, a high viral load persists. 5 Fulminant murine hepatitis and fgl2 gene expression were shown to be genetically linked and it is likely that host genetic factors are also important in human fulminant hepatitis.…”

Section: Discussionmentioning

confidence: 99%

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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

108

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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Section: Discussionmentioning

confidence: 99%

“…33 We have previously reported that IL-1 and TNF-␣ induce endothelial cell transcription of fgl2 linking cytokines and induction of coagulation. 18 However, antibodies to TNF or IL-1 were unable to prevent the hepatic necrosis caused by MHV-3. 3 The role of the immune coagulation system in fulminant hepatic failure is controversial.…”

Section: Discussionmentioning

confidence: 99%

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

108

116

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“…The receptor for MHV-3, CD66 (also known as CEACAM1), is expressed by macrophages 86 , and infection of these cells has a central role in the pathogenesis of the liver failure that is seen in these animals. Macrophages from susceptible mouse strains that are infected with MHV-3 upregulate the production of several pro-inflammatory molecules both in vitro and in vivo, including a transmembrane procoagulant molecule, fibrinogen-like protein 2 (FGL2; also known as fibroleukin) 6,[87][88][89] (FIG. 4).…”

Section: Mhv-3-mediated Lethal Hepatitis: Induction Of Expression Of mentioning

confidence: 99%

Immunopathogenesis of coronavirus infections: implications for SARS

2005

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At the end of 2002, the first cases of severe acute respiratory syndrome (SARS) were reported, and in the following year, SARS resulted in considerable mortality and morbidity worldwide. SARS is caused by a novel species of coronavirus (SARS-CoV) and is the most severe coronavirus-mediated human disease that has been described so far. On the basis of similarities with other coronavirus infections, SARS might, in part, be immune mediated. As discussed in this Review, studies of animals that are infected with other coronaviruses indicate that excessive and sometimes dysregulated responses by macrophages and other pro-inflammatory cells might be particularly important in the pathogenesis of disease that is caused by infection with these viruses. It is hoped that lessons from such studies will help us to understand more about the pathogenesis of SARS in humans and to prevent or control outbreaks of SARS in the future.

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“…The induction of a unique macrophage prothrombinase (fgl2 prothrombinase) in response to MHV-3 infection correlates with the severity of infection. This unregulated elaboration of fgl2 prothrombinase during infection appears to be a major contributor to the pathogenesis of the lethal hepatitis observed in susceptible strains of mice (Dindzans et al, 1986;Pope et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Coronavirus MHV-3-Induced Apoptosis in Macrophages

et al. 1998

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Infection with mouse hepatitis virus strain 3 (MHV-3) results in lethal fulminant hepatic necrosis in fully susceptible BALB/c mice compared to the minimal disease observed in resistant strain A/J mice. Macrophages play a central role in the pathogenesis of MHV-3-induced hepatitis. In the present study we have shown that MHV-3 infection of macrophages induces these cells to undergo apoptosis. Three methods to detect apoptosis were applied: flow cytometry analysis of nuclear DNA content, fluorescence microscopic visualization of apoptotic cells labeled by the TUNEL assay, and gel electrophoresis to detect DNA laddering. Apoptosis in A/J and BALB/c macrophages was first detected at 8 h postinfection (p.i.) and reached a maximum by 12 h p.i. The degree of MHV-3-induced apoptosis was much greater in A/J-derived macrophages than in BALB/c-derived cells. Apoptosis was inversely correlated with the development of typical MHV cytopathology, namely syncytia formation. Infected macrophages from A/J mice did not form synctia in contrast to the extensive synctia formation observed in BALB/c-derived macrophages. In MHV-3-infected BALB/c macrophage cultures, apoptotic cells were not incorporated into syncytia. Apoptosis was also inversely correlated with the expression of MHV-3-induced fgl2 prothrombinase in macrophages. These results add the murine coronavirus MHV-3 to the list of RNA-containing viruses capable of inducing apoptosis.

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Pattern of disease after murine hepatitis virus strain 3 infection correlates with macrophage activation and not viral replication

Cited by 40 publications

References 56 publications

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

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

Immunopathogenesis of coronavirus infections: implications for SARS

Coronavirus MHV-3-Induced Apoptosis in Macrophages

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