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Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice.

McClary H, Koch R, Chisari FV, Guidotti LG - J. Exp. Med. (2000)

Bottom Line: Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens.The S. mansoni-dependent antiviral effect was partially blocked by genetically deleting IFN-gamma, although it was unaffected by deletion of IFN-alpha/beta.These results indicate that IFN-gamma (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-gamma.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens. S. mansoni infection induces T helper cell type 2 (Th2)-type cytokines in the liver of humans and mice. The intrahepatic induction of nitric oxide (NO) and Th1-type cytokines, such as interferon (IFN)-gamma and IFN-alpha/beta, inhibits HBV replication noncytopathically in the liver of transgenic mice. To examine whether S. mansoni infection and the accompanying induction of Th2-type cytokines could interfere with HBV replication in the liver, HBV transgenic mice were infected with S. mansoni. By 5 wk after infection, HBV replication disappeared concomitant with the intrahepatic induction of NO and Th1-type cytokines, and in the absence of Th2-type cytokines. By 6-8 wk after infection, HBV replication remained undetectable and this was associated with further induction of NO and Th1-type cytokines together with the appearance of Th2-type cytokines. The S. mansoni-dependent antiviral effect was partially blocked by genetically deleting IFN-gamma, although it was unaffected by deletion of IFN-alpha/beta. These results indicate that IFN-gamma (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-gamma. Similar events may suppress HBV replication during human S. mansoni infection.

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Intracellular localization of HBcAg in wild-type and IFN-γ–deficient HBV transgenic mice during S. mansoni infection. Age-, sex-, and serum HBeAg–matched transgenic mice from lineage 1.3.46 that were either heterozygous (+/−) or homozygous (−/−) for the IFN-γ  mutations were exposed to water containing cercariae and killed on week 8 after exposure. Liver sections obtained from uninfected HBV-IFN-γ+/− mice, S. mansoni–infected HBV–IFN-γ+/− or HBV–IFN-γ2/− mice were stained for the presence of HBcAg. Note that in uninfected HBV–IFN-γ+/− mice (A), cytoplasmic HBcAg is mainly detectable in centrilobular hepatocytes surrounding the central veins (top). These are the cells that sustain high levels of HBV replication. Also note that cytoplasmic HBcAg disappeared from centrilobular hepatocytes of S. mansoni–infected HBV-IFN-γ+/− (B) and was still detectable in the cytoplasm of centrilobular hepatocytes of S. mansoni–infected HBV–IFN-γ2/− mice (C). Adult worms (asterisk) and eggs (arrowheads) are indicated. Immunoperoxidase stain for HBcAg, original magnification: ×200.
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Figure 2: Intracellular localization of HBcAg in wild-type and IFN-γ–deficient HBV transgenic mice during S. mansoni infection. Age-, sex-, and serum HBeAg–matched transgenic mice from lineage 1.3.46 that were either heterozygous (+/−) or homozygous (−/−) for the IFN-γ mutations were exposed to water containing cercariae and killed on week 8 after exposure. Liver sections obtained from uninfected HBV-IFN-γ+/− mice, S. mansoni–infected HBV–IFN-γ+/− or HBV–IFN-γ2/− mice were stained for the presence of HBcAg. Note that in uninfected HBV–IFN-γ+/− mice (A), cytoplasmic HBcAg is mainly detectable in centrilobular hepatocytes surrounding the central veins (top). These are the cells that sustain high levels of HBV replication. Also note that cytoplasmic HBcAg disappeared from centrilobular hepatocytes of S. mansoni–infected HBV-IFN-γ+/− (B) and was still detectable in the cytoplasm of centrilobular hepatocytes of S. mansoni–infected HBV–IFN-γ2/− mice (C). Adult worms (asterisk) and eggs (arrowheads) are indicated. Immunoperoxidase stain for HBcAg, original magnification: ×200.

Mentions: By weeks 6, 7, and 8 after infection, hepatic granulomas (Fig. 2 B) increased in number and size (data not shown) and HBV replication remained suppressed. Since viral replication occurs inside of HBcAg-positive nucleocapsid particles in the cytoplasm of centrilobular hepatocytes (Fig. 2 A) in these transgenic mice 10, it is not surprising that HBcAg disappeared from the cytoplasm of these cells (Fig. 2 B), along with the disappearance of HBV replicative forms (Fig. 1). The intrahepatic expression of iNOS, Th1-type cytokines, and T lymphocyte, macrophage, and NK cell markers progressively increased, reaching its peak by week 8 after infection. This was accompanied by the induction of Th2-type cytokines (IL-4, IL-5, and IL-10) that started by week 6 and also peaked by week 8 (Fig. 1). These results were somewhat surprising since others have reported that the peak of Th2-type cytokine response after S. mansoni infection in mice (week 8) coincides with the downregulation of Th1-type cytokines (for review see reference 8). Using a quantitative assay (RNase Protection) to measure the intrahepatic content of cytokine messages, we confirmed in this study that Th2-type cytokines peaked on week 8, but this did not coincide with any waning of the type 1 immune response in the liver, which also peaked by week 8 (Fig. 1).


Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice.

McClary H, Koch R, Chisari FV, Guidotti LG - J. Exp. Med. (2000)

Intracellular localization of HBcAg in wild-type and IFN-γ–deficient HBV transgenic mice during S. mansoni infection. Age-, sex-, and serum HBeAg–matched transgenic mice from lineage 1.3.46 that were either heterozygous (+/−) or homozygous (−/−) for the IFN-γ  mutations were exposed to water containing cercariae and killed on week 8 after exposure. Liver sections obtained from uninfected HBV-IFN-γ+/− mice, S. mansoni–infected HBV–IFN-γ+/− or HBV–IFN-γ2/− mice were stained for the presence of HBcAg. Note that in uninfected HBV–IFN-γ+/− mice (A), cytoplasmic HBcAg is mainly detectable in centrilobular hepatocytes surrounding the central veins (top). These are the cells that sustain high levels of HBV replication. Also note that cytoplasmic HBcAg disappeared from centrilobular hepatocytes of S. mansoni–infected HBV-IFN-γ+/− (B) and was still detectable in the cytoplasm of centrilobular hepatocytes of S. mansoni–infected HBV–IFN-γ2/− mice (C). Adult worms (asterisk) and eggs (arrowheads) are indicated. Immunoperoxidase stain for HBcAg, original magnification: ×200.
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Related In: Results  -  Collection

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Figure 2: Intracellular localization of HBcAg in wild-type and IFN-γ–deficient HBV transgenic mice during S. mansoni infection. Age-, sex-, and serum HBeAg–matched transgenic mice from lineage 1.3.46 that were either heterozygous (+/−) or homozygous (−/−) for the IFN-γ mutations were exposed to water containing cercariae and killed on week 8 after exposure. Liver sections obtained from uninfected HBV-IFN-γ+/− mice, S. mansoni–infected HBV–IFN-γ+/− or HBV–IFN-γ2/− mice were stained for the presence of HBcAg. Note that in uninfected HBV–IFN-γ+/− mice (A), cytoplasmic HBcAg is mainly detectable in centrilobular hepatocytes surrounding the central veins (top). These are the cells that sustain high levels of HBV replication. Also note that cytoplasmic HBcAg disappeared from centrilobular hepatocytes of S. mansoni–infected HBV-IFN-γ+/− (B) and was still detectable in the cytoplasm of centrilobular hepatocytes of S. mansoni–infected HBV–IFN-γ2/− mice (C). Adult worms (asterisk) and eggs (arrowheads) are indicated. Immunoperoxidase stain for HBcAg, original magnification: ×200.
Mentions: By weeks 6, 7, and 8 after infection, hepatic granulomas (Fig. 2 B) increased in number and size (data not shown) and HBV replication remained suppressed. Since viral replication occurs inside of HBcAg-positive nucleocapsid particles in the cytoplasm of centrilobular hepatocytes (Fig. 2 A) in these transgenic mice 10, it is not surprising that HBcAg disappeared from the cytoplasm of these cells (Fig. 2 B), along with the disappearance of HBV replicative forms (Fig. 1). The intrahepatic expression of iNOS, Th1-type cytokines, and T lymphocyte, macrophage, and NK cell markers progressively increased, reaching its peak by week 8 after infection. This was accompanied by the induction of Th2-type cytokines (IL-4, IL-5, and IL-10) that started by week 6 and also peaked by week 8 (Fig. 1). These results were somewhat surprising since others have reported that the peak of Th2-type cytokine response after S. mansoni infection in mice (week 8) coincides with the downregulation of Th1-type cytokines (for review see reference 8). Using a quantitative assay (RNase Protection) to measure the intrahepatic content of cytokine messages, we confirmed in this study that Th2-type cytokines peaked on week 8, but this did not coincide with any waning of the type 1 immune response in the liver, which also peaked by week 8 (Fig. 1).

Bottom Line: Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens.The S. mansoni-dependent antiviral effect was partially blocked by genetically deleting IFN-gamma, although it was unaffected by deletion of IFN-alpha/beta.These results indicate that IFN-gamma (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-gamma.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens. S. mansoni infection induces T helper cell type 2 (Th2)-type cytokines in the liver of humans and mice. The intrahepatic induction of nitric oxide (NO) and Th1-type cytokines, such as interferon (IFN)-gamma and IFN-alpha/beta, inhibits HBV replication noncytopathically in the liver of transgenic mice. To examine whether S. mansoni infection and the accompanying induction of Th2-type cytokines could interfere with HBV replication in the liver, HBV transgenic mice were infected with S. mansoni. By 5 wk after infection, HBV replication disappeared concomitant with the intrahepatic induction of NO and Th1-type cytokines, and in the absence of Th2-type cytokines. By 6-8 wk after infection, HBV replication remained undetectable and this was associated with further induction of NO and Th1-type cytokines together with the appearance of Th2-type cytokines. The S. mansoni-dependent antiviral effect was partially blocked by genetically deleting IFN-gamma, although it was unaffected by deletion of IFN-alpha/beta. These results indicate that IFN-gamma (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-gamma. Similar events may suppress HBV replication during human S. mansoni infection.

Show MeSH
Related in: MedlinePlus