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Hepatitis C, innate immunity and alcohol: friends or foes?

Osna NA, Ganesan M, Kharbanda KK - Biomolecules (2015)

Bottom Line: Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients.In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity.The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

View Article: PubMed Central - PubMed

Affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA. nosna@unmc.edu.

ABSTRACT
Hepatitis C and alcohol are the most widespread causes of liver disease worldwide. Approximately 80% of patients with a history of hepatitis C and alcohol abuse develop chronic liver injury. Alcohol consumption in hepatitis C virus (HCV)-infected patients exacerbates liver disease leading to rapid progression of fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatocytes are the main sites of HCV-infection and ethanol metabolism, both of which generate oxidative stress. Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients. In this review paper, we analyze the effects of ethanol metabolism and other factors on HCV replication. In addition, we illustrate the mechanisms of how HCV hijacks innate immunity and how ethanol exposure regulates this process. We also clarify the effects of HCV and ethanol metabolism on interferon signaling-a crucial point for activation of anti-viral genes to protect cells from virus-and the role that HCV- and ethanol-induced impairments play in adaptive immunity which is necessary for recognition of virally-infected hepatocytes. In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity. The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

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Sensing of viral (HCV) dsRNA by TLR3 and activation of IFNβ production.
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biomolecules-05-00076-f002: Sensing of viral (HCV) dsRNA by TLR3 and activation of IFNβ production.

Mentions: For viral dsRNA recognition, the major PRRs include intracellular retinoic-inducible gene 1 (RIG1) and melanoma differentiation associated gene 5 (MDA5), as well as Toll-like receptor 3 (TLR 3) expressed on the membrane of liver cells. Interestingly, lack of TLR3 and a mutation in RIG-1 in Huh 7.5 cells make them highly permissive to HCV-replication [29] that allows successful usage of these cells for in vitro HCV studies. After infection, the C-terminal domain of RIG1/MDA5 undergoes a conformational change, driving a response through the mitochondrial antiviral signaling protein (MAVS), which serves as an adaptor in IFN signaling and is localized both at peroxisomes and mitochondria [30,31]. Peroxisomal MAVS activates early interferon sensitive genes (ISG) by induction of interferon regulated factors 1 and 3 (IRF1 and IRF3), in the absence of interferon, while mitochondrial MAVS activates TBK1 and IKK kinases to phosphorylate IRF3, leading to IFN induction and NFκB activation (reviewed by [32]), summarized in Figure 2.


Hepatitis C, innate immunity and alcohol: friends or foes?

Osna NA, Ganesan M, Kharbanda KK - Biomolecules (2015)

Sensing of viral (HCV) dsRNA by TLR3 and activation of IFNβ production.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384112&req=5

biomolecules-05-00076-f002: Sensing of viral (HCV) dsRNA by TLR3 and activation of IFNβ production.
Mentions: For viral dsRNA recognition, the major PRRs include intracellular retinoic-inducible gene 1 (RIG1) and melanoma differentiation associated gene 5 (MDA5), as well as Toll-like receptor 3 (TLR 3) expressed on the membrane of liver cells. Interestingly, lack of TLR3 and a mutation in RIG-1 in Huh 7.5 cells make them highly permissive to HCV-replication [29] that allows successful usage of these cells for in vitro HCV studies. After infection, the C-terminal domain of RIG1/MDA5 undergoes a conformational change, driving a response through the mitochondrial antiviral signaling protein (MAVS), which serves as an adaptor in IFN signaling and is localized both at peroxisomes and mitochondria [30,31]. Peroxisomal MAVS activates early interferon sensitive genes (ISG) by induction of interferon regulated factors 1 and 3 (IRF1 and IRF3), in the absence of interferon, while mitochondrial MAVS activates TBK1 and IKK kinases to phosphorylate IRF3, leading to IFN induction and NFκB activation (reviewed by [32]), summarized in Figure 2.

Bottom Line: Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients.In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity.The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

View Article: PubMed Central - PubMed

Affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA. nosna@unmc.edu.

ABSTRACT
Hepatitis C and alcohol are the most widespread causes of liver disease worldwide. Approximately 80% of patients with a history of hepatitis C and alcohol abuse develop chronic liver injury. Alcohol consumption in hepatitis C virus (HCV)-infected patients exacerbates liver disease leading to rapid progression of fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatocytes are the main sites of HCV-infection and ethanol metabolism, both of which generate oxidative stress. Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients. In this review paper, we analyze the effects of ethanol metabolism and other factors on HCV replication. In addition, we illustrate the mechanisms of how HCV hijacks innate immunity and how ethanol exposure regulates this process. We also clarify the effects of HCV and ethanol metabolism on interferon signaling-a crucial point for activation of anti-viral genes to protect cells from virus-and the role that HCV- and ethanol-induced impairments play in adaptive immunity which is necessary for recognition of virally-infected hepatocytes. In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity. The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

Show MeSH
Related in: MedlinePlus