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TGF-β isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling
Li-Li Zou1, Jian-Rui Li1,2, Hu Li1,2
1CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Transforming growth factor beta (TGF-β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-β isoforms, including TGF-β1, TGF-β2 and TGF-β3, remain unclear. Here, we demonstrated that all of the three TGF-β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-β/SMAD signalling pathway-dependent and TGF-β/SMAD signalling pathway-independent manners. TGF-β isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-β1 and TGF-β2, not TGF-β3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-β isoforms in the HCV-related liver disease progression.
Insights
Transforming growth factor beta (TGF-β) isoforms inhibit hepatitis C virus (HCV) replication through multiple mechanisms. However, TGF-β1 and TGF-β2 can also promote liver fibrosis, impacting HCV disease progression.
Area of Science:
- Virology
- Immunology
- Hepatology
Background:
- Transforming growth factor beta (TGF-β) influences viral liver disease by controlling viral spread and inflammation.
- The specific antiviral roles and mechanisms of TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3) in hepatitis C virus (HCV) infection are not fully understood.
Purpose of the Study:
- To investigate the antiviral activities of TGF-β isoforms against HCV.
- To elucidate the mechanisms underlying TGF-β's effects on HCV propagation and liver fibrosis.
Main Methods:
- Utilized an infectious HCV cell culture system with Huh7.5 cells.
- Analyzed TGF-β isoform expression and their impact on viral entry and replication.
- Assessed liver fibrosis markers (collagen type I alpha-1, α-smooth muscle actin) in LX-2 cells.
Main Results:
- All three TGF-β isoforms were upregulated in HCV-infected cells and inhibited HCV propagation with varying potency.
- TGF-β isoforms interfered with HCV entry and intracellular replication via SMAD-dependent and independent pathways.
- Elevated TGF-β1 and TGF-β2, but not TGF-β3, induced liver fibrosis markers in LX-2 cells.
Conclusions:
- TGF-β isoforms possess distinct antiviral activities against HCV, affecting multiple stages of the viral life cycle.
- While exhibiting antiviral properties, TGF-β1 and TGF-β2 contribute to liver fibrosis, adding complexity to their role in HCV-related liver disease.
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