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Published on: September 1, 2015
Subversion of plasmacytoid and myeloid dendritic cell functions in chronic HCV infection
Gyongyi Szabo1, Angela Dolganiuc
1Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605-2324, USA. gyongyi.szabo@umassmed.edu
Insights
Chronic hepatitis C virus (HCV) infection impairs dendritic cell (DC) function. Both plasmacytoid DC (PDC) and myeloid DC (MDC) show reduced numbers and impaired functions, contributing to persistent HCV infection.
Area of Science:
- Immunology
- Virology
- Hepatology
Background:
- Hepatitis C virus (HCV) infection often becomes chronic due to inadequate immune responses.
- Dendritic cells (DCs) are crucial for initiating innate and adaptive immunity against viral infections, including HCV.
- Understanding DC dysfunction in chronic HCV is vital for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the frequency and function of plasmacytoid dendritic cells (PDCs) and myeloid dendritic cells (MDCs) in patients with chronic HCV infection.
- To explore the mechanisms underlying DC defects in chronic HCV, including the role of viral proteins and Toll-like receptors (TLRs).
Main Methods:
- Quantification and functional assays (IFN-alpha production, allostimulatory capacity) of PDCs and MDCs from chronic HCV patients and healthy controls.
- Assessment of monocyte-derived MDC maturation and function following LPS stimulation.
- In vitro studies using HCV core and NS3 proteins to induce MDC defects.
- Experiments with TLR2 and TLR4 deficient/mutant mice to evaluate viral recognition pathways.
Main Results:
- Significantly reduced numbers and impaired IFN-alpha production capacity of blood PDCs in chronic HCV patients.
- Normal frequency but decreased allostimulatory capacity of monocyte-derived MDCs in chronic HCV patients, even after LPS-induced maturation.
- HCV core and NS3 proteins induced MDC defects, suggesting a viral-induced mechanism.
- TLR2, but not TLR4, was critical for innate immune cell recognition of HCV core and NS3 proteins; CD14 co-receptor did not enhance TLR2 recognition.
Conclusions:
- Both PDC and MDC functions are significantly impaired in patients with chronic HCV infection.
- DC dysfunction in chronic HCV is likely mediated by the interaction of viral products (core, NS3) with innate immune cells, particularly via TLR2.
- These findings highlight the critical role of DC impairment in the persistence of HCV infection and suggest potential targets for immunomodulatory therapies.
Abstract:
Insufficient elimination of the hepatitis C virus (HCV) during acute infection results in chronic disease in the majority of patients due to weak virus-specific immune responses. Dendritic cells (DC) play a central role in recognition of HCV and in induction of innate and adaptive immune responses. In this study, we evaluated the frequency and functions of plasmacytoid dendritic cells (PDC) and myeloid dendritic cells (MDC) in patients with chronic HCV infection. We found that both the numbers and IFNalpha production capacity of blood PDC were significantly reduced in patients with chronic HCV infection compared to normal controls. While the frequency of MDC was not affected in chronic HCV, the allostimulatory capacity of monocyte-derived MDC was significantly decreased compared to normals. Lipopolysaccharide (LPS)-induced maturation improved the allostimulatory capacity of HCV infected patients' MDC that still remained significantly lower compared to normal controls. Our experiments revealed that MDC defects can be induced by HCV core and NS3 proteins suggesting virus-induced mechanisms for the DC defects in HCV infection. Finally, using toll-like receptor 2 (TLR2) and TLR4 deficient or mutant mice, we demonstrated that TLR2 but not TLR4 was critical in recognition of HCV core and NS3 proteins by innate immune cells. Further, TLR2 recognition of HCV core and NS3 was not augmented by co-expression of the TLR co-receptor, CD14. These data demonstrate that both PDC and MDC functions are impaired in patients with chronic HCV infection and DC defects are likely related to interaction of HCV viral products with innate immune cells.
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