Current therapies of chronic hepatitis B by nucleot(s)ide analogues can inhibit formation of new infectious viral particles but do not eliminate HBV because HBV establishes in hepatocytes a stable covalently closed circular DNA (cccDNA). Pegylated interferon α (IFN-α) treatment can be considered as an alternative therapy, which results in sustained inhibition of HBV proteins, destruction of cccDNA and cure in up to 15% of patients. These discoveries attract attention to plasmacytoid dendritic cells (pDCs), which are a major source of type I interferon (IFN-I, α/β/ω) and proinflammatory cytokines in human organism. However, HBV infection does not induce, but impairs production of IFN-α in pDCs. Several mechanisms could be involved in the inhibition of pDC functions, including secretions of HBV proteins or virus particles, but also secretions of extracellular vesicles (exosomes, microsomes, apoptotic bodies) of cellular origin. To determine the factor(s) responsible for the inhibition of pDC function, we will develop a hepatic microenvironment model. In this model, we will investigate the effect of HBV on pDC function after a close cell contact during co-culture between infected hepatocytes and naive pDCs, or alternatively, after exposure of naïve pDCs to different fractions of cell-free supernatant (HBV proteins, virus particles, extracellular vesicles) of HBV-infected hepatocytes. We will also investigate whether pharmacologic targeting of regulatory receptor signaling, namely MEK1/2-ERK pathway, can improve functionality of HBV-exposed pDCs. The identification of these inhibitory mechanisms could lead to a better understanding of the modulation of the innate immune response and to the identification of the targets able to restore pDCs functions. The objective of our study is to restore functions of pDCs exposed to HBV in order to inhibit HBV production, to target cccDNA in HBV-infected hepatocytes and to use reinvigorated pDCs in adjuvant therapy.
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2017-01 až 2019-12 Sensing of hepatitis B virus-infected hepatocytes by plasmacytoid dendritic cells. Grantová Agentura České Republiky (GAČR, Czech Science Foundation), PI; | Grant: 17-15422S
2017-01 až 2021-12 Gilead Sciences Research Center/ÚOCHB, AV ČR, “Towards novel strategies to target chronic hepatitis B”, CoPI
2017-04 až 2022-03 Phenotype and function of head and neck squamous cell carcinoma immune cells as predictive markers of clinical response. Ministry of health of the Czech republic (AZV); Co-PI | Grant: 17-28055A
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