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Mechanisms of innate immune alterations in HCV infection and its modulation by alcohol use

TÉMAKIÍRÁS

Intézmény: Semmelweis Egyetem
klinikai orvostudományok
Klinikai orvostudományok Doktori Iskola

témavezető: Szabó Gyöngyi
helyszín: USA
helyszín rövidítés: USA


A kutatási téma leírása:

Clinical studies indicate that alcohol use is an independent risk factor for progression of liver disease in chronic hepatitis C (HCV) infection. The lack of a strong HCV-specific immune response is a major component of decreased viral elimination while non-specific inflammatory cell activation, rather than direct HCV toxicity, mediates hepatocellular injury. We have previously reported that acute alcohol use is associated with reduced antigen-specific immune activation and it has been shown that chronic alcohol consumption results in increased activation of non-specific inflammatory pathways. Little is known, however, about the cellular and molecular pathways by which alcohol leads to accelerated progression in HCV disease. We hypothesize that alcohol and HCV interact to activate non-specific pro-inflammatory cascades in chronic HCV infection and this process may contribute to progression of liver damage. Based on our preliminary results, we propose that the pattern recognition receptor, toll-like receptor 2 (TLR2), mediates cellular activation by HCV core and NS3 proteins and that alcohol may increase inflammatory cell activation by interacting with TLR2-mediated pathways. Our preliminary results show that myeloid dendritic cells (DCs), the most potent antigen presenting cell type, have reduced T-cell activation capacity in patients with chronic HCV infection and this can be further decreased by alcohol treatment of DCs. Thus, we propose that HCV-mediated TLR2 activation and alcohol interact to inhibit functional maturation of dendritic cells, thereby decreasing antigen-specific T cell activation and viral recognition. The Specific Aims of this project are:
1. To investigate interactions between HCV- and alcohol-induced inflammatory pathways to determine mechanisms contributing to increased inflammatory cascade activation. We will evaluate pro-inflammatory cytokine and chemokine induction at the protein and mRNA levels and on the NF-B/Rel nuclear regulatory pathway in monocytes from normal controls and from patients with chronic HCV infection with and without ongoing alcohol use and/or after in vitro alcohol treatment.
2. To investigate the pattern recognition receptor, TLR2, as a putative receptor in cell activation by HCV proteins.
3. To evaluate the interactions between alcohol and HCV proteins on TLR2-mediated cell activation pathways.
4. To delineate the role of TLR2-mediated signaling by HCV core and NS3 proteins in the reduced dendritic cell differentiation in HCV infected patients and to evaluate the effect of alcohol on TLR2-mediated signals in DC development.
Results from these experiments will provide novel data on TLR2, a putative innate immune receptor, in the mediation of inflammatory cell activation by HCV and reveal molecular pathways by which alcohol consumption modulates the response to HCV and/or its proteins. Our experiments will dissect the role of the individual inflammatory stimuli (HCV, alcohol, LPS) in the complex activation of inflammatory pathways in patients with chronic alcohol use and HCV infection that may provide target for therapeutic interventions. These studies will also delineate the role of TLR2-mediated signals and their modulation by alcohol in the reduced differentiation and T cell stimulatory functions of DCs in HCV infection that may contribute to the persistent viral infection.

felvehető hallgatók száma: 3

Jelentkezési határidő: 2016-10-31

 
Minden jog fenntartva © 2007, Országos Doktori Tanács - a doktori adatbázis nyilvántartási száma az adatvédelmi biztosnál: 02003/0001. Program verzió: 1.2318 ( 2016. XI. 26. )