Virus-host interactions in hepatitis B virus infection

Urtzi AR Red

 

Urtzi Garaigorta

Group Leader

Contact

Research summary

Our laboratory is interested in unraveling the nature of the virus-host interactions and pathways that regulate the formation and homeostasis of the hepatitis B virus cccDNA pool, a hallmark of virus persistence. We combine genetic screenings with virological, cellular and molecular approaches to identify and characterize the mode-of-action of new cellular factors that regulate the HBV infection.

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Publications

Billioud G, Kruse RL, Carrillo M, Whitten-Bauer C, Gao D, Kim A, Chen L, McCaleb ML, Crosby JR, Hamatake R, Hong Z, Garaigorta U, Swayze E, Bissig KD, Wieland S. In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides. Journal of Hepatology 2016; 64 (4):781-789.

Padmanabhan P, Garaigorta U, Dixit MD. Emergent properties of the interferon signaling network may underlie the success of hepatitis C treatment. Nature Communications 2014; 16 (5):3872-3880.

Garaigorta U, Heim MH, Boyd B, Wieland S, Chisari FV. Hepatitis C virus induces the formation of stress granules whose proteins regulate late steps in the virus life cycle.. Journal of Virology 2012; 86 (20):11043-11056.

Dreux M, Garaigorta U, Boyd B, Decembre E, Chung J, Whitten-Bauer C, Wieland S, Chisari FV. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host & Microbe 2012; 12 (4):558-570.

Garaigorta U, Chisari FV. Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host & Microbe 2009; 6 (6):513-522.

 

Funding

logo ministerio eco com 2016-2019: Convocatoria 2016 - Proyectos I+D+I. Programa estatal de investigación, desarrollo e innovación orientada a los retos de la sociedad. Regulation of hepatitis B virus infection by DNA damage response proteins. Ref. SAF2016-75169-R.

 

 

 

Hepatitis B virus (HBV) represents an important human pathogen causing both acute and chronic hepatitis. It is estimated that over 240 million people are chronically infected and more than 780,000 people die every year due to complications of HBV, including liver cirrhosis and hepatocellular carcinoma. Our laboratory is focused on studying basic aspects of the HBV infection. In particular we are interested in the identification and characterization of cellular factors that regulate the HBV infection, its persistence and its pathogenesis. The final goal of our studies is to define the mechanisms by which HBV establishes persistence in the infected cell, with the hope that this knowledge will help developing new curative antiviral strategies for the treatment of chronic HBV infections.

In the last years we performed shRNA-based loss-of-function genetic screenings in the HepG2-NTCP HBV infection system to identify cellular factors that regulate the novo HBV infection. In such experiments we interrogated 80 different proteins, all of them belonging to the DNA damage response pathways and identified a total of ten proteins as regulators of the infection. While two of the identified proteins seem to be required for the infection, the other eight proteins seem to be restriction factors. Two of the latest, Aquarius (AQR) and Senataxin (SETX) have been validated in independent experiments and the results suggest that they act as restriction factors for the accumulation of the HBV cccDNA pool, a hallmark of virus persistence. We are currently performing experiments to understand the mechanism behind the regulation of cccDNA accumulation by AQR and SETX. On the other hand, we are performing new experiments to validate the rest of the proteins that were identified in the screenings.

In addition to these basic studies we are setting up an in-house cell-based ELISA that will allow us to carry out pharmacological screenings to identify new small molecules with antiviral activity against HBV.

 

Imagen 1

Genetic screening set up performed to identify cellular proteins that regulate the HBV infection.

 

 

Imagen 2

Increased HBV infection in AQR (E8 & H8) and SETX (B9 & D9) down-regulated cells.


 

 

Grupo Garaigorta Lab BR

 

Name
Position
Contact
Urtzi Garaigorta Principal investigator
Andoni Gómez Moreno Predoctoral scientist

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