Characterization of host restriction factors interfering with replication and persistency of hepatitis B and D viruses
Final Report Abstract
Hepatitis B and D are serious global health problems. These viruses can cause short-term and long-term liver infections. Over 254 million people have chronic HBV and at least 11 million have chronic HDV worldwide. These infections cause about one million deaths a year. There is a vaccine for HBV that works also for HDV, but there is currently no cure for chronic HBV/HDV infections. One of the main problems in curing chronic HBV is the presence of a special form of the viral DNA, called cccDNA, which rests in the nuclei of liver cells and acts as a persistent reservoir source of infection. HDV coinfection makes things more complicated because it needs HBV to make the surface proteins for HDV to complete its replication cycle. During evolution, HBV has developed ways to at least avoid activating the immune system, but HDV activates immune responses that can stop HBV from replicating. However, we do not fully understand how these immune responses work. This research project aimed to explore how specific proteins in the host cells interfere with the replication of HBV and/or HDV during chronic infections. Understanding these interactions could lead to new targets and ways to treat these chronic viral infections. We detected that some cellular proteins, like APOBEC and DNMT3A can work as host viral restriction factors, by either inducing the destruction of HBV cccDNA or reducing viral replication by transcriptional shutdown (methylation) of cccDNA. We also found out that an interferon-induced factor (IFITM3) of the host cell is a novel binding partner for the HBV/HDV high affinity receptor (NTCP), and controls specifically the entry of HBV/HDV into hepatocytes of the liver. In parallel, we exceeded our basic research on host-virus interaction on HDV replication also by comparing the replication capabilities of HDV, and other HDV-like viruses that have been recently found in rodents (RDeV) and snakes (SDeV). SDeV has the narrowest host cell range, while RDeV has the broadest. In mice, HDV and RDeV, but not SDeV, efficiently replicate in the liver. This shows that these viruses can adapt to different hosts. Our analysis helps to understand how these viruses can change hosts. Identifying these cellular factors will be important for predicting and preventing the spread of these viruses to humans.
Publications
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Replenishment of Hepatitis B Virus cccDNA Pool Is Restricted by Baseline Expression of Host Restriction Factors In Vitro. Microorganisms, 7(11), 533.
Brezgin, Sergey; Kostyusheva, Anastasiia; Bayurova, Ekaterina; Gordeychuk, Ilya; Isaguliants, Maria; Goptar, Irina; Nikiforova, Anastasiia; Smirnov, Valery; Volchkova, Elena; Glebe, Dieter; Kostyushev, Dmitry & Chulanov, Vladimir
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Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification. Emerging Microbes & Infections, 10(1), 2264-2275.
Kostyusheva, Anastasiya; Brezgin, Sergey; Glebe, Dieter; Kostyushev, Dmitry & Chulanov, Vladimir
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Immunity and Viral Infections: Modulating Antiviral Response via CRISPR–Cas Systems. Viruses, 13(7), 1373.
Brezgin, Sergey; Kostyusheva, Anastasiya; Bayurova, Ekaterina; Volchkova, Elena; Gegechkori, Vladimir; Gordeychuk, Ilya; Glebe, Dieter; Kostyushev, Dmitry & Chulanov, Vladimir
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CRISPR-Cas systems for diagnosing infectious diseases. Methods, 203, 431-446.
Kostyusheva, Anastasiya; Brezgin, Sergey; Babin, Yurii; Vasilyeva, Irina; Glebe, Dieter; Kostyushev, Dmitry & Chulanov, Vladimir
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IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection. Viruses, 14(4), 727.
Palatini, Massimo; Müller, Simon Franz; Kirstgen, Michael; Leiting, Silke; Lehmann, Felix; Soppa, Lena; Goldmann, Nora; Müller, Christin; Lowjaga, Kira Alessandra Alicia Theresa; Alber, Jörg; Ciarimboli, Giuliano; Ziebuhr, John; Glebe, Dieter & Geyer, Joachim
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Comparative analysis of human, rodent and snake deltavirus replication. PLOS Pathogens, 20(3), e1012060.
Khalfi, Pierre; Denis, Zoé; McKellar, Joe; Merolla, Giovanni; Chavey, Carine; Ursic-Bedoya, José; Soppa, Lena; Szirovicza, Leonora; Hetzel, Udo; Dufourt, Jeremy; Leyrat, Cedric; Goldmann, Nora; Goto, Kaku; Verrier, Eloi; Baumert, Thomas F.; Glebe, Dieter; Courgnaud, Valérie; Gregoire, Damien; Hepojoki, Jussi & Majzoub, Karim
