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  Viral hepatitis (Jin ZHONG)

The main research interests


We are mainly focusing on research on the functions and mechanisms of structural or non-structural viral proteins and the anti-viral activity of some key host factors during virus infection. We use influenza A virus and HCV as viral models to study the mechanism between the interplay of the virus and the host. We use coronavirus and EV71 as viral models to study the viral ion channels and the contribution of channel activity to virus release. Besides, viral ion channels and viral polymerase are selected as the drug targets to screen anti-viral drugs.


Part 1 Study on viral ion-channel proteins

Homologous viral ion-channel proteins in coronavirus

Besides our first identification of viral ion-channel protein in SARS-CoV (Proc Natl Acad Sci, 2006, 103:12540-12545.), we further find that many human coronaviruses including HCoV-229E of Class I, HCoV-OC43 of Class II and SARS-CoV Class IIb all encode homologous viroporins, ORF3a, which function as an ion channel. The viroporins may further activate voltage dependent L-type calcium channel indirectly, and a drug against calcium channel Nimodipine (ND) is able to inhibit plaque formation and virus release (unpublished data). In swine coronavirus, we also found that ORF3 in PEDV (Porcine Epidemic Diarrhea Virus) presents an ion channel property, and may contribute to virus release (FEBS Letters. 2012, 586, 4 : 384–391). Further molecular mechanism study in how these viral ion-channel proteins regulate virus release will be important for viral ion-channel based drug development.

Viral ion-channel proteins in other important pathogens

More importantly, our viroporin reseasch has extend to the newly epidemic human virus EV71(Enterovirus 71) circulating in children in Asia-pacific region. We find that EV71 2B protein induces a chloride current when it is expressed in Xenopus oocytes. A chloride channel inhibitor, DIDS, reduces virus-induced cytopathic effect and virus particles release in RD cells. These data suggest that 2B protein may play an important role in the virus production and is a potential anti-viral drug target (Fig.1, Cell Research, 2011, 1-5.).


Fig1. (A) Raw current of 2B-HA expressed oocytes. (B, C) I-V curve. (D). The error bars of three independent experiments. A plaque assay (E), CPE (F), TCID50 (G) in RD cells infected with EV71 virus were performed in cells treated with or without DIDS.


Part 2 Interplay of influenza A virus and the host systems

Influenza A virus is highly variable and a major viral respiratory pathogen that can cause severe illness in human. The non-structural protein 1 (NS1 protein) and polymerase complex are two major factors for efficient infection rate and high virulence of influenza A virus. They are also the main viral components extensively interact with the host systems in virus-host interplay.

Host SUMOylation modification under influenza A infection

We find that NS1 of a highly pathogenic avian influenza H5N1 virus interacts with human Ubc9 and is SUMOylated in transfected and infected cells at its C-terminus. SUMOylation enhances NS1 stability and thus promotes rapid growth of influenza A virus. Studies on different influenza A virus strains of human and avian origins showed that the majority of viruses possess a NS1 protein that is modified by SUMO1, except for the recently emerged swine-origin influenza A virus (S-OIV) H1N1. (Fig.2, Journal of Virology, 2011, Jan. 85(2):1086–98). The SUMOylation of other influenza viral proteins and host proteins are also changed post infection, and are under identification.

Arrest of host cell cycle by influenza A virus

Many viruses interact with the host cell division cycle to favor their own growth. We find that influenza A virus replication results in G0/G1 phase accumulation of infected cells to facilitate viral protein expression and progeny virus production. The G0/G1 phase cell cycle arrest is likely to be a common strategy since the effect was also observed in other strains such as H3N2, H9N2, PR8 H1N1 and pandemic swine H1N1 viruses (Fig.3, Journal of Virology, 2010, Dec; 84(24):12832-40) . Studying on the underlying mechanisms will help to discover new viral-host interactions and anti-viral drug development.

Contribution of polymerase to influenza A pathogenicity and anti-polymerase activity drug screen

A lysine (K) residue in PB2 627 results in high RNA polymerase activity and viral replication of influenza A virus in mammalian cells. When 627K is mutated to glutamine (E), polymerase activity is reduced and viral replication is restricted. We identified two the amino acids in avian influenza PB1 which has the complementary activity for PB2-627E (J Gen Virol. 2011; 93(Pt 3):531-40.). We are also establishing in vivo replicon system to screen anti-polymerase drugs.                        


Fig2. (A) SUMOylation of influenza A virus NS1 protein in infected A549 cells. (B) SUMOylation of NS1 in WT virus promotes rapid virus growth in early infection stage.


Fig3. G0/G1 phase accumulation induced by influenza A virus A/WSN/33 (H1N1) infection


Part 3 Development of efficient influenza vaccines

Influenza A virus is successful in evolution due to its antigenic variation, which appears in two forms: antigenic shift and antigenic drift. This epidemiological property may cause emergence of new epidemic and pandemic viruses every year, and influenza A vaccine needs to be updated annually. Nevertheless, some newly emerging influenza A virus is still able to escape the vaccine protection because of being excluded in the seasonal vaccine component. As a result, a universal influenza vaccine is urgently needed and is an inexorable trend for pandemics protection in the future.

We have developed an efficient DNA vaccine against influenza A virus, which expresses both HA and NP genes in a bi-promotor plasmid. This DNA vaccine is able to elicit both efficient humoral and cellular immune responses to homo- and hetero- subtypic viruses (Viral Immunol, 2011 Feb; 24(1):45-56). Currently, we are dedicating in develop high-yielding cell-based influenza A vaccine strain, and universal influenza A vaccines.


Part 4 Host innate immunity and virus infection

  Regulation of inflammasome and inflammation response by viral proteins

Inflammation is a very important anti-viral response in host innate immunity against virus infection. On one way, proper level of inflammation response is essential to efficiently activate adaptive immunity for virus clearance. On the other way, hyper-or dys inflammation will cause viral pneumonia in respiratory infection and lead to organ dysfunction. Therefore, the regulation and balance in inflammation response contribute to the outcome of an infection. In our lab, we are focusing on human respiratory viruses including influenza A virus and coronavirus to investigate the regulation of inflammation response and inflammasome by their viral proteins.

  Host restriction gene in innate immunity to counteract HCV infection

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease world widely. Many tipartite motif-containing (TRIM) family proteins have been identified to have anti-viral activity against a broad range of viruses. Our lab have identified  anti-viral and inflammation regulation activities of TRIM30Nature Immunology2008 Apr;9(4):369-77. Based on a cDNA microarray data (36,000 genes), protein-motif or domain analysis and available bioinformatics analysis, we have identified another TRIM family protein stimulated about 15.7-fold by IFNa and up-regulated during HCV infection in Huh-7 cells. Over-expression of this TRIM protein suppressed HCV replication.

  Type I IFN signal pathway and DC/macrophage response in infection

Type I IFNs produced very soon following viral infection are well studied cytokines with anti-viral and immune-modulating functions. We are dedicating to investigate the regulation of type I IFN and the regulation of DC/macrophage response by viral components and their contribution to pathogenicity.


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