Chronic Hepatitis B virus infections affect about 350 million people worldwide and constitute a significant risk factor for fibrosis and hepatocellular carcinoma (HCC). HBV alters mitochondrial dynamics. HBV has been shown to induce autophagy of mitochondria (Mitophagy) as evidenced by Parkin translocation to mitochondria. We propose to investigate a possible link between mitochondrial dynamics induced by HBV and innate immunity. HBV cripples host innate immunity to maintain chronic persistent infection. Here, we propose to investigate the molecular mechanisms of HBV- induced suppression of innate immune signaling from mitochondrial platform. The key player in this process is a mitochondrial antiviral signaling protein (MAVS). There is sufficient supporting information, which shows that Parkin, an E3 ubiquitin ligase, interacts with MAVS on the mitochondria and that Parkin causes the ubiquitination of MAVS. These investigations will elucidate how MAVS is targeted by Parkin in a supracomplex and affects downstream antiviral signaling of interferon synthesis. These interactions and ubiquitinations eventually cripple innate immunity. These studies will provide unique insights into molecular mechanisms of HBV-induced mitochondrial dynamics and its effects on altering host innate immune response and open new avenues of investigations in the elucidation of innate immune pathways.

Public Health Relevance

Chronic Hepatitis B virus infections affect about 350 million people worldwide and are a major risk factor for fibrosis and hepatocellular carcinoma (HCC). This proposal focuses on the role of HBV in altering the mitochondrial dynamics and its impact on host innate immunity leading to chronic liver injury associated with HBV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI125350-03
Application #
9696767
Study Section
Virology - B Study Section (VIRB)
Program Officer
Koshy, Rajen
Project Start
2017-06-23
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kim, Seong-Jun; Ahn, Dae-Gyun; Syed, Gulam H et al. (2018) The essential role of mitochondrial dynamics in antiviral immunity. Mitochondrion 41:21-27