Dr. Yuan has long been committed to study the mechanisms of viral infection, especially chronic HBV infection (CHB) and development of novel antiviral strategy. As there are still 250 million chronic HBV-infected patients in the world and no effective cures available, Dr. Yuan’s group has established new cccDNA detection technology, cell and animal models, elucidated the role and mechanism of HBV-encoded proteins in the chronic infection, and proposed new antiviral theories and schemes such as new subtype interferon and epigenetic regulation of HBV cccDNA etc., which lays an important foundation for the optimization of functional cure strategies for chronic hepatitis B. As one of the founding member of the ICE-HBV, Dr. Yuan has been dedicated to promote global collaboration in HBV cure, and has contributed a number of protocols of HBV cccDNA study to the society. To meet the challenges of emerging infectious diseases, Dr. Yuan has been actively involved in the building up Shanghai Municipal Public Health Center, a fortress-like medical and scientific research base. He established a Pathogen Detection Network for monitoring emerging infectious pathogens and diseases in Shanghai, and developed technical platforms for discovering new pathogens. His team led to identify the world’s first human infection with H7N9 avian-origin influenza virus, effectively helping to constrain the disease becoming a pandemic outbreak. He also led the first isolation of SARS-CoV-2 strain SH01 in East China area and construction of the first published non-infectious replicon system of SH01, which has been used for screening of antiviral drugs. He has published 150+ papers in internationally peer-reviewed journals such as Science, NEJM, Lancet, Nat Immunol, JCI, JEM, Hepatology, JVI and PLoS Pathog etc., and filed more than 10 patent applications.
In the past twenty years, Dr. Yuan has trained more than 60 graduate students. He is extremely responsive to student’s needs, always gives timely feedback and constantly serves as a role model for trainees. In 2019, as nominated by graduates of the Shanghai Medical School of Fudan University, Dr. Yuan received the award of “Outstanding Mentor in the Minds of Graduate Students”. Besides, he always encourages and promotes his postdoctoral fellows and junior researchers to lead research projects, manuscript writing, progress reporting, and grant applications towards their independent careers. Several of his previous graduates and postdoctoral fellows are now recognized experts in their respective fields.
As the director of the Virology Society of the Chinese Society for Microbiology and the chairman of the Shanghai Microbiology Society, he organized the annual meeting of the National Virology Society to promote exchanges from different fields; established a committee of young virologists to cultivate and improve the scientific research level of young virologists. He also organized science popularization and publicity to improve public awareness of SARS-CoV-2 and the epidemic. As the leader of the expert group, he actively made suggestions and urged the government to strengthen scientific research on SARS-CoV-2.
Professional services
Dr. Yuan served as the president of the Chinese Medical Virology Society, leading the organization of the annual meeting of the National Virology Society to promote exchanges from different fields; established a committee of young virologists to cultivate and improve the scientific research level of young virologists.
In 2012 and 2013, as the secretary-general and the conference organizer in Shanghai, he successfully organized the 14th International Conference on Viral Hepatitis and Liver Disease, and the International Conference on Molecular Biology of Hepatitis B Virus held in Shanghai, with 1500 and 500 conference attendants, respectively, expanding the exchange of scientists between China and other countries in the world. In 2006, a global initiative dedicated to an HBV cure, the International Coalition to Eliminate Hepatitis B (ICE-HBV) was established. As one of the founding member of the ICE-HBV, Dr. Yuan has been dedicated to promote global collaboration in HBV cure, and has contributed a number of protocols of HBV cccDNA study to the society.
As the current director of the Virology Society of the Chinese Society for Microbiology and the chairman of the Shanghai Microbiology Society, he has actively organized science popularization and publicity to improve public awareness of the COVID-19 pandemic. As the leader of the expert group, he actively made suggestions and urged the government to strengthen scientific research on SARS-CoV-2.
As the leader of the Fudan University Expert Group on the Prevention and Control of COVID-19 pandemic, he organized the scientific formulation of response plans to ensure the smooth, orderly and safe campus and ensure that the study and life of all teachers and students are basically normal. He has coordinated the operation of Biosafety Level 3 (BSL-3) Laboratories to carry out research on the pathogenesis and replication mechanism of SARS-CoV-2 and development of antiviral drugs and vaccines.
Dr. Yuan serves as the associate editor for Emerging Microbes and Infections and also editorial board member for several other journals. He has served as ad hoc reviewer for academic journals, including Hepatology, Plos Pathogens, and Cell Research etc. In addition, he served as an ad hoc reviewer for the National Nature Science Foundation of China (NSFC), Hong Kong Research Grant Council (RGC), and the Agency for Science, Technology and Research (A*STAR) of Singapore, etc.
Significant accomplishments
In-depth study on HBV cccDNA
HBV cccDNA is a key factor involved in HBV persistence and the failure of chronic hepatitis B cure. Dr. Yuan detected intrahepatic cccDNA using FISH and ISH, resolving molecular snapshots related with HBV subcellular activities (PLoS Pathog 2021, mBio 2023), uncovering a “mosaic” distribution pattern of HBV nucleic acids and antigens in human livers (JCI 2016, featured), and providing new virological insights into the HBV life cycle. He developed novel model systems of cccDNA: 1) long-term in vitro maintenance of primary human hepatocytes supporting infection and replication of HBV and HCV (Science 2019; Microbiol Spectr 2021). 2) novel cccDNA cell and mouse model combining the Cre/loxP-mediated recombination and AAV vector delivery strategy (Antiviral Res 2018, 2020). He revealed role of the epigenetic machinery in regulating the activity (Hepatology 2017) and stability (Hepatology 2022, featured) of HBV cccDNA and conceptually designed and tested strategy targeting cccDNA using genome editing tools (Mol Ther 2014), opening the possibility for developing novel anti-HBV strategies.
Interaction between HBV and interferon innate immune response
Type I IFN and innate immune responses can be activated by virus infection and play an important role in antiviral immunity; however, HBV infection induces little IFN and the response to IFN-α treatment is low. He clarified the mechanisms of viral load-dependent HBV antagonism, including induction of the expansion of mMDSCs by HBsAg, promoting specific CD8+ tolerance (J Immunol 2013, 2015; JEM 2022), HBV spliced proteins as inhibitors of RIG-I/TLR3/STING-mediated pattern recognition (J Gen Virol 2010; JVI 2015) and the IFN-JAK-STAT signaling in hepatocytes (Hepatology 2013; Sci Rep 2015). He further found that IFN-α induced non-parenchymal liver cells to release exosomes loaded with antiviral molecules (Nat Immunol 2013, featured; JVI 2018) and screened for IFN-alpha subtype with the highest anti-HBV potency, revealing that concerted IFN-alpha and IFN-gamma responses in liver are associated with potent HBV suppression (Hepatology 2021, featured). He generated gene knock-in mice with extracellular-humanized IFNAR1/2 (IFNAR-hEC) useful for elucidating antiviral and immunomodulatory functions of human IFN-Is and conducting preclinical studies(Emerg Microbes Infect. 2023). He developed Chimeric antigen receptors of HBV envelope proteins to inhibit hepatitis B surface antigen secretion(Gut 2023).These studies deepen the understanding of the interaction between HBV and IFN, with implications for improved IFN therapy and HBV curative strategies.
Identification of world’s first human infection with avian-origin H7N9 IAV and isolation of the first SARS-CoV-2 strain (SH01) in East China area, providing the first non-infectious replicon system of SH01 to Gilead Sciences for screening antiviral drugs
Dr. Yuan established a pathogen detection network for emerging infectious diseases in Shanghai, and developed technical platforms for discovering new pathogens. He and his team identified world’s first human infection with H7N9 avian influenza virus (NEJM 2013) and drug-resistance mutation (Lancet 2013). He also led the first isolation of SARS-CoV-2 strain SH01 in East China area and construction of the first published non-infectious replicon system of SH01 (Antiviral Res 2021), which was non-exclusively licensed to Gilead Sciences for screening of antiviral drugs.
Because of his research achievements, he and his team have won the Natural Science Award of the Ministry of Education, the Shanghai Natural Science Award, and the National Science and Technology Special Prize.