As a virologist, I apply state-of-art multidisciplinary technology to understand mechanisms of virus replication, transmission and host immune responses against virus infection. During my Ph.D. training in Dr. Ronald Montelaro’s lab at University of Pittsburgh, I was the first to apply a bi-molecular fluorescence complementation assay to study virus-host interactions and virus assembly for retroviruses, influenza virus and hepatitis C virus. By comparing different retrovirus assembly/budding pathways, I found HIV Gag membrane targeting and assembly was regulated as early as viral mRNA nuclear export. After graduation I joined Dr. Walther Mothes’ lab at Yale University to study virus cell-to-cell transmission. I first demonstrated polarized de novo assembly/budding of MLV at the cell-cell contact sites using 4-D live-cell imaging technique. I also recorded surfacing of released MLV virus particles at the infected cell surface. These studies contribute to the virus cell-to-cell transmission research that is currently under active study.
After joining Vitalant Research Institute (previously named as Blood Systems Research Institute), I started to study anti-viral mechanisms of neutralizing antibodies (NAbs) against the emerging alphavirus, chikungunya virus (CHIKV). Leading collaborations with several laboratories in various fields including cryo-electron microscopy (cryoEM), antibody isolation, viral evolution, etc., I made discoveries of novel antiviral mechanisms for NAbs against CHIKV: a) Through crosslinking multiple domains of neighboring envelope glycoproteins (GPs) on virion, NAbs inhibit virus entry by preventing domain movement required for fusion loop activation; b) Through crosslinking GPs expressed on the surface of CHIKV-infected cells, NAbs inhibit virus budding by disrupting organization of GPs required for enwrapping the membrane around nucleocapsids; c) Through coalescence of GPs into dense patches of GP-NAb immune complexes on the surface of infected cells, NAbs potently activate ADCC from immune effector cells via engaging FcRs by dense Fc. This model of “triply functional” antiviral mechanisms for ultra-potent human NAbs was published as a cover story on Cell Host & Microbe and recommended by F1000Prime. Guided by virus cryoEM structure, I also developed chimeric CHIKV carrying dense foreign antigens in repetitive pattern and demonstrated its superior immunogenicity in animal models, suggesting that chimeric alphavirus may be an excellent vaccine platform.
My current research focuses on two projects: a) understanding the mechanisms for NAbs to protect the host from CHIKV infection. I will apply antibody-engineering technique to disrupt specific antiviral mechanism of NAbs and therefore dissect different antiviral mechanisms both in vitro and in vivo. These studies will guide the design and optimization of ultra-potent therapeutic antibodies. b) Understanding the molecular mechanism for icosahedral virus assembly/budding and host-pathogen interactions in situ by cellular cryo-electron tomography (cryoET).