Shunbin Ning, Ph.D.
Assistant Professor of Medicine
Description of Research
Dr. Ning is interested in the interaction between the tumor virus Epstein-Barr Virus (EBV/HHV4) and the host innate immune system. Interferon (IFN) Regulatory Factors (IRFs), a small family of transcription factors, play important roles in many cellular processes such as innate immune responses and apoptosis. Of special interest, several IRFs, including the three oncogenic IRFs, IRF7, -2, and -4, as well as IRF5, are intimately associated with EBV latency, which is associated with a large spectrum of lymphomas and carcinomas. Dysregulation of EBV-specific immune responses is not only important for EBV latency and oncogenesis, but also a characteristic of EBV-associated autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).
- Regulation and function of IRF7 in innate immunity and EBV latency:
IRF7 is induced and activated upon pathogen infections, and together with IRF3, are the key transcriptional regulators of type I IFNs. Intriguingly, IRF7 is also induced and activated by the EBV principal oncoprotein, LMP1, a member of the TNF receptor (TNFR) superfamily. However, regulation of IRF7 activity and its function in the EBV context are largely unclear. Dr. Ning taking high-throughput strategies to identify IRF7-interacting regulators and transcriptional targets from EBV-infected B lymphocytes. This study is important to uncover the roles of IRF7 in both EBV latency/oncogenesis and IFN regulation in innate immune responses. Importantly, Dr. Ning has identified miR-155, one of the few well studied miRNAs that is known to be involved in both innate immunity and tumorigenesis, as a transcriptional target for IRF7 and -4 in EBV- and HTLV1-infected cells.
- Evasion of innate immune responses by EBV:
EBV has been a model for studying host-virus interactions. Like other herpesviruses, EBV establishes life-long persistent infections in their hosts. To achieve this, EBV has evolved much more elaborate and sophisticated strategies such as invoking the host ubiquitination-proteasome system to evade host immune responses compared to another gamma herpesvirus, KSHV/HHV8, which encodes a larger volume of proteins for this purpose. The first focus is to understand how EBV evades IRF7-mediated IFN responses but retains its oncogenic activity in its latency programs.
- EBV latency and oncogenesis:
As the first identified oncovirus, EBV has been established as a model for the study of virus-associated cancers. EBV latent genes are essential as primary contributors to oncogenesis. Regulation of host cell function by the latent genes is important for EBV oncogenesis. EBV latency states are captured in cell lines, which are a useful surrogate for this study.
Dr. Ning's studies will employ innovative approaches and strategies of Cell Biology, Immunology, Molecular Biology, and Virology to investigate the molecular events and signaling pathways underlying host-pathogen interaction in EBV-associated malignancies. The long-term goal of these studies is to identify molecular targets for EBV immunotherapeutic and antiviral therapeutic applications.
- LMP1, the principal oncoprotein of EBV, is transcriptionally induced by IRF7
- IRF5 and A20, both expressed at high levels in EBV latency 3, negatively regulate LMP1-stimulated IRF7 activity through distinct mechanisms
- IRF7 is activated by LMP1 through a TRAF6 and RIP1-mediated ubiquitination pathway
- BIC, the gene encoding miR-155, has been identified as the first miRNA-encoding gene for IRFs, and their interaction may be important for viral transformation.
Selected Cancer-Related Publications
- Wang L, Toomey NL, Diaz LA, Walker G, Ramos JC, Barber GN, Ning S. Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression. J Virol 85:8328-37, 2011. Read more »
- Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function. Genes Immun 12:399-414, 2011. Read more »
- Ning S, Pagano JS. The A20 Deubiquitinase Activity Negatively Regulates LMP1 Activation of IRF7. J Virol 84:6130-8, 2010. Read more »
- Whitehurst C, Ning S, Bentz G, Dufour F, Gershburg E, Shackelford J, Langelier Y, Pagano J. The EBV deubiquitinating enzyme, BPLF1, reduces EBV ribonucleotide reductase activity. J Virol 83(9): 4345-4353, 2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):