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 pivotal roles in many facets of host defense system such as innate immune response and apoptosis. Of special interest, several IRFs, including the three oncogenic IRFs, IRF7, -4, and -2, as well as IRF5, are intimately associated with EBV latent infection, 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).
1.Regulation and function of IRFs in innate immunity and EBV latency:
IRF7 is induced and activated upon pathogen infection, and together with IRF3, is the key transcriptional regulator of type I IFNs. IRF4 is a lymphocyte-specific factor which serves as an important prognosis and diagnosis marker for certain types of hematological malignancies. Intriguingly, expression of IRF4 and -7 is induced by EBV latent infection. However, their regulation and function in EBV oncogenesis are poorly understood. Dr. Ning takes high throughput strategies to profile global tyrosine phosphorylation associated with EBV latent infection, and to identify IRFs co-regulators and transcriptional targets. These studies are paramount to understand the interaction of IRFs with EBV latency/oncogenesis as well as the IFN regulation in innate immune response.
2.Evasion of innate immune response by EBV infection:
EBV has been a model for studying host-virus interaction. Like other herpesviruses, EBV establishes life-long persistent infection in its host. 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 response but retains its oncogenic activity in its latency programs.
3.EBV latency and oncogenesis:
As the first identified oncovirus, EBV has been established as a model for the study of viral oncogenesis. 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.
- IRF4 is activated through Src-mediated tyrosine phosphorylation in virus-transformed cells.
- 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 »
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):