University of Nebraska - Lincoln
School of Biological Sciences
Nebraska Center for Virology
238 Morrison Center
Lincoln, NE 68583-0900
Phone - 402.472.5905
Fax - 402.472.3323
Publications and Research Interests
Epstein-Barr virus (EBV) is a human herpesvirus of increasing medical importance. EBV infection has been associated with the development of several human cancers. In immunocompromised individuals, such as organ transplant recipients or AIDS patients, EBV almost certainly causes two fatal cancers: post-transplantation lymphoproliferative disorder (PTLD) and AIDS-associated central nerve system (CNS) lymphoma. Other than cancers, EBV is associated with other autoimmune diseases such as systemic lupus erythematosus (SLE, or lupus) as well as multiple sclerosis (MS). Our main interests are the host-herpesvirus interactions, and our research will be a blend of virology, molecular and cellular biology, immunology, and pathology. The major focuses are:
1) The functions and regulations of IRFs in EBV transformation. Interferon regulatory factors (IRFs) are a small family of transcriptional factors with multiple functions including but not limited to host defense, oncogenesis, apoptosis, viral latency, as well as immune responses. Dr. Zhang was the first to discover the interferon regulatory factor 7 (IRF-7), to identify the first functional interferon stimulated response element (ISRE) in a mammalian viral promoter, and to unearth a novel signal pathway related to IRF7 and EBV latency and transformation. EBV transforms human primary B cells in tissue culture and establishes latency. We are taking both genetic and biochemical manipulations to dissect the involvement of cellular factors and signaling pathways in the regulation of IRFs and their roles in EBV-mediated oncogenesis.
2) Interaction between host immunity and herpesvirus. The host immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. IRFs play critical roles in host immunity against virus, and at the same time, the viruses have a variety of mechanisms to alleviate adverse effects of the host immune system. EBV and another herpesvirus (Kaposi's sarcoma-associated herpesvirus, KSHV, also called human herpesvirus 8, HHV8), have intrinsic relations with host immune system. Furthermore, EBV is closely associated with autoimmune diseases such as lupus and multiple sclerosis. We are studying the relation among herpesvirus, immunity, and IRFs for their roles in viral replication, pathogenesis in cancer and autoimmune diseases.
3) Genetic modification and personalize human induced pluripotent stem cells. Human Induced pluripotent stem cells (hiPSC) have enormous experimental, diagnostic and therapeutic potential. The iPSC technology eliminates the ethical concerns attached to embryonic stem cells and is able to provide person- and patient-specific PSCs. However, there are many unresolved questions related to the iPSC technology. These include the target cell types, the choice of factors to reprogram cells, as well as the methods to deliver and/or remove these factors. We are interested in generating a personalized hiPSC genetic system for modification of hiPSC for wide variety of applications.
Selected Recent Publications
Florencia Meyer, Erica Ehlers, Andrew Steadman, Thomas Waterbury, Mingxia Cao, and Luwen Zhang, TLR-TRIF pathway enhances the expression of KSHV replication and transcription activator. J Biol Chem. 2013 Jul 12;288(28):20435-42.
Xu, D, Erica Ehlers, Andrew Steadman, and Luwen Zhang, CD20 antibody enhances cells for type I interferon productions. PLoS ONE 8(6): e67900. doi:10.1371/journal.pone.0067900. 2013
Valente RM, Ehlers E, Xu D, Ahmad H, Steadman A, Blasnitz L, Zhou Y, Meng B, Zhang L. Toll-Like Receptor 7 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1. PLoS ONE 7(8): e43317. doi:10.1371/journal.pone.0043317. 2012
Ahmad, H, R. Gubbels, E. Ehlers, F. Meyer, T. Waterbury, R. Lin, and L. Zhang. Kaposi’s sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta interferon (TRIF). J Biol Chem. 286:7865-72. . 2011
Xu D, Meyer F, Ehlers E, Blasnitz L, Zhang L. Interferon Regulatory Factor 4 (IRF-4) Targets IRF-5 to Regulate Epstein-Barr Virus Transformation. J Biol Chem. 286:18261-7. 2011.
Xu, D., Zhao, L., Del Valle, L., Miklossy, J., and Zhang, L. Interferon regulatory factors 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol. 82:6251-8. 2008.
Jiang, Y., D. Xu, Y. Zhao, and L. Zhang. Mutual Inhibition between Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Lytic Replication Initiators in Dually-Infected Primary Effusion Lymphoma. PLoS One. 3:e1569. 2008.
Xu, D., Zhao, L., Del Valle, L., Miklossy, J., and L. Zhang. Interferon regulatory factors 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol. 82:6251-8. 2008.
Xu, D., J. Zhang, T. Coleman, A. Fagot, C. Kotalik, L. Zhao, P. Trevidi, C. Jones, and L. Zhang. Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication In Primary Effusion Lymphomas. J. Virol. 81(11):6068-78. 2007.
Xu D, K. Brumm, L. Zhang. The latent membrane protein 1 of Epstein-Barr virus primes EBV latency cells for type I interferon production. J Biol Chem. 281: 9163-9169. 2006.
Zhang, J., J. Wang, C. Wood, and L. Zhang. KSHV/HHV-8 replication and transcription activator (RTA) regulates both viral and cellular genes via interferon-stimulated response elements. J Virol. 79: 5640-52. 2005.
Wang J, J. Zhang, L. Zhang, Harrington W Jr, West JT, Wood C. Modulation of Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Activator Transactivation by Interferon Regulatory Factor 7. J Virol. 79:2420-31. 2005.
Zhang, J., S. Das, C. Kotalik,, A. Pattnaik, and L. Zhang. The latent membrane protein 1 of Epstein-Barr virus establishes an antiviral state via induction of interferon-stimulated genes. J Biol Chem. 279:46335-46342. 2004c.
Zhang, L., J. Zhang, Q. Lambert, C. J. Der, L. Del Valle, J. Miklossy, K. Khalili, Y. Zhou,and J. S. Pagano. Interferon regulatory factor 7 is associated with EBV-transformed CNS lymphoma and has oncogenic properties. J. Virol. 12987-12995. 2004b.
Zhang, L. ,K. Hong, J. Zhang, and J. S. Pagano. Multiple signal transducers and activators of transcription (STATs) are induced by EBV LMP-1. Virology. 323:141-152. 2004a.
Zhang, L. and J.S. Pagano. Structure and Function of Interferon Regulatory Factor 7. J. Interferon Cytokine Res. 22: 95-101. 2002a.
Zhang, L., L. Wu, K. Hong, and J.S. Pagano. Intracellular signaling molecules activated by Epstein Barr virus for induction of interferon regulatory factor 7. J. Virol. 75:12393-401. 2001.
Zhang, L. and J.S. Pagano. Interferon Regulatory Factor 7: a Key Cellular Mediator of LMP-1 in EBV Latency and Transformation. Seminars in Cancer Biology 11:445-53. 2001.
University of Kansas Medical Center,
PhD, Biochemistry and Molecular Biology
Shandong Agricultural University,
Assistant Professor, School of Biological Sciences, NE Center for Virology, University of Nebraksa - Lincoln
Research Assistant Professor, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Research Associate, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Postdoctoral Fellow, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Honors and Special Scientific Recognition:
April, 1995 Recipient of Postdoctoral Fellowship Award by the National Institute of Health
March, 1994 Recipient of Lineberger Fellowship Award by the Lineberger Comprehensive Cancer Center of the University of North Carolina at Chapel Hill.
March, 1993 Honors for Ph.D. dissertation, by the graduate school of the University of Kansas Medical Center at Kansas City