HMS Virology

Virology Faculty Member - Benjamin Gewurz

Benjamin Gewurz

Assistant Professor of Medicine
Harvard Medical School, Brigham and Women's Hospital
Associate Head, Virology Program

Brigham and Women's Hospital
Channing Laboratory, Infectious Disease Lab
181 Longwood Ave.
Boston, MA 02115
Tel: 617-525-4282
Email: bgewurz@bwh.harvard.edu
Visit my lab page here.



OVERVIEW:
EBV is an oncogenic gamma-herpesvirus that persistently infects >95% of adults worldwide. EBV causes infectious mononucleosis and human cancers. ~200,000 cancers are attributable to EBV each year worldwide. Intriguingly, these include lymphomas with distinct viral genome expression patterns: Burkitt lymphoma, Hodgkin lymphoma, HIV-associated lymphomas, post-transplant lymphomas and immune-senescence-associated lymphomas. EBV is also associated with epithelial malignancies, including nasopharyngeal and gastric carcinomas.  Our research focuses on how EBV reprograms key lymphocyte growth, survival, metabolic and immune-evasion pathways to enable persistent host infection, with the long-term goal of identifying targets for therapeutic intervention.

EBV’s association with cancer is an outgrowth of its relationship with host cells. Upon infection of primary B lymphocytes, EBV enters a state of viral latency, but is hardly quiescent. Rather, the EBV Latency III program expresses two membrane proteins, six nuclear factors and microRNAs to transform resting B-lymphocytes into rapidly growing lymphoblasts. EBV-infected cells enter germinal centers, where the viral genome expression pattern switches to the Latency II program. In Latency II, the viral membrane proteins LMP1 and LMP2A mimic CD40 and B-cell receptor signaling, and the genome-tethering factor EBNA1 is the only viral nuclear protein expressed.  As B-cells differentiate into memory cells, EBV switches to the Latency I state, where EBNA1 is the only viral protein expressed. This restricted viral latency state evades immune-detection. Host and viral factors that reprogram EBV latency states are incompletely understood.

Viral lytic replication is necessary for persistent host infection and for transmission between hosts.  Plasma cell differentiation triggers EBV lytic reactivation through incompletely defined mechanisms.
Current research includes:

CRISPR/Cas9 analysis of the EBV host/pathogen relationship.  We are using CRISPR genetic analysis to perform genome-wide screens and focused studies of host factors that control key stages of the EBV lifecycle. These include investigation of EBV-induced host dependency factors that enable transformed B-cell growth and survival, that reprogram EBV latency states, and that control the latency/lytic switch. We are also using CRISPR to identify mechanisms by which EBV evades key immune pathways, including subversion of the PDL1/PD1 T-cell immune checkpoint.
We are using multiplexed tandem-mass spectrometry to identify how EBV remodels the B-cell proteome during lytic versus latent B-cell infection. We are interested in defining EBV rewires host metabolic pathways to support lytic replication versus B-cell growth transformation.

Rare primary immunodeficiencies highlight mechanisms that control EBV and result in markedly elevated EBV viral loads and B-cell cancers. We are using immunologic and whole exome approaches to identify and characterize novel primary human immunodeficiency syndromes that result in the inability to control EBV infection.



Last Update: 11/27/2017



Publications

Wang LW, Jiang S, Gewurz BE. (2017) Epstein-Barr Virus LMP1-Mediated Oncogenicity.
J Virol. 2017 Oct 13;91(21). pii: e01718-16.

Ersing I, Nobre L, Wang LW, Soday L, Ma Y, Paulo JA, Narita Y, Ashbaugh CW, Jiang C, Grayson NE, Kieff E, Gygi SP, Weekes MP, Gewurz BE. (2017) A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells. Cell Rep. 2017 May 16;19(7):1479-1493

Ma Y, Walsh MJ, Bernhardt K, Ashbaugh CW, Trudeau SJ, Ashbaugh IY, Jiang S, Jiang C, Zhao B, Root DE, Doench JG, Gewurz BE. (2017) CRISPR/Cas9 Screens Reveal Epstein-Barr Virus-Transformed B Cell Host Dependency Factors. Cell Host Microbe ; 21(5):

Minamitani T, Ma Y, Zhou H, Kida H, Tsai CY, Obana M, Okuzaki D, Fujio Y, Kumanogoh A, Zhao B, Kikutani H, Kieff E, Gewurz BE, Yasui T. (2017) Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. Proc Natl Acad Sci;114(18):4751-4756.

Ma, Y, Walsh, M, Bernhardt, K, Ashbaugh, CW, Trudeau, SJ, Ashbaugh, I, Jiang, S, Zhao, B, Root, DE,Doench, JG, and Gewurz, BE (2017). CRISPR/Cas9 Screens Reveal Epstein-Barr Virus Transformed B-Cell Host Dependency Factors. Cell Host & Microbe 21(5):580-591.

Ersing, I, Nobre, L, Wang, LW, Soday, L, Ma, Y, Paulo, JA, Ashbaugh, CW, Jiang, C, Grayson, NE, Kieff,E,Gygi, SP, Weekes, MP**, and Gewurz, BE**. (2017) A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B-cells. Cell Reports 19(7):1479-1493.

Minamatani, T, Ma, Y, Zhou, H, Kikutani, H, Zhao, B, Kieff**, E, Gewurz**, BE, Yasui**, T. (2017) A Mouse Model of Epstein-Barr virus LMP1 and LMP2A Driven Germinal Center B-cell Lymphoproliferative Disease.  Proc Natl Acad Sci USA, 114(18):4751-4756

Hunter, J.E., Butterworth, J.A., Zhao, B., Sellier, H., Campbell, K.J., Thomas, H.D., Bacon, C.M., Cockell, S.J., Gewurz, B.E. & Perkins, N.D. The NF-kappaB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma. Oncogene 35, 3476-3484 (2016).

Blondel, C.J., Park, J.S., Hubbard, T.P., Pacheco, A.R., Kuehl, C.J., Walsh, M.J., Davis, B.M., Gewurz, B.E., Doench, J.G. & Waldor, M.K. CRISPR/Cas9 Screens Reveal Requirements for Host Cell Sulfation and Fucosylation in Bacterial Type \III\ Secretion System-Mediated Cytotoxicity. Cell Host & Microbe 20, 226 - 237 (2016).

Minamitani, T, Yasui, T, Ma, Y, Zhou, H, Okuzaki, D, Tsai, CY, Sakakibara, S, Gewurz, BE, Kieff, E, Kikutani, H. (2015) Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A Proc Natl Acad Sci USA, 112(37):11612-7. 

Greenfeld, H, Takasaki, K, Walsh, M, Ersing, I, Bernhardt, K, Ma, Y, Fu, B, Mollo, SB, Zhou, H, Li, S, and Gewurz, BE. TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation. PLOS Pathogens 2015:11(5), e1004890.  

Hunter, JE, Butterworth, JA, Zhao, B, Sellier, H, Campbell, KJ, Thomas, HD, Bacon, CM, Cockell, SJ, Gewurz, BE, and Perkins, ND. The NF-kB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma. Oncogene 2015; 35(26):3476-84.

Zhou, H, Schmidt, SC, Jiang, S, Willox, B, Bernhardt, K, Liang, J, Johannsen, EC, Kharchenko, P, Gewurz, BE, Kieff, E, Zhao, B. Epstein-Barr Virus oncoprotein super-enhancers control B cell growth. Cell Host & Microbe 2015; 17(2):205-16.

Iannetti, A, Ledoux, AC, Tudhope, SJ, Sellier, H, Zhao, B, Mowla, S, Moore, A, Hummerich, H, Gewurz, BE, Cockell, SJ, Jat, PS, Willmore, E, Perkins, ND. (2014). Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence.  Plos Genetics, 10(9), e1004642.

Zhao, B, Barrera, LA, Ersing, I, Willox, B, Schmidt, SC, Greenfeld, H, Zhou, H, Mollo, SB, Shi, TT, Takasaki, K, Jiang, S, Cahir-McFarland, E, Kellis, M, Bulyk, ML, Kieff, E, Gewurz, BE. (2014). The NF-kB genomic landscape in lymphoblastoid B cells. Cell Reports, 8(5),1595-606. 

Zhou, X, Gewurz, BE, Ritchie, JM, Takasaki, K, Kieff, E, Davis, B, Waldor, MK. (2013). Distinct regions of a Vibrio parahaemolyticus type III effector mediate intestinal colonization vs. diarrhea and blockade of MAPK and NF-kB innate immune pathways. Cell Reports 3(5),1690-702

Gewurz, BE, Mar, JC, Padi, M, Zhao, B, Shinners, NP, Takasaki, K, Bedoya, E, Zou, J, Quackenbush, J, Kieff, E. (2011). Canonical NF-kB activation is essential for Epstein-Barr Virus Latent Membrane Protein 1 TES2/CTAR2 gene regulation. J. Virology, 85(13), 6764-73. 

Gewurz, BE, Towfic, F, Mar, JC, Shinners, NP, Takasaki, K, Zhao, B, Cahir-McFarland, E, Quackenbush, J, Xavier, R, and Kieff, E. (2012). Genome-wide siRNA screen for mediators of NF-kB activation. Proc Natl Acad Sci USA, 85(13), 6764-73. 



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