Virology Faculty Member - Joyce Fingeroth

Joyce Fingeroth

Associate Professor of Medicine

Beth Israel Deaconess Medical Ctr.
CLS, 445
330 Brookline Ave.
Boston, MA 2115
Tel: 617-735-2056
Fax: 617-975-5240
Email: jfingero@caregroup.harvard.edu



Our laboratory studies the entry of gammaherpesviruses into cells. The Epstein-Barr virus (EBV) receptor is a 140 Mr glycoprotein expressed on human B-lymphocytes, follicular dendritic cells (FDCs), some T lymphocytes, epithelial and smooth muscle cells and occasionally other cell types. It is the major (high affinity) cellular attachment protein for EBV. The spectrum of EBV-related neoplasms reflects the cellular distribution of this protein. The EBVR is also the receptor for the C3d fragment of complement component C3 (complement receptor type 2, CD2), for CD23, for alpha interferon and possibly for additional proteins. On human B-lymphocytes CD21 transduces a signal that amplifies proliferation induced by the B-cell receptor and prevents apoptosis. On B cells, CD21 participates in ligand internalization whereas on FDCs CD21 tethers complement coated pathogens (including HIV) to the cell surface. The structural biology of the CD21 interaction with its viral ligand, EBV gp350 and with cellular ligands is unknown. In addition, the nature of receptor signaling and cytoskeletal interaction in different cells - events that may contribute to the efficiency of EBV transformation, is not well understood. The function of CD21 is studied using the tools of molecular biology, protein biochemistry, x-ray crystallography and cellular immunology to relate the regulation and structure of the molecule to its function as a virus receptor.

Additional work has included investigation of early events important for establishment of KSHV infection.

Other studies in the laboratory address the relationship of EBV infection to the development of virus-associated malignancies. Viral gene regulation of lymphocyte differentiation- associated genes, RAG-1, RAG-2 was demonstrated showing that in addition to inducing proliferation, EBV genes regulate maturation associated proteins and may cause dysregulation of VDJ or other recombination processes that predispose to development of chromosomal translocations as is observed in EBV+ Burkitt's lymphoma.

Translational studies in the laboratory have focused on characterizing the expression, localization and substrate specificity of the EBV and KSHV) (HHV-8) thymidine kinase proteins as targets for antiviral and also anti-tumor therapy. The goal is to induce in vivo EBV/KSHV genes that are capable of killing virus-infected tumor cells upon activation of thymidine analog pro-drugs and/or other novel nucleoside antivirals, decreasing dependence on more toxic chemotherapy. Characterization of these proteins has revealed that they are not classical TKs, but likely play additional roles in virus biology. The localization of EBVTK to the centrosome in unique among herpesviruses and suggests it may function in virus entry/egress, in regulation of the lytic cell cycle or may contribute to the development of aneuploidy, as seen in EBV-associated Hodgkins disease.













Last Update: 10/22/2013



Publications

Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT. The EBV receptor of human B lymphocytes is the C3d Receptor (CR2). PNAS 1984; 81:4510.

Fingeroth JD. Comparative Structure and Evolution of Murine CR2: The Homolog of the human C3d/EBV receptor (CD21). J. Immunol 1990; 144:3458.

Kuhn-Hallek I, Sage DR, Stein L, Groelle H, Fingeroth JD. Expression of Recombination Activating Genes (RAG-1 and RAG-2) in EBV-bearing B cells. Blood 1995; 85:1289.

Gustafson E, Chillemi A, Sage D, Fingeroth JD. The EBV thymidine kinase does not phosphorylate ganciclovir or acyclovir and demonstrates a narrow substrate specificity compared to the HSV Type 1 thymidine kinase. AAC 1998; 42:2923.

Gustafson E., Schinazi, R and J.D. Fingeroth. HHV8 ORF 21 encodes a thymidine and thymidylate kinase of narrow substrate specificity that efficiently phosphorylates AZT but not Ganciclovir. J Virol 2000; 74:684.

Dezube B.J, Zambela, M, Sage, DR, Wang, JF, and JD Fingeroth. Characterization of HHV-8 Infection of Human Vascular Endothelial Cells: Early Events. Blood 2002; 100:888.

Prota A E, Sage D.R., Stehle T.S. and Fingeroth JD. The Crystal Structure of Human CD21: Implications for EBV and C3d binding. PNAS 2002; 99:10641.

Gill M.B., Roecklein-Canfield J, Sage DR, Zambela-Soediono M, Longtine JA, Uknis M, and Fingeroth JD. EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: Formininteractions with the cytoplasmic domain of human CD21. J Cell Sci 2004; 117:2709.

Hong Y-K., Foreman K, Hirakawa S, Shin J, Nguyen L, Sage DR, Dezube BJ, Fingeroth JD and M Detmar. Lymphatic re-programming of vascular endothelium by Kaposi's sarcoma-associated herpesvirus. Nat Genet 2004; 36:683.

Zhang X, Wang JF, Chandran B, Persaud K, Pytowski B, Fingeroth J, Groopman J. KSHV Activation of VEGFR-3 Alters Endothelial Function and Enhances Infection, J Biol Chem 2005; 280:26216.

Gill MB, Kutok JL, Fingeroth JD. EBVTK is a centrosomal resident precisely localized to the periphery of centrioles. J Virol 2007; 81:6523.



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