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Identification of Epstein-Barr Virus (EBV) lytic products involved in B cell-mediated immune evasion

Grant number: 19/03804-0
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2020
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Deilson Elgui de Oliveira
Grantee:Brunno Felipe Ramos Caetano
Supervisor: Benjamin Gewurz
Host Institution: Instituto de Biotecnologia (IBTEC). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Research place: Harvard University, Boston, United States  
Associated to the scholarship:17/20352-0 - Assessment of Epstein-Barr virus miR-BARTs effects on in vitro properties of human-derived lymphomas and the expression of cell signaling pathways involved in lymphomagenesis, BP.DR


The Epstein-Barr virus (EBV), formally designated human herpesvirus 4 (HHV-4) - is a ubiquitous virus that causes lifelong latent infection in over 90% of the world's human adult population. EBV infection is regarded as carcinogenic to humans and associated with a variety of human cancers, especially endemic Burkitt Lymphoma (BL) and nasopharyngeal carcinomas (NPC). Following primary infection, EBV transiently runs a short lytic program before it establishes a predominant latent infection. Although the EBV oncogenic effects are mostly regarded to viral latency products, the viral lytic cycle plays pivotal roles in the development and maintenance of EBV-associated cancers, but its mechanisms remain largely elusive. EBV early lytic factors were found to target cell-surface and intracellular B-cell receptor (BCR) for ubiquitination and subsequently proteasomal degradation. Therefore, this study aims to investigate whether the expression of BZLF1 or BRLF1 early immediate genes by EBV impact the expression and/or activity of the B-cell receptor complex (BCR). EBV mutants lacking BZLF1 or BRLF1 early immediate genes will be produced by CRISPR/Cas9-mediated knockout in P3HR1 BL cell line. Changes in the levels of BCR and other associated proteins will be assessed by immunoblots. Once BCR downregulation is observed, phenotype rescue experiments will be performed by ectopic expression of either BZLF1 and BRFL1 early immediate genes in EBV-negative BL cell line BJAB. The data obtained will contribute to better understanding of possible EBV-mediated immunoevasion mechanisms during lytic reactivation and its implications for the pathogenesis of EBV-associated lymphomas. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAETANO, BRUNNO FELIPE R.; JORGE, BEATRICE ADRIANNE S.; MUELLER-COAN, BARBARA GRASIELE; DE OLIVEIRA, DEILSON ELGUI. Epstein-Barr virus microRNAs in the pathogenesis of human cancers. Cancer Letters, v. 499, p. 14-23, . (19/05061-4, 17/20352-0, 17/22312-5, 19/03804-0, 18/12164-1)

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