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Open AccessArticle

The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases

1
Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada
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Beatrice Hunter Cancer Research Institute, 5850 College Street, Halifax, NS B3H 4R2, Canada
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CHEO Research Institute/Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada
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Department of Pediatrics, Dalhousie University, 5980 University Ave, Halifax, NS B3K 6R8, Canada
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Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
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Department of Radiation Oncology, 5820 University Ave, Halifax, NS B3H 1V7, Canada
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Department of Pathology, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(1), 12; https://doi.org/10.3390/v12010012
Received: 7 November 2019 / Revised: 17 December 2019 / Accepted: 18 December 2019 / Published: 20 December 2019
(This article belongs to the Special Issue Recent Advances in Herpesviruses Research: What's in the Pipeline?)
Kaposi’s sarcoma associated-herpesvirus (KSHV, also known as human herpesvirus-8) is a gammaherpesvirus that establishes life-long infection in human B lymphocytes. KSHV infection is typically asymptomatic, but immunosuppression can predispose KSHV-infected individuals to primary effusion lymphoma (PEL); a malignancy driven by aberrant proliferation of latently infected B lymphocytes, and supported by pro-inflammatory cytokines and angiogenic factors produced by cells that succumb to lytic viral replication. Here, we report the development of the first in vivo model for a virally induced lymphoma in zebrafish, whereby KSHV-infected PEL tumor cells engraft and proliferate in the yolk sac of zebrafish larvae. Using a PEL cell line engineered to produce the viral lytic switch protein RTA in the presence of doxycycline, we demonstrate drug-inducible reactivation from KSHV latency in vivo, which enabled real-time observation and evaluation of latent and lytic phases of KSHV infection. In addition, we developed a sensitive droplet digital PCR method to monitor latent and lytic viral gene expression and host cell gene expression in xenografts. The zebrafish yolk sac is not well vascularized, and by using fluorogenic assays, we confirmed that this site provides a hypoxic environment that may mimic the microenvironment of some human tumors. We found that PEL cell proliferation in xenografts was dependent on the host hypoxia-dependent translation initiation factor, eukaryotic initiation factor 4E2 (eIF4E2). This demonstrates that the zebrafish yolk sac is a functionally hypoxic environment, and xenografted cells must switch to dedicated hypoxic gene expression machinery to survive and proliferate. The establishment of the PEL xenograft model enables future studies that exploit the innate advantages of the zebrafish as a model for genetic and pharmacologic screens. View Full-Text
Keywords: Kaposi’s sarcoma-associated herpesvirus (KSHV); human herpesvirus-8; zebrafish; ddPCR; xenotransplantation; primary effusion lymphoma (PEL); hypoxia Kaposi’s sarcoma-associated herpesvirus (KSHV); human herpesvirus-8; zebrafish; ddPCR; xenotransplantation; primary effusion lymphoma (PEL); hypoxia
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Pringle, E.S.; Wertman, J.; Melong, N.; Coombs, A.J.; Young, A.L.; O’Leary, D.; Veinotte, C.; Robinson, C.-A.; Ha, M.N.; Dellaire, G.; Druley, T.E.; McCormick, C.; Berman, J.N. The Zebrafish Xenograft Platform—A Novel Tool for Modeling KSHV-Associated Diseases. Viruses 2020, 12, 12.

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