Abstract
BackgroundEpstein-Barr virus (EBV) is an oncogenic virus implicated in the pathogenesis of several human malignancies. However, due to the lack of a suitable animal model, a number of fundamental questions pertaining to the biology of EBV remain poorly understood. Here, we explore the potential of rabbits as a model for EBV infection and investigate the impact of immunosuppression on viral proliferation and gene expression.MethodsSix healthy New Zealand white rabbits were inoculated intravenously with EBV and blood samples collected prior to infection and for 7 weeks post-infection. Three weeks after the last blood collection, animals were immunosuppressed with daily intramuscular injections of cyclosporin A at doses of 20 mg/kg for 15 days and blood collected twice a week from each rabbit. The animals were subsequently sacrificed and tissues from all major organs were collected for subsequent analysis.ResultsFollowing intravenous inoculation, all 6 rabbits seroconverted with raised IgG and IgM titres to EBV, but viral DNA in peripheral blood mononuclear cells (PBMCs) could only be detected intermittently. Following immunosuppression however, EBV DNA could be readily detected in PBMCs from all 4 rabbits that survived the treatment. Quantitative PCR indicated an increase in EBV viral load in PBMCs as the duration of immunosuppression increased. At autopsy, splenomegaly was seen in 3/4 rabbits, but spleens from all 4 rabbit were EBV PCR positive. EBER-in situ hybridization and immunoshistochemistry revealed the presence of a large number of EBER-positive and LMP-1 positive lymphoblasts in the spleens of 3/4 rabbits. To a lesser extent, EBER-positive cells were also seen in the portal tract regions of the liver of these rabbits. Western blotting indicated that EBNA-1 and EBNA-2 were also expressed in the liver and spleen of infected animals.ConclusionEBV can infect healthy rabbits and the infected cells proliferate when the animals are immunocompromised. The infected cells expressed several EBV-latent gene products which are probably driving the proliferation, reminiscent of what is seen in immunocompromised individuals. Further work is required to explore the potential of rabbits as an animal model for studying EBV biology and tumorigenesis.
Highlights
Epstein-Barr virus (EBV) is a human lymphotropic herpesvirus implicated in the pathogenesis of a number of malignancies of both epithelial and lymphoid origin, including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), post-transplant lymphoproliferative disease
We show that rabbits can be infected with EBV and further show that the infected cells proliferate under immunosuppressive conditions, similar to what has been described for allograft recipients on immunosuppressive drugs [21,38]
The infectivity of the virus in the culture supernatant was assessed by its ability to successfully immortalize human peripheral blood mononuclear cells (PBMCs) in vitro [40]
Summary
Epstein-Barr virus (EBV) is a human lymphotropic herpesvirus implicated in the pathogenesis of a number of malignancies of both epithelial and lymphoid origin, including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), post-transplant lymphoproliferative disease (PTLD) and Hodgkin lymphoma (HL) [1]. What is clear is that EBV establishes a life-long persistence in resting memory B-lymphocytes [15,16] The frequency of these cells is tightly regulated in the healthy individuals [17] and probably evade the host immune response by down-regulating essential cellular activation molecules and limiting viral gene expression to one or two proteins only [18,19]. Disruption of this tightly regulated system, as seen in allograft recipients receiving immunosuppressive therapy, can lead to EBV-driven lymphoproliferative disorders (PTLD) [20,21,22,23]. We explore the potential of rabbits as a model for EBV infection and investigate the impact of immunosuppression on viral proliferation and gene expression
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