Tree Shrew Is a Suitable Animal Model for the Study of Epstein Barr Virus

Abstract

Epstein-Barr virus (EBV) is a human herpesvirus that latently infects approximately 95% of adults and is associated with a spectrum of human diseases including Infectious Mononucleosis and a variety of malignancies. However, understanding the pathogenesis, vaccines and antiviral drugs for EBV-associated disease has been hampered by the lack of suitable animal models. Tree shrew is a novel laboratory animal with a close phylogenetic relationship to primates, which is a critical advantage for many animal models for human disease, especially viral infections. Herein, we first identified the key residues in the CR2 receptor that bind the gp350 protein and facilitate viral entry. We found that tree shrew shares 100% sequence identity with humans in these residues, which is much higher than rabbits (50%) and rats (25%). In vitro analysis showed that B lymphocytes of tree shrews are susceptible to EBV infection and replication, as well as EBV-enhanced cell proliferation. Moreover, results of in vivo experiments show that EBV infection in tree shrews resembles EBV infection in humans. The infected animals exhibited transient fever and loss of weight accompanied by neutropenia and high viremia levels during the acute phase of the viral infection. Thereafter, tree shrews acted as asymptomatic carriers of the virus in most cases that EBV-related protein could be detected in blood and tissues. However, a resurgence of EBV infection occurred at 49 dpi. Nanopore transcriptomic sequencing of peripheral blood in EBV-infected animals revealed the dynamic changes in biological processes occurring during EBV primary infection. Importantly, we find that neutrophil function was impaired in tree shrew model as well as human Infectious Mononucleosis datasets (GSE85599 and GSE45918). In addition, retrospective case reviews suggested that neutropenia may play an important role in EBV escaping host innate immune response, leading to long-term latent infection. Our findings demonstrated that tree shrew is a suitable animal model to evaluate the mechanisms of EBV infection, and for developing vaccines and therapeutic drugs against EBV.

RNA-Seq and miRNA-Seq data from Epstein-Barr virus-infected tree shrews reveal a ceRNA network contributing to immune microenvironment regulation

“…However, our understanding of the immunological mechanisms involved in EBV infection is limited, particularly under in vivo conditions, because there are no suitable animal models. Previously, we found that tree shrews are susceptible to EBV infection and exhibit characteristics similar to those of humans [ 7 , 16 ]. Using the tree shrew model, we found dramatic changes within the blood microenvironment with the progression of EBV infection.…”

“…However, no systematic study has been done on the interaction between lncRNAs and miRNAs in remodelling the microenvironment after EBV infection, owing to the lack of suitable animal models. We previously reported that the tree shrew ( Tupaia belangeri chinensis ) is a suitable animal model for evaluating the mechanisms of EBV infection [ 7 ].…”

Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective

“…Rabbits have also been reported as susceptible to EBV infection ( 96 – 99 ), but no EBV-associated pathologies have been shown, and as humanized mice, their epithelial cells are not susceptible to infection ( 100 ). Similarly, Chinese tree shrews were recently reported to be susceptible to EBV B cell infection ( 101 ), but a previous study by the same group suggests that their epithelial cells are not infected by EBV ( 102 ). Both rabbits and tree shrews have yet to be used as challenge models to test EBV vaccine efficacy.…”

Progress in Prophylactic and Therapeutic EBV Vaccine Development Based on Molecular Characteristics of EBV Target Antigens

“…Research in 2017 showed the first signs of a potential animal model for EBV after 8 out of 10 tree shrews, mammals native to tropical forests, showed signs of infection after intravenous injection with EBV [31]. Accordingly, follow-up research showed that tree shrews have one hundred percent identity with humans in CR2 residues critical for attachment to gp350 [32]. Besides homology in CR2, tree shrews are suitable animal models because of their small size and short reproductive cycle as well as life span [33].…”