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Virology Journal
Published in: Virology Journal 1/2017

Open Access 01-12-2017 | Research

A study of Epstein-Barr virus infection in the Chinese tree shrew(Tupaia belangeri chinensis)

Authors: Zhi Wang, Xiang Yi, Long Du, Hong Wang, Jie Tang, Menglin Wang, Chenglin Qi, Heng Li, Yongjing Lai, Wei Xia, Anzhou Tang

Published in: Virology Journal | Issue 1/2017

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Abstract

Background

Epstein–Barr virus (EBV) is closely associated with many human diseases, including a variety of deadly human malignant tumours. However, due to the lack of ideal animal models,the biological characteristics of EBV, particularly its function in tumourigenesis, have not been determined. Chinese tree shrews (Tupaia belangeri chinensis), which are similar to primates, have been used to establish a variety of animal models and have recently received much attention. Here, we established tree shrews as a model for EBV infection by intravenous injection.

Methods

Ten tree shrews were inoculated with EBV by intravenous injection,and blood was collected at regular intervals thereafter from the femoral artery or vein to detect EBV markers.

Results

Eight of 10 tree shrews showed evidence of EBV infection. In the 8 EBV-infected tree shrews, EBV copy number increased intermittently or transiently, EBV-related gene expression was detected, and anti-EBV antibodies increased to varying degrees. Macroscopic hepatomegaly was observed in 1 tree shrew, splenomegaly was observed in 4 tree shrews, and enlarged mesenteric lymph nodes were observed in 3 tree shrews. Haematoxylin and eosin (HE) staining showed splenic corpuscle hyperplasia in the spleens of 4 tree shrews and inflammatory cell infiltration of the liver of 1 tree shrew and of the mesenteric lymph nodes of 3 tree shrews. EBER in situ hybridization(ISH) and immunohistochemical (IHC) staining showed that EBER-, LMP1- and EBNA2- positive cells were present in the spleens and mesenteric lymph nodes of some tree shrews. Western blotting (WB) revealed EBNA1-positive cells in the spleens of 4 tree shrews. EBV markers were not detected by HE, EBER-ISH or IHC in the lung or nasopharynx.

Conclusions

These findings suggest that EBV can infect tree shrews via intravenous injection. The presented model offers some advantages for exploring the pathophysiology of EBV infection in humans.
Literature
1.
Sun L, Che K, Zhao Z, Liu S, Xing X, Luo B. Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from Northern China. Virol J. 2015;12:135.CrossRefPubMedPubMedCentral
2.
Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, et al. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis. 2013;207(1):80–8.CrossRefPubMed
3.
Li H, Liu S, Hu J, Luo X, Li N, MB A, et al. Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis. Int J Biol Sci. 2016;12(11):1309–18.CrossRefPubMedPubMedCentral
4.
Thorley-Lawson DA, Babcock GJ. A model for persistent infection with Epstein-Barr virus: the stealth virus of human B cells. Life Sci. 1999;65(14):1433–53.CrossRefPubMed
5.
Babcock GJ, Hochberg D, Thorley-Lawson AD. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity. 2000;13(4):497–506.CrossRefPubMed
6.
Sugimoto M, Tahara H, Ide T, Furuichi Y. Steps involved in immortalization and tumorigenesis in human B-lymphoblastoid cell lines transformed by Epstein-Barr virus. Cancer Res. 2004;64(10):3361–4.CrossRefPubMed
7.
Kuppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol. 2003;3(10):801–12.CrossRefPubMed
8.
Kelly GL, Milner AE, Baldwin GS, Bell AI, Rickinson AB. Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 2006;103(40):14935–40.CrossRefPubMedPubMedCentral
9.
Cancian L, Bosshard R, Lucchesi W, Karstegl CE, Farrell PJ. C-terminal region of EBNA-2 determines the superior transforming ability of type 1 Epstein-Barr virus by enhanced gene regulation of LMP-1 and CXCR7. PLoS Pathog. 2011;7(7):e1002164.CrossRefPubMedPubMedCentral
10.
Zhang B, Kracker S, Yasuda T, Casola S, Vanneman M, Homig-Holzel C, et al. Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. Cell. 2012;148(4):739–51.CrossRefPubMedPubMedCentral
11.
Harada S, Kieff E. Epstein-Barr virus nuclear protein LP stimulates EBNA-2 acidic domain-mediated transcriptional activation. J Virol. 1997;71(9):6611–8.PubMedPubMedCentral
12.
Xu FH, Xiong D, Xu YF, Cao SM, Xue WQ, Qin HD, et al. An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein-Barr virus activation. J Natl Cancer Inst. 2012;104(18):1396–410.CrossRefPubMed
13.
Shope T, Dechairo D, Miller G. Malignant lymphoma in cottontop marmosets after inoculation with Epstein-Barr virus. Proc Natl Acad Sci U S A. 1973;70(9):2487–91.CrossRefPubMedPubMedCentral
14.
Niedobitek G, Agathanggelou A, Finerty S, Tierney R, Watkins P, Jones EL, et al. Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans. Am J Pathol. 1994;145(4):969–78.PubMedPubMedCentral
15.
Cleary ML, Epstein MA, Finerty S, Dorfman RF, Bornkamm GW, Kirkwood JK, et al. Individual tumors of multifocal EB virus-induced malignant lymphomas in tamarins arise from different B-cell clones. Science. 1985;228(4700):722–4.CrossRefPubMed
16.
Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335(6187):256–9.CrossRefPubMed
17.
Molinie V, Pouchot J, Navratil E, Aubert F, Vinceneux P, Barge J. Primary Epstein-Barr virus-related non-Hodgkin's lymphoma of the pleural cavity following long-standing tuberculous empyema. Arch Pathol Lab Med. 1996;120(3):288–91.PubMed
18.
Chijioke O, Muller A, Feederle R, Barros MH, Krieg C, Emmel V, et al. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep. 2013;5(6):1489–98.CrossRefPubMedPubMedCentral
19.
Hartlage AS, Liu T, Patton JT, Garman SL, Zhang X, Kurt H, et al. The Epstein-Barr Virus Lytic Protein BZLF1 as a Candidate Target Antigen for Vaccine Development. Cancer Immunol Res. 2015;3(7):787–94.CrossRefPubMedPubMedCentral
20.
Wilson JB, Bell JL, Levine AJ. Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J. 1996;15(12):3117–26.PubMedPubMedCentral
21.
Hannigan A, Qureshi AM, Nixon C, Tsimbouri PM, Jones S, Philbey AW, et al. Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo. Mol Cancer. 2011;10(1):11.CrossRefPubMedPubMedCentral
22.
Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V, Raab-Traub N. Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci U S A. 1998;95(20):11963–8.CrossRefPubMedPubMedCentral
23.
Takashima K, Ohashi M, Kitamura Y, Ando K, Nagashima K, Sugihara H, et al. A new animal model for primary and persistent Epstein-Barr virus infection: human EBV-infected rabbit characteristics determined using sequential imaging and pathological analysis. J Med Virol. 2008;80(3):455–66.CrossRefPubMed
24.
Okuno K, Takashima K, Kanai K, Ohashi M, Hyuga R, Sugihara H, et al. Epstein-Barr virus can infect rabbits by the intranasal or peroral route: an animal model for natural primary EBV infection in humans. J Med Virol. 2010;82(6):977–86.CrossRefPubMed
25.
Khan G, Ahmed W, Philip PS, Ali MH, Adem A. Healthy rabbits are susceptible to Epstein-Barr virus infection and infected cells proliferate in immunosuppressed animals. Virol J. 2015;12:28.CrossRefPubMedCentral
26.
Kanai K, Kato K, Sano H, Nagata K, Okuno K, Kuwamoto S, et al. In vitro Epstein-Barr virus infection model of rabbit lymphocytes from peripheral blood or spleen. Intervirology. 2011;54(1):17–24.CrossRefPubMed
27.
Yang C, Ruan P, Ou C, Su J, Cao J, Luo C, et al. Chronic hepatitis B virus infection and occurrence of hepatocellular carcinoma in tree shrews (Tupaia belangeri chinensis). Virol J. 2015;12:26.CrossRefPubMedPubMedCentral
28.
Fan Y, Huang ZY, Cao CC, Chen CS, Chen YX, Fan DD, et al. Genome of the Chinese tree shrew. Nat Commun. 2013;4:1426.CrossRefPubMed
29.
Li R, Xu W, Wang Z, Liang B, Wu JR, Zeng R. Proteomic characteristics of the liver and skeletal muscle in the Chinese tree shrew (Tupaia belangeri chinensis). Protein Cell. 2012;3(9):691–700.CrossRefPubMedPubMedCentral
30.
Zhan MY, Liu CB, Li CM, Zhang WY, Zhu C, Pang QF, et al. A preliminary study of hepatitis A virus in Chinese tupaia (author's transl). Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1981;3(3):148–52.PubMed
31.
Wang Q, Schwarzenberger P, Yang F, Zhang J, Su J, Yang C, et al. Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): a model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans. Virol J. 2012;9:170.CrossRefPubMedPubMedCentral
32.
Amako Y, Tsukiyama-Kohara K, Katsume A, Hirata Y, Sekiguchi S, Tobita Y, et al. Pathogenesis of hepatitis C virus infection in Tupaia belangeri. J Virol. 2010;84(1):303–11.CrossRefPubMed
33.
Pang QF, Liu JC, Wan XB, Qiu FX, Xu AY. Experimental infection of adult Tupaia belangeri yunalis with human rotavirus. Chin Med J. 1983;96(2):85–94.PubMed
34.
Schoeb TR, DaRif CA. Adenoviral infection in infant tree shrews. J Am Vet Med Assoc. 1984;185(11):1363–6.PubMed
35.
Li L, Li Z, Wang E, Yang R, Xiao Y, Han H, et al. Herpes Simplex Virus 1 Infection of Tree Shrews Differs from That of Mice in the Severity of Acute Infection and Viral Transcription in the Peripheral Nervous System. J Virol. 2015;90(2):790–804.CrossRefPubMedPubMedCentral
36.
Li SA, Lee WH, Zhang Y. Two bacterial infection models in tree shrew for evaluating the efficacy of antimicrobial agents. Dongwuxue Yanjiu. 2012;33(1):1–6.PubMed
37.
McBrien NA, Arumugam B, Metlapally S. The effect of daily transient +4 D positive lens wear on the inhibition of myopia in the tree shrew. Invest Ophthalmol Vis Sci. 2012;53(3):1593–601.CrossRefPubMed
38.
Wu X, Chang Q, Zhang Y, Zou X, Chen L, Zhang L, et al. Relationships between body weight, fasting blood glucose concentration, sex and age in tree shrews (Tupaia belangeri chinensis). J Anim Physiol Anim Nutr (Berl). 2013;97(6):1179–88.CrossRef
39.
Okano M, Gross TG. Epstein-Barr virus-associated hemophagocytic syndrome and fatal infectious mononucleosis. Am J Hematol. 1996;53(2):111–5.CrossRefPubMed
40.
Klein E, Kis LL, Klein G. Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions. Oncogene. 2007;26(9):1297–305.CrossRefPubMed
41.
MacArthur GJ, Wilson AD, Birchall MA, Morgan AJ. Primary CD4+ T-cell responses provide both helper and cytotoxic functions during Epstein-Barr virus infection and transformation of fetal cord blood B cells. J Virol. 2007;81(9):4766–75.CrossRefPubMedPubMedCentral
42.
Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood. 2008;111(3):1420–7.CrossRefPubMedPubMedCentral
43.
Zhang Y, Ohyashiki JH, Takaku T, Shimizu N, Ohyashiki K. Transcriptional profiling of Epstein-Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection. Br J Cancer. 2006;94(4):599–608.CrossRefPubMedPubMedCentral
44.
Bauer G. Simplicity through complexity: immunoblot with recombinant antigens as the new gold standard in Epstein-Barr virus serology. Clin Lab. 2001;47(5–6):223–30.PubMed
45.
Zuo L, Yu H, Liu L, Tang Y, Wu H, Yang J, et al. The copy number of Epstein-Barr virus latent genome correlates with the oncogenicity by the activation level of LMP1 and NF-kappaB. Oncotarget. 2015;6(38):41033–44.CrossRefPubMedPubMedCentral
46.
Tsurumi T, Fujita M, Kudoh A. Latent and lytic Epstein-Barr virus replication strategies. Rev Med Virol. 2005;15(1):3–15.CrossRefPubMed
47.
Schillinger M, Kampmann M, Henninger K, Murray G, Hanselmann I,Bauer G. Variability of humoral immune response to acute Epstein-Barr virus (EBV) infection: Evaluation of the significance of serological markers.
48.
Henle W, Henle G, Andersson J, Ernberg I, Klein G, Horwitz CA, et al. Antibody responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-1 and EBNA-2 in acute and chronic Epstein-Barr virus infection. Proc Natl Acad Sci U S A. 1987;84(2):570–4.CrossRefPubMedPubMedCentral
49.
Araujo I, Foss HD, Hummel M, Anagnostopoulos I, Barbosa HS, Bittencourt A, et al. Frequent expansion of Epstein-Barr virus (EBV) infected cells in germinal centres of tonsils from an area with a high incidence of EBV-associated lymphoma. J Pathol. 1999;187(3):326–30.CrossRefPubMed
50.
Kurth J, Hansmann ML, Rajewsky K, Kuppers R. Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Proc Natl Acad Sci U S A. 2003;100(8):4730–5.CrossRefPubMedPubMedCentral
51.
Dittmer DP, Hilscher CJ, Gulley ML, Yang EV, Chen M, Glaser R. Multiple pathways for Epstein-Barr virus episome loss from nasopharyngeal carcinoma. Int J Cancer. 2008;123(9):2105–12.CrossRefPubMedPubMedCentral
52.
Turk SM, Jiang R, Chesnokova LS, Hutt-Fletcher LM. Antibodies to gp350/220 enhance the ability of Epstein-Barr virus to infect epithelial cells. J Virol. 2006;80(19):9628–33.CrossRefPubMedPubMedCentral
53.
Shannon-Lowe C, Rowe M. Epstein-Barr virus infection of polarized epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathog. 2011;7(5):e1001338.CrossRefPubMedPubMedCentral
54.
Bornkamm GW, Behrends U, Mautner J. The infectious kiss: newly infected B cells deliver Epstein-Barr virus to epithelial cells. Proc Natl Acad Sci U S A. 2006;103(19):7201–2.CrossRefPubMedPubMedCentral
55.
Xiao J, Palefsky JM, Herrera R, Tugizov SM. Characterization of the Epstein-Barr virus glycoprotein BMRF-2. Virology. 2007;359(2):382–96.CrossRefPubMed
56.
Kirschner AN, Sorem J, Longnecker R, Jardetzky TS. Structure of Epstein-Barr virus glycoprotein 42 suggests a mechanism for triggering receptor-activated virus entry. Structure. 2009;17(2):223–33.CrossRefPubMedPubMedCentral
57.
Jin W, Li C, Du T, Hu K, Huang X, Hu Q. DC-SIGN plays a stronger role than DCIR in mediating HIV-1 capture and transfer. Virology. 2014;458-459:83–92.CrossRefPubMed
58.
Hui-Yuen J, McAllister S, Koganti S, Hill E, Bhaduri-McIntosh S. Establishment of Epstein-Barr virus growth-transformed lymphoblastoid cell lines. J Vis Exp. 2011;57
59.
Ryan JL, Fan H, Glaser SL, Schichman SA, Raab-Traub N, Gulley ML. Epstein-Barr virus quantitation by real-time PCR targeting multiple gene segments: a novel approach to screen for the virus in paraffin-embedded tissue and plasma. J Mol Diagn. 2004;6(4):378–85.CrossRefPubMedPubMedCentral
60.
Babcock GJ, Thorley-Lawson DA. Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors. Proc Natl Acad Sci U S A. 2000;97(22):12250–5.CrossRefPubMedPubMedCentral
61.
Yu D, Xu L, Liu XH, Fan Y, Lu LB, Yao YG. Diverse interleukin-7 mRNA transcripts in Chinese tree shrew (Tupaia belangeri chinensis). PLoS One. 2014;9(6):e99859.CrossRefPubMedPubMedCentral
62.
Khan G, Coates PJ, Kangro HO, Slavin G. Epstein Barr virus (EBV) encoded small RNAs: targets for detection by in situ hybridisation with oligonucleotide probes. J Clin Pathol. 1992;45(7):616–20.CrossRefPubMedPubMedCentral
63.
Chang KL, Chen YY, Shibata D, Weiss LM. Description of an in situ hybridization methodology for detection of Epstein-Barr virus RNA in paraffin-embedded tissues, with a survey of normal and neoplastic tissues. Diagn Mol Pathol. 1992;1(4):246–55.CrossRefPubMed
64.
Khan G. Screening for Epstein-Barr virus in Hodgkin's lymphoma. Methods Mol Biol. 2009;511:311–22.CrossRefPubMed
Metadata
Title
A study of Epstein-Barr virus infection in the Chinese tree shrew(Tupaia belangeri chinensis)
Authors
Zhi Wang
Xiang Yi
Long Du
Hong Wang
Jie Tang
Menglin Wang
Chenglin Qi
Heng Li
Yongjing Lai
Wei Xia
Anzhou Tang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2017
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-017-0859-5

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