Immune Netw.  2014 Feb;14(1):1-6. 10.4110/in.2014.14.1.1.

Reproduction of Epstein-Barr Virus Infection and Pathogenesis in Humanized Mice

Affiliations
  • 1Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. fujiwara-s@ncchd.go.jp

Abstract

Epstein-Barr virus (EBV) is etiologically associated with a variety of diseases including lymphoproliferative diseases, lymphomas, carcinomas, and autoimmune diseases. Humans are the only natural host of EBV and limited species of new-world monkeys can be infected with the virus in experimental conditions. Small animal models of EBV infection, required for evaluation of novel therapies and vaccines for EBV-associated diseases, have not been available. Recently the development of severely immunodeficient mouse strains enabled production of humanized mice in which human immune system components are reconstituted and express their normal functions. Humanized mice can serve as infection models for human-specific viruses such as EBV that target cells of the immune system. This review summarizes recent studies by the author's group addressing reproduction of EBV infection and pathogenesis in humanized mice.

Keyword

Epstein-Barr virus; Humanized mouse; Lymphoproliferative disease; Rheumatoid arthritis; Immune response; Persistent infection

MeSH Terms

Animals
Arthritis, Rheumatoid
Autoimmune Diseases
Epstein-Barr Virus Infections
Haplorhini
Herpesvirus 4, Human*
Humans*
Immune System
Lymphoma
Mice*
Models, Animal
Reproduction*
Vaccines
Viruses
Vaccines

Reference

1. Longnecker RM, Kieff E, Cohen JI. Epstein-Barr virus. In : Knipe DM, Howley PM, editors. Fields Virology. 6th ed. Philadelphia, PA: Lippincott Williams and Wlikins;2013. p. 1898–1959.
2. Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol. 2007; 25:587–617.
Article
3. Shope T, Dechairo D, Miller G. Malignant lymphoma in cottontop marmosets after inoculation with Epstein-Barr virus. Proc Natl Acad Sci USA. 1973; 70:2487–2491.
Article
4. Epstein MA, zur Hausen H, Ball G, Rabin H. Pilot experiments with EB virus in owl monkeys (Aotus trivirgatus). III. Serological and biochemical findings in an animal with reticuloproliferative disease. Int J Cancer. 1975; 15:17–22.
Article
5. Johannessen I, Crawford DH. In vivo models for Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (BLPD). Rev Med Virol. 1999; 9:263–277.
Article
6. Takashima K, Ohashi M, Kitamura Y, Ando K, Nagashima K, Sugihara H, Okuno K, Sairenji T, Hayashi K. 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; 80:455–466.
Article
7. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100:3175–3182.
Article
8. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004; 304:104–107.
Article
9. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005; 174:6477–6489.
Article
10. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006; 12:1316–1322.
Article
11. Fujiwara S, Matsuda G, Imadome K. Humanized mouse models of Epstein-Barr virus infection and associated diseases. Pathogens. 2013; 2:153–176.
Article
12. Akkina R. New generation humanized mice for virus research: comparative aspects and future prospects. Virology. 2013; 435:14–28.
Article
13. Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K, Nakahata T. Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model. Blood. 2003; 102:873–880.
Article
14. Watanabe S, Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y, Dewan MZ, Yu Z, Ito M, Morio T, Shimizu N, Honda M, Yamamoto N. Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood. 2007; 109:212–218.
Article
15. Watanabe S, Ohta S, Yajima M, Terashima K, Ito M, Mugishima H, Fujiwara S, Shimizu K, Honda M, Shimizu N, Yamamoto N. Humanized NOD/SCID/IL2Rgamma (null) mice transplanted with hematopoietic stem cells under nonmyeloablative conditions show prolonged life spans and allow detailed analysis of human immunodeficiency virus type 1 pathogenesis. J Virol. 2007; 81:13259–13264.
Article
16. Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, Ito M, Shimizu N, Honda M, Yamamoto N, Fujiwara S. A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. J Infect Dis. 2008; 198:673–682.
Article
17. Strowig T, Gurer C, Ploss A, Liu YF, Arrey F, Sashihara J, Koo G, Rice CM, Young JW, Chadburn A, Cohen JI, Munz C. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 2009; 206:1423–1434.
Article
18. Ma SD, Hegde S, Young KH, Sullivan R, Rajesh D, Zhou Y, Jankowska-Gan E, Burlingham WJ, Sun X, Gulley ML, Tang W, Gumperz JE, Kenney SC. A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J Virol. 2011; 85:165–177.
Article
19. Ma SD, Yu X, Mertz JE, Gumperz JE, Reinheim E, Zhou Y, Tang W, Burlingham WJ, Gulley ML, Kenney SC. An Epstein-Barr Virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model. J Virol. 2012; 86:7976–7987.
Article
20. White RE, Ramer PC, Naresh KN, Meixlsperger S, Pinaud L, Rooney C, Savoldo B, Coutinho R, Bodor C, Gribben J, Ibrahim HA, Bower M, Nourse JP, Gandhi MK, Middeldorp J, Cader FZ, Murray P, Munz C, Allday MJ. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest. 2012; 122:1487–1502.
Article
21. Wahl A, Linnstaedt SD, Esoda C, Krisko JF, Martinez-Torres F, Delecluse HJ, Cullen BR, Garcia JV. A cluster of virus-encoded microRNAs accelerates acute systemic Epstein-Barr virus infection but does not significantly enhance virus-induced oncogenesis in vivo. J Virol. 2013; 87:5437–5446.
Article
22. Cocco M, Bellan C, Tussiwand R, Corti D, Traggiai E, Lazzi S, Mannucci S, Bronz L, Palummo N, Ginanneschi C, Tosi P, Lanzavecchia A, Manz MG, Leoncini L. CD34+ cord blood cell-transplanted Rag2-/- gamma(c)-/- mice as a model for Epstein-Barr virus infection. Am J Pathol. 2008; 173:1369–1378.
Article
23. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365:2205–2219.
Article
24. Niller HH, Wolf H, Ay E, Minarovits J. Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease. Adv Exp Med Biol. 2011; 711:82–102.
Article
25. Toussirot E, Roudier J. Pathophysiological links between rheumatoid arthritis and the Epstein-Barr virus: an update. Joint Bone Spine. 2007; 74:418–426.
Article
26. Takei M, Mitamura K, Fujiwara S, Horie T, Ryu J, Osaka S, Yoshino S, Sawada S. Detection of Epstein-Barr virus-encoded small RNA 1 and latent membrane protein 1 in synovial lining cells from rheumatoid arthritis patients. Int Immunol. 1997; 9:739–743.
Article
27. Kuwana Y, Takei M, Yajima M, Imadome K, Inomata H, Shiozaki M, Ikumi N, Nozaki T, Shiraiwa H, Kitamura N, Takeuchi J, Sawada S, Yamamoto N, Shimizu N, Ito M, Fujiwara S. Epstein-Barr virus induces erosive arthritis in humanized mice. PLoS One. 2011; 6:e26630.
Article
28. Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N, Katano I, Ito R, Ito M, Minegishi M, Minegishi N, Tsuchiya S, Sugamura K. The analysis of the functions of human B and T cells in humanized NOD/shiscid/gammac(null) (NOG) mice (hu-HSC NOG mice). Int Immunol. 2009; 21:843–858.
Article
29. Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, Ito M, Shimizu N, Yamamoto N, Fujiwara S. T cell-mediated control of Epstein-Barr virus infection in humanized mice. J Infect Dis. 2009; 200:1611–1615.
Article
30. Kikuta H, Sakiyama Y, Matsumoto S, Oh-Ishi T, Nakano T, Nagashima T, Oka T, Hironaka T, Hirai K. Fatal Epstein-Barr virus-associated hemophagocytic syndrome. Blood. 1993; 82:3259–3264.
Article
31. Kawaguchi H, Miyashita T, Herbst H, Niedobitek G, Asada M, Tsuchida M, Hanada R, Kinoshita A, Sakurai M, Kobayashi N, Mizutani S. Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome. J Clin Invest. 1993; 92:1444–1450.
Article
32. Kawa-Ha K, Ishihara S, Ninomiya T, Yumura-Yagi K, Hara J, Murayama F, Tawa A, Hirai K. CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest. 1989; 84:51–55.
Article
33. Jones JF, Shurin S, Abramowsky C, Tubbs RR, Sciotto CG, Wahl R, Sands J, Gottman D, Katz BZ, Sklar J. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med. 1988; 318:733–741.
Article
34. Kikuta H, Taguchi Y, Tomizawa K, Kojima K, Kawamura N, Ishizaka A, Sakiyama Y, Matsumoto S, Imai S, Kinoshita T, Koizumi S, Osato T, Kobayashi I, Hamada I, Hirai K. Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature. 1988; 333:455–457.
Article
35. Ishihara S, Tawa A, Yumura-Yagi K, Murata M, Hara J, Yabuuchi H, Hirai K, Kawa-Ha K. Clonal T-cell lymphoproliferation containing Epstein-Barr (EB) virus DNA in a patient with chronic active EB virus infection. Jpn J Cancer Res. 1989; 80:99–101.
Article
36. Imadome K, Yajima M, Arai A, Nakazawa A, Kawano F, Ichikawa S, Shimizu N, Yamamoto N, Morio T, Ohga S, Nakamura H, Ito M, Miura O, Komano J, Fujiwara S. Novel mouse xenograft models reveal a critical role of CD4+ T cells in the proliferation of EBV-infected T and NK cells. PLoS Pathog. 2011; 7:e1002326.
37. Sato K, Misawa N, Nie C, Satou Y, Iwakiri D, Matsuoka M, Takahashi R, Kuzushima K, Ito M, Takada K, Koyanagi Y. A novel animal model of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in humanized mice. Blood. 2011; 117:5663–5673.
Article
38. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci USA. 2010; 107:13022–13027.
Article
Full Text Links
  • IN
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr