title: A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses.
abstract: The functional human immune system, including T, B, and natural killer lymphocytes, is reconstituted in NOD/Shi-scid/IL-2Rgamma(null) (NOG) mice that receive hematopoietic stem cell transplants. Here, we show that these humanized mice can recapitulate key aspects of Epstein-Barr virus (EBV) infection in humans. Inoculation with approximately 1 x 10(3) TD(50) (50% transforming dose) of EBV caused B cell lymphoproliferative disorder, with histopathological findings and latent EBV gene expression remarkably similar to that in immunocompromised patients. Inoculation with a low dose of virus (<or=1 x 10(1) TD(50)), in contrast, resulted in apparently asymptomatic persistent infection. Levels of activated CD8(+) T cells increased dramatically in the peripheral blood of infected mice, and enzyme-linked immunospot assay and flow cytometry demonstrated an EBV-specific T cell response. Immunoglobulin M antibody specific to the EBV-encoded protein BFRF3 was detected in serum from infected mice. The NOG mouse is the most comprehensive small-animal model of EBV infection described to date and should facilitate studies of the pathogenesis, prevention, and treatment of EBV infection.
authors.affiliation: Department of Infectious Diseases, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Yajima
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Imadome
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Terashima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Honda
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007111:Immunity, Cellular; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D000914:Antibodies, Viral