A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses.
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.
Yajima
Misako
M
Department of Infectious Diseases, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
Imadome
Ken-Ichi
K
Nakagawa
Atsuko
A
Watanabe
Satoru
S
Terashima
Kazuo
K
Nakamura
Hiroyuki
H
Ito
Mamoru
M
Shimizu
Norio
N
Honda
Mitsuo
M
Yamamoto
Naoki
N
Fujiwara
Shigeyoshi
S
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
D000914:Antibodies, Viral