Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice.
BACKGROUND
The lack of a suitable animal model to study viral and immunological mechanisms of human dengue disease has been a deterrent to dengue research.


RESULTS
We sought to establish an animal model for dengue virus (DENV) infection and immunity using non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain knockout (NOD-scid IL2rgamma(null)) mice engrafted with human hematopoietic stem cells. Human CD45(+) cells in the bone marrow of engrafted mice were susceptible to in vitro infection using low passage clinical and established strains of DENV. Engrafted mice were infected with DENV type 2 by different routes and at multiple time points post infection, we detected DENV antigen and RNA in the sera, bone marrow, spleen and liver of infected engrafted mice. Anti-dengue IgM antibodies directed against the envelope protein of DENV peaked in the sera of mice at 1 week post infection. Human T cells that developed following engraftment of HLA-A2 transgenic NOD-scid IL2rgamma(null) mice with HLA-A2(+) human cord blood hematopoietic stem cells, were able to secrete IFN-gamma, IL-2 and TNF-alpha in response to stimulation with three previously identified A2 restricted dengue peptides NS4b 2353((111-119)), NS4b 2423((181-189)), and NS4a 2148((56-64)).


CONCLUSIONS
This is the first study to demonstrate infection of human cells and functional DENV-specific T cell responses in DENV-infected humanized mice. Overall, these mice should be a valuable tool to study the role of prior immunity on subsequent DENV infections.
Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Smita
S
Jaiswal
Todd
T
Pearson
Heather
H
Friberg
Leonard D
LD
Shultz
Dale L
DL
Greiner
Alan L
AL
Rothman
Anuja
A
Mathew
D000818:Animals; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology*; D005312:Fetal Blood / Q000166:cytology / Q000821:virology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000821:virology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID / Q000276:immunology*; D010455:Peptides / Q000737:chemistry; D012313:RNA / Q000378:metabolism
D015789:HLA-A2 Antigen; D007376:Interleukin-2; D010455:Peptides; D012313:RNA