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.
Jaiswal
Smita
S
Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Pearson
Todd
T
Friberg
Heather
H
Shultz
Leonard D
LD
Greiner
Dale L
DL
Rothman
Alan L
AL
Mathew
Anuja
A
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