Center for Infectious Disease and Vaccine Research; Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Diabetes Division
Dengue Virus; Disease Models, Animal; Mice, Inbred NOD; HLA-A2 Antigen; Immunity
Life Sciences | Medicine and Health Sciences
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
Rights and Permissions
Copyright: © 2009 Jaiswal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS One. 2009 Oct 5;4(10):e7251. Link to article on publisher's site
Jaiswal, Smita; Pearson, Todd; Friberg, Heather; Shultz, Leonard D.; Greiner, Dale L.; Rothman, Alan L.; and Mathew, Anuja, "Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice" (2009). Open Access Articles. 2085.