Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice.

Abstract

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.

• Authors: Smita Jaiswal, Todd Pearson, Heather Friberg, Leonard D Shultz, Dale L Greiner, Alan L Rothman, Anuja Mathew
• Journal: PloS one (PLoS One) Vol. 4 Issue 10 Pg. e7251 (Oct 05 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19802382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-A2 Antigen
• Interleukin-2
• Peptides
• RNA

Topics

• Animals
• Dengue (immunology)
• Dengue Virus (immunology)
• Fetal Blood (cytology, virology)
• HLA-A2 Antigen (immunology)
• Hematopoiesis
• Hematopoietic Stem Cells (cytology, virology)
• Humans
• Interleukin-2 (immunology)
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID (immunology)
• Peptides (chemistry)
• RNA (metabolism)