dengue virus infection and virus-specific hla-a2 restricted immune responses in humanized nod-scid il2rγnull mice登革病毒感染和病毒特异性hla a2限制免疫反应在人性化nod-scid il2rγnull老鼠.pdfVIP

Dengue Virus Infection and Virus-Specific HLA-A2 Restricted Immune Responses in Humanized NOD-scid IL2rcnull Mice 1 2 1 3 2 1 Smita Jaiswal , Todd Pearson , Heather Friberg , Leonard D. Shultz , Dale L. Greiner , Alan L. Rothman , Anuja Mathew1* 1 Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 2 Diabetes Division, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 3 Jackson Laboratory, Bar Harbor, Maine, United States of America 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 c-chain knockout (NOD-scid IL2rcnull) 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 IL2rcnull mice with HLA-A2+ human cord blood hematopoietic stem cells, were able to secrete IFN-c,