Dengue virus (DEN), a NIAID bio-defense category A pathogen, causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent arthropod-borne viral illnesses in humans worldwide. Due to the lack of an adequate animal model, the immunopathogenic mechanisms of DHF/DSS are presently unclear. We have optimized a mouse model for primary DEN infection and have determined that the murine interferon (IFN) system is more important than T and B cell dependent immunity for defense against primary DEN infection. Our long-term goal is to elucidate how the IFN system coordinates the anti-DEN immune response in mice. This proposal will test the hypothesis that IFNalpha/ beta producing plasmacytoid dendritic cells (PDCs) regulate the early immune response to primary DEN infection in mice. First, the role of PDCs in producing IFN-alpha/beta early during primary DEN infection in mice will be determined. Second, the role of IFN-alpha/beta in regulating natural killer (NK) cell proliferation, cytotoxicity, and production of IFN-gamma in mice with primary DEN infection will be examined. These two aims are designed to identify the major cellular source(s) and target(s) of murine IFNalpha/ beta in primary DEN infection and to determine their importance in limiting early viral infection. PDCs will be purified from tissues of uninfected and DEN-infected mice and examined for their production of IFNalpha/ beta and regulation of NK cell activities in both in vitro and in vivo settings. Loss-of-function models for murine PDCs and NK cells will be used to determine their relevance in mediating early viral clearance. A better understanding of the IFN-dependent immune response to DEN infection in mica may lead to the development of (i) a murine model that is more relevant to human DEN infection and disease, (ii) rational approaches for the design of anti-viral therapies and vaccines, and (iii) a greater understanding of the role of PDCs and the immune response to virus infections that are primarily controlled by the IFN system. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI060989-02
Application #
7080441
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Cassetti, Cristina
Project Start
2005-07-01
Project End
2007-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$107,168
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Zellweger, Raphael M; Prestwood, Tyler R; Shresta, Sujan (2010) Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7:128-39
Yauch, Lauren E; Zellweger, Raphaƫl M; Kotturi, Maya F et al. (2009) A protective role for dengue virus-specific CD8+ T cells. J Immunol 182:4865-73
Prestwood, Tyler R; Prigozhin, Daniil M; Sharar, Kristin L et al. (2008) A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by establishing increased systemic viral loads. J Virol 82:8411-21