IMMUNOLOGY AND PATHOGENESIS OF VIRAL HEMORRHAGIC FEVERS A Mouse Model for Studying Dengue Virus Pathogenesis and Immune Response Katherine L. Williams, a Simona Zompi, a P. Robert Beatty, b and Eva Harris a a Division of Infectious Diseases and Vaccinology, School of Public Health, and b Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, California, USA A small animal model for studying dengue disease is of critical importance to furthering many areas of dengue research, including host immunity, disease pathogenesis, and drug and vaccine development. Recent characterization of the AG129 mouse model has demonstrated it to be one of the only models at this time that permits infection by all four serotypes of dengue virus (DENV), supports replication in relevant cell and tissue types comparable to human infection, and allows antibody-mediated protection and enhancement of DENV infection. Thus, this model enables testing hypotheses arising from epidemiological observations and in vitro experiments in an in vivo system with a functional adaptive immune response. This review provides a brief overview of the development of a mouse model of DENV infection, describes the work completed to date characterizing the AG129 model, and examines several of the unanswered questions remaining in the field. Key words: dengue; mouse model; antibody-dependent enhancement; AG129 mice Introduction Dengue virus (DENV) is a mosquito-borne virus of the Flaviviridae family and is related to yellow fever, West Nile (WNV), and Japanese Encephalitis viruses. 1 Endemic to tropical and subtropical regions of the world, DENV is the most medically important arthropod-borne virus worldwide and a major public health challenge. Three billion people are at risk for DENV infection, with an estimated 50 mil- lion cases of dengue fever (DF) annually and 250,000–500,000 cases of the potentially fatal dengue hemorrhagic fever/dengue shock syn- drome (DHF/DSS), characterized by vascular leak leading to hypotensive shock. 2 The four DENV serotypes (DENV1-4) are transmitted to humans primarily by the mosquitoes Aedes Address for correspondence: Eva Harris, Division of Infectious Dis- eases and Vaccinology, School of Public Health, University of California, Berkeley, 1 Barker Hall, Berkeley, CA 94720-7354. Voice: 510-642-4845; fax: 510-642-6350. eharris@berkeley.edu aegypti and Ae. albopictus. The clinical course of DHF/DSS is initially quite similar to DF; however, at defervescence, DHF/DSS patients rapidly deteriorate into life-threatening condi- tions characterized by vascular leak, hemor- rhagic manifestations, and thrombocytopenia with or without shock. 3 The inability to dif- ferentiate between DF and DHF/DSS at early stages of illness contributes to the difficulty in treating the disease. Further, individuals previ- ously infected with DENV are at increased risk of severe disease upon secondary infection with a different (heterologous) serotype. 4 At present, no effective antiviral therapy or vaccine exists, and treatment is largely supportive in nature. Role of the Adaptive Immune Response in Modulating Secondary DENV Infection Host factors, including human leukocyte antigen (HLA) polymorphisms and prior Immunology and Pathogenesis of Viral Hemorrhagic Fevers: Ann. N.Y. Acad. Sci. 1171: E12–E23 (2009). doi: 10.1111/j.1749-6632.2009.05057.x c  2009 New York Academy of Sciences. E12