a non mouse-adapted dengue virus strain as a new model of severe dengue infection in ag129 mice一个非mouse-adapted登革热病毒株的新模型严重的登革热感染ag129老鼠.pdfVIP

A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice 1 1 2 3 4 1 Grace K. Tan , Jowin K. W. Ng , Scott L. Trasti , Wouter Schul , George Yip , Sylvie Alonso * 1 Department of Microbiology, Immunology Programme, National University of Singapore, Singapore, Singapore, 2 Comparative Medicine Centre, National University of Singapore, Singapore, Singapore, 3 Novartis Institute for Tropical Diseases (NITD), Singapore, Singapore, 4 Department of Anatomy, National University of Singapore, Singapore, Singapore Abstract The spread of dengue (DEN) worldwide combined with an increased severity of the DEN-associated clinical outcomes have made this mosquito-borne virus of great global public health importance. Progress in understanding DEN pathogenesis and in developing effective treatments has been hampered by the lack of a suitable small animal model. Most of the DEN clinical isolates and cell culture-passaged DEN virus strains reported so far require either host adaptation, inoculation with a high dose and/or intravenous administration to elicit a virulent phenotype in mice which results, at best, in a productive infection with no, few, or irrelevant disease manifestations, and with mice dying within few days at the peak of viremia. Here we describe a non-mouse-adapted DEN2 virus strain (D2Y98P) that is highly infectious in AG129 mice (lacking interferon-a/ b and -c receptors) upon intraperitoneal administration. Infection with a high dose of D2Y98P induced cytokine storm, massive organ damage, and severe vascular leakage, leading to haemorrhage and rapid death of the animals at the peak of viremia. In contrast, very interestingly and uniquely, infection with a low dose of D2Y98P l