Dengue virus(DENV)is a single-stranded RNA virus transmitted by mosquitoes in tropical and subtropical regions.It causes dengue fever,dengue hemorrhagic fever and dengue shock syndrome in patients.Each year,390 million people are estimated to be infected by four serotypes of dengue virus,creating a great burden on global public health and local economy.So far,no antiviral drug is available for dengue disease,and the newly licensed vaccine is far from satisfactory.One large obstacle for dengue vaccine and drug development is the lack of suitable small animal models.Although some DENV infection models have been developed,only a small number of viral strains can infect immunodeficient mice.In this study,with biologically cloned viruses from a single clinical isolate,we have established two mouse models of DENV infection,one is severe lethal infection in immunocompromised mice,and the other resembles self-limited disease manifestations in Balb/c mice with transient blockage of type IIFN responses.This study not only offers new small animal models of dengue viral infection,but also provides new viral variants for further investigations on dengue viral pathogenesis.