Characterization and Optimization of Primary Dengue Viral Infection in a Humanized Mouse Model

Abstract

Dengue virus (DENV), a potentially life-threatening disease affecting millions each year, remains a major global health threat. The scarcity of animal models mimicking human symptoms of DENV infection has slowed our understanding of disease pathogenesis and development of anti-viral therapies. Here, we investigate the use of previously established humanized HIS-NFA2/hFLT3LG mice to model immune responses following DENV infection. We first generated a diverse library of 20 infectious clones based on patient-derived viral strains—serving as an important tool for both this study and subsequent characterizations. Using two of these low-passage DENV clinical isolates, we demonstrate that HIS-NFA2/hFLT3LG mice can support viral replication. Additionally, these humanized mice display key clinical symptoms of DENV, including viremia and thrombocytopenia. We further characterized DENV-infected HIS-NFA2/hFLT3LG mice on the basis of their cellular and humoral immunity, finding that DENV-specific responses were activated similar to those seen in patients. In summary, we demonstrate that HIS-NFA2/hFLT3LG mice are susceptible to infection with clinical DENV clinical isolates, mount virus-specific adaptive immune response, and mimic key disease manifestations. Although additional refinements to the model are required, we anticipate that our HIS-NFA2/hFLT3LG system will be widely useful to mechanistically study DENV pathogenesis and for assessing the efficacy of anti-DENV therapeutics.