Dengue Viral Pathogenesis and Immune Responses in Humanized Mice

Abstract

Dengue is an insect-borne viral infection of significant global public health concern. Viral and host factors and prior humoral and cellular immunity are key contributors to severe dengue illness, dengue hemorrhagic fever (DHF). Progress in dengue research has been hampered by the lack of an ideal animal model that recapitulates key aspects of the immune responses and disease. In this regard, the generation of novel humanized mouse models presents a unique opportunity to overcome deficiencies of traditional mouse and nonhuman primate models. Two leading models of immunodeficient humanized mice, the human hematopoietic stem cell (hu-HSC) and bone marrow-liver-thymus (BLT) mice have recently been used to study dengue. Both models permit productive dengue viral infection, fever, and thrombocytopenia. Insect viral transmission has been examined in the hu-HSC model. Consistent virus-specific immunoglobulin M (IgM) responses, weak immunoglobulin G (IgG) responses with neutralizing activity, and virus-specific T cell responses are generated in hu-HSC and BLT mice. However, both humoral and cellular responses in humanized models need further improvement to match responses detected in humans. These studies are a good foundation to further our understanding of key aspects of dengue virus infection, immunity, and pathogenesis.