title: Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice.
abstract: Dengue viruses (DENV) are transmitted to humans by the bite of Aedes aegypti or Aedes albopictus mosquitoes, with millions of infections annually in over 100 countries. The diseases they produce, which occur exclusively in humans, are dengue fever (DF) and dengue hemorrhagic fever (DHF). We previously developed a humanized mouse model of DF in which mice transplanted with human hematopoietic stem cells produced signs of DENV disease after injection with low-passage, wild-type isolates. Using these mice, but now allowing infected A. aegypti to transmit dengue virus during feeding, we observed signs of more severe disease (higher and more sustained viremia, erythema, and thrombocytopenia). Infected mice mounted innate (gamma interferon [IFN-γ] and soluble interleukin 2 receptor alpha [sIL-2Rα]) and adaptive (anti-DENV antibodies) immune responses that failed to clear viremia until day 56, while a mosquito bite alone induced strong immunomodulators (tumor necrosis factor alpha [TNF-α], IL-4, and IL-10) and thrombocytopenia. This is the first animal model that allows an evaluation of human immunity to DENV infection after mosquito inoculation.
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cox
authors.forename: Javier
authors.initials: J
authors.lastname: Mota
authors.forename: Soila
authors.initials: S
authors.lastname: Sukupolvi-Petty
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Rebeca
authors.initials: R
authors.lastname: Rico-Hesse
mesh_terms: D000330:Aedes / Q000821:virology; D000818:Animals; D003715:Dengue / Q000276:immunology* / Q000635:transmission / Q000821:virology; D003716:Dengue Virus / Q000276:immunology* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007299:Insect Bites and Stings / Q000821:virology; D007303:Insect Vectors / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013921:Thrombocytopenia / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma