title: Mouse models of dengue virus infection for vaccine testing.
abstract: Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines.
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, United States; Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Sarathy
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, United States; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Gregg N
authors.initials: GN
authors.lastname: Milligan
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, United States; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Nigel
authors.initials: N
authors.lastname: Bourne
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, United States; Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States; Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX, United States; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, United States. Electronic address: abarrett@utmb.edu.
authors.forename: Alan D T
authors.initials: AD
authors.lastname: Barrett
mesh_terms: D000818:Animals; D003715:Dengue / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000276:immunology* / Q000302:isolation & purification*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D018345:Mice, Knockout; D016019:Survival Analysis
chemical_list: D053059:Dengue Vaccines
keywords: Dengue; Interferon receptor; Mouse model; Vaccine