Mouse models of dengue virus infection for vaccine testing

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7051-7060
Number of pages10
JournalVaccine
Volume33
Issue number50
DOIs
StatePublished - Dec 10 2015

Fingerprint

Dengue virus
Dengue Virus
Virus Diseases
dengue
Vaccines
animal models
Dengue
vaccines
infection
mice
immunity
testing
Interferon Receptors
interferons
Infection
Immunity
mosquito-borne diseases
viruses
receptors
Antibody-Dependent Enhancement

Keywords

  • Dengue
  • Interferon receptor
  • Mouse model
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine

Cite this

Mouse models of dengue virus infection for vaccine testing. / Sarathy, Vanessa; Milligan, Gregg; Bourne, Nigel; Barrett, Alan.

In: Vaccine, Vol. 33, No. 50, 10.12.2015, p. 7051-7060.

Research output: Contribution to journalArticle

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