A lethal model of disseminated dengue virus type 1 infection in AG129 mice

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The mosquito-borne disease dengue is caused by four serologically and genetically related flaviviruses termed DENV-1 to DENV-4. Dengue is a global public health concern, with both the geographical range and burden of disease increasing rapidly. Clinically, dengue ranges from a relatively mild self-limiting illness to a severe life-threatening and sometimes fatal disease. Infection with one DENV serotype produces life-long homotypic immunity, but incomplete and short-term heterotypic protection. The development of small-animal models that recapitulate the characteristics of the disseminated disease seen clinically has been difficult, slowing the development of vaccines and therapeutics. The AG129 mouse (deficient in interferon alpha/beta and gamma receptor signalling) has proven to be valuable for this purpose, with the development of models of disseminated DENV-2,-3 and -4 disease. Recently, a DENV-1 AG129 model was described, but it requires antibody-dependent enhancement (ADE) to produce lethality. Here we describe a new AG129 model utilizing a non-mouse-adapted DENV-1 strain, West Pacific 74, that does not require ADE to induce lethal disease. Following high-titre intraperitoneal challenge, animals experience a virus infection with dissemination to multiple visceral tissues, including the liver, spleen and intestine. The animals also become thrombocytopenic, but vascular leakage is less prominent than in AG129 models with other DENV serotypes. Taken together, our studies demonstrate that this model is an important addition to dengue research, particularly for understanding the pathological basis of the disease between DENV serotypes and allowing the full spectrum of activity to test comparisons for putative vaccines and antivirals.

Original languageEnglish (US)
Article number000923
Pages (from-to)2507-2519
Number of pages13
JournalJournal of General Virology
Volume98
Issue number10
DOIs
StatePublished - Oct 1 2017

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Dengue Virus
Virus Diseases
Dengue
Antibody-Dependent Enhancement
Vaccines
Interferon alpha-beta Receptor
Flavivirus
Culicidae
Intestines
Antiviral Agents
Blood Vessels
Immunity
Spleen
Animal Models
Public Health
Liver
Infection
Research
Serogroup

Keywords

  • AG129 mouse
  • Dengue virus
  • Flavivirus
  • Mouse model
  • Pathogenicity

ASJC Scopus subject areas

  • Virology

Cite this

A lethal model of disseminated dengue virus type 1 infection in AG129 mice. / Milligan, Gregg; Sarathy, Vanessa; White, Mellodee M.; Greenberg, M. Banks; Campbell, Gerald; Pyles, Richard; Barrett, Alan; Bourne, Nigel.

In: Journal of General Virology, Vol. 98, No. 10, 000923, 01.10.2017, p. 2507-2519.

Research output: Contribution to journalArticle

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