Mouse Models to Study Dengue Virus Immunology and Pathogenesis

Abstract

The development of a compelling murine model of dengue virus (DENV) infection has been challenging, because DENV clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows investigation of questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination) contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of anti-viral drugs or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV-infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies.

CD8 + T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice

“…However, some DENV strains replicate in IFNAR Ϫ/Ϫ mice to detectable levels (47), which allows for assessment of the effect of priming on subsequent DENV challenge. Those experiments would be impossible in wildtype (WT) mice in which DENV does not replicate to measurable levels (47). Consistent with results obtained from experiments using AG129 mice, homotypic priming with 1 ϫ 10 6 PFU DENV2 (strain PL046) 2 weeks prior to DENV2 challenge (2 ϫ 10 5 PFU, strain S221) reduced viral RNA titers in the livers of IFNAR Ϫ/Ϫ mice upon challenge, even when CD8 ϩ T cells were depleted before challenge (Fig.…”

“…To evaluate the effect of nonlethal DENV priming on a subsequent lethal challenge with a different DENV serotype (heterotypic challenge) shortly after priming, we first used a model of DENV infection in 129/Sv mice lacking type I and II IFN receptors (AG129 mice). We chose this model because some DENV strains replicate in AG129 mice and cause a disease that recapitulates many features of DENV infection in humans and can be lethal (39,41,46,47). AG129 mice were nonlethally primed with 1 ϫ 10 4 PFU DENV4 (strain H241) 2 weeks prior to challenge with 1 ϫ 10 5 PFU DENV2 (strain S221), and survival was monitored.…”

“…The lack of replication in WT mice may be explained by the fact that DENV interferes with IFN signaling to establish infection in humans but is unable to do so in mice (51)(52)(53)(54). Therefore, mice deficient in IFN signaling have been increasingly used as a model to study DENV-induced pathology and immunity (26,30,47,48,(55)(56)(57)(58)(59)(60)(61).…”

Mast cell–macrophage dynamics in modulation of dengue virus infection in skin

“…34 Previous studies showed that intradermal inoculation of a wide range of DENV doses (4 9 10 7 to 3 9 10 9 PFU/mouse) in mice caused different levels of haemorrhage and thrombocytopenia. 25 Using this model in our study (1 9 10 9 DENV PFU/mouse), we found that Kit W-sh/W-sh mice are more susceptible to intradermal DENV infection than WT mice, as indicated by increased NS3 staining at the skin inoculation site.…”

The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling

“…Mice are widely used as an animal model to study flavivirus pathogenicity and antiviral tests (29)(30)(31). To this end, we systematically characterized the neurovirulence and neuroinvasiveness of DTMUV in mice.…”