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Review
. 2019 Jan 8;11(1):35.
doi: 10.3390/v11010035.

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

Alejandro Marín-Lopez  1   2 , Eva Calvo-Pinilla  3 , Sandra Moreno  4 , Sergio Utrilla-Trigo  5 , Aitor Nogales  6 , Alejandro Brun  7 , Erol Fikrig  8 , Javier Ortego  9
Affiliations
Review

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

Alejandro Marín-Lopez et al. Viruses. .

Abstract

Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate animal model is a critical concern. Adult mice with gene knockouts of the interferon α/β (IFN-α/β) receptor (IFNAR(-/-)) have been described as a model of arbovirus infections. Studies with the natural hosts of these viruses are limited by financial and ethical issues, and in some cases, the need to have facilities with a biosafety level 3 with sufficient space to accommodate large animals. Moreover, the number of animals in the experiments must provide results with statistical significance. Recent advances in animal models in the last decade among other gaps in knowledge have contributed to the better understanding of arbovirus infections. A tremendous advantage of the IFNAR(-/-) mouse model is the availability of a wide variety of reagents that can be used to study many aspects of the immune response to the virus. Although extrapolation of findings in mice to natural hosts must be done with care due to differences in the biology between mouse and humans, experimental infections of IFNAR(-/-) mice with several studied arboviruses closely mimics hallmarks of these viruses in their natural host. Therefore, IFNAR(-/-) mice are a good model to facilitate studies on arbovirus transmission, pathogenesis, virulence, and the protective efficacy of new vaccines. In this review article, the most important arboviruses that have been studied using the IFNAR(-/-) mouse model will be reviewed.

Keywords: IFNAR(−/−) mice model; arbovirus; interferon; pathology; vaccines.

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Conflict of interest statement

All the authors declare no conflicts. We apologize to those colleagues whose work we were unable to cite because of space considerations.

Figures

Figure 1
Figure 1
Signal transduction by the type I IFN receptors in wild-type (WT) or IFNAR−/− mice. Transcription of IFN genes is induced rapidly in response to viral infection. Cells sense viruses using multiple signaling pathways that ultimately will activate several transcription factors and their subsequent translocation into the nucleus, resulting in the activation of type I IFN (IFNα/β) genes. In WT mice, the released type I IFN is bound by the specific receptors IFNAR1/IFNAR2 trigging phosphorylation of JAK1/TYK2 kinases that activate STAT1 and STAT2. Phosphorylated STAT1/STAT2 heterodimers bind IRF9 and the complex is translocated to the nucleus where it induces expression of ISGs with ISRE-dependent promoters. The expression of ISGs will induce an antiviral state to prevent viral infection. However, in IFNAR1−/− mice, the antiviral state is not created, and cells are more susceptible to be infected. JAK, Janus activated kinase; TYK2, tyrosine kinase 2, ISRE, IFN-stimulated response element; ISG, IFN-stimulated gene; OAS, oligoadenylate synthetase; MX, myxovirus resistance; ISG15, IFN-stimulated gene factor 15; TRIM, tripartite motif-containing proteins; IFITM, IFN-induced transmembrane proteins; IRF, IFN-regulatory factors; STAT, signal transducer and activator of transcription; NF-κ B, nuclear factor of kappa light polypeptide gene enhancer in B-cells.
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