Murine models of dengue virus infection for novel drug discovery

ABSTRACT

Introduction

Dengue virus (DENV) is the causative agent of the most prevalent human disease transmitted by mosquitoes in tropical and subtropical regions worldwide. At present, no antiviral drug is available and the difficulties to develop highly protective vaccines against the four DENV serotypes maintain the requirement of effective options for dengue chemotherapy.

Areas covered

The availability of animal models that reproduce human disease is a very valuable tool for the preclinical evaluation of potential antivirals. Here, the main murine models of dengue infection are described, including immunocompetent wild-type mice, immunocompromised mice deficient in diverse components of the interferon (IFN) pathway and humanized mice. The main findings in antiviral testing of DENV inhibitory compounds in murine models are also presented.

Expert opinion

At present, there is no murine model that fully recapitulates human disease. However, immunocompromised mice deficient in IFN-α/β and -γ receptors, with their limitations, have shown to be the most suitable system for antiviral preclinical testing. In fact, the AG129 mouse model allowed the identification of celgosivir, an inhibitor of cellular glucosidases, as a promising option for DENV therapy. However, clinical trials still were not successful, emphasizing the difficulties in the transition from preclinical testing to human treatment.

KEYWORDS:

• Antiviral
• AG129 mice
• dengue virus
• humanized mice
• immunocompetent mice
• mouse model
• preclinical testing

Article highlights

• Animal models are essential tools for research on DENV pathogenesis, vaccine development and antiviral testing.

• Currently, there is no a murine model of DENV primary or antibody-mediated infection fully representative of human illness.

• The signs of DENV infection diverge according to mouse species, virus strain and via of infection.

• In vivo antiviral screening of virus- and host-targeted DENV inhibitors has advanced in the last decades mainly through using interferon-deficient murine models of DENV infection.

• The preclinical testing in AG129 mice allowed the identification of potential antivirals with promising perspectives for human chemotherapy.

This box summarizes key points contained in the article.

Acknowledgement

AB Byrne is a fellow from CONICET and CC Garcia, EB Damonte and LB Talarico are career researchers from the same institution

List of abbreviations

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Universidad de Buenos Aires, Argentina.