Humanized Mice in Dengue Research: A Comparison with Other Mouse Models

Abstract

Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research.

Dengue mouse models for evaluating pathogenesis and countermeasures

“…Nonobese diabetic/SCID (NOD/SCID) mice engrafted with human CD34 + hematopoietic stem cells and inoculated with DENV showed features of human Dengue such as thrombocytopenia and rash [76]. Other variations of humanized mice using different immunodeficient mouse backgrounds and sources of human cells for reconstitution have been used for DENV infection and reviewed recently [77]. An advantage to using humanized mice is the ability to study human immune cell responses to DENV infection and tropism in human leukocytes.…”

Dengue virus: epidemiology, biology, and disease aetiology

“…One mouse model (AG129) has been established, showing both mild and severe symptoms and clinical features of dengue (Sarathy et al 2018) which can be used both in the trial of a candidate vaccine and also in the discovery of antiviral drugs. Some genetically engineered or transgenic mouse dengue models have also been established for research purposes (C57BL/6J hTNF+++, IFNα/βR −/− Tg, Tg HLA-A*02:01, and B10.Tg HLA-DR3) (reviewed in Coronel-Ruiz et al 2020). Tupaia belangeri (northern treeshrew) fibroblast cells were reported to show permissibility and susceptibility for DENV infection and replication (Bustos-Arriaga et al 2011).…”

Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review

“…Moreover, it is also required that the animal model inoculated with a particular virus must demonstrate the same signs as in natural infection. For example, in the case of DENV, none of the humanized mice exhibited the classical features of hemorrhage and the leakage of plasma [214]. That is why a combination of several different models is needed to test the therapeutic efficacy of a novel antiviral or vaccine candidate against different flaviviruses.…”