Can non-human primates serve as models for investigating dengue disease pathogenesis?

Abstract

Dengue Virus (DV) infects between 50 and 100 million people globally, with public health costs totaling in the billions. It is the causative agent of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), vector-borne diseases that initially predominated in the tropics. Due to the expansion of its mosquito vector, Aedes spp., DV is increasingly becoming a global problem. Infected individuals may present with a wide spectrum of symptoms, spanning from a mild febrile to a life-threatening illness, which may include thrombocytopenia, leucopenia, hepatomegaly, hemorrhaging, plasma leakage and shock. Deciphering the underlining mechanisms responsible for these symptoms has been hindered by the limited availability of animal models that can induce classic human pathology. Currently, several permissive non-human primate (NHP) species and mouse breeds susceptible to adapted DV strains are available. Though virus replication occurs in these animals, none of them recapitulate the cardinal features of human symptomatology, with disease only occasionally observed in NHPs. Recently our group established a DV serotype 2 intravenous infection model with the Indian rhesus macaque, which reliably produced cutaneous hemorrhages after primary virus exposure. Further manipulation of experimental parameters (virus strain, immune cell expansion, depletion, etc.) can refine this model and expand its relevance to human DF. Future goals include applying this model to elucidate the role of pre-existing immunity upon secondary infection and immunopathogenesis. Of note, virus titers in primates in vivo and in vitro, even with our model, have been consistently 1000-fold lower than those found in humans. We submit that an improved model, capable of demonstrating severe pathogenesis may only be achieved with higher virus loads. Nonetheless, our DV coagulopathy disease model is valuable for the study of select pathomechanisms and testing DV drug and vaccine candidates.

A Lethal Murine Infection Model for Dengue Virus 3 in AG129 Mice Deficient in Type I and II Interferon Receptors Leads to Systemic Disease

“…DENV is transmitted by Aedes mosquitoes to humans in the urban cycle, while the sylvatic (jungle) transmission cycle involves mosquitoes and monkeys. Therefore, nonhuman primates (NHP) have been studied as a model of nonlethal infection, as the majority of the studies have not shown clinical signs of infection; however, promising new models include some features of human disease, and have been reviewed recently (4,5,6). Notwithstanding the limitations, the NHP model has been used to test live attenuated and recombinant vaccine candidates (7,8).…”

Trials and tribulations on the path to developing a dengue vaccine

“…Non-human primate species are permissive to DENV infection but typically do not display clinical pathology [24][25][26]. A recent literature review provides a comprehensive summary of primate species' virologic and clinical responses to infection with a variety of DENV strains [27].…”

Antibody response to dengue virus

“…route resulted in hemorrhage and petechiae on day 3e5 of primary infection [81]. Further standardization of virus strains or other experimental conditions will be an important promise to have a reliable model [82].…”