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.
Highlights
Dengue Virus (DV), the causative agent of dengue fever (DF), is the most important vector-borne human pathogen, infecting between 50 and 100 million people annually (Who, 2012)
The results suggest that megakaryocytes represent the initial target of DV in bone marrow (BM), rather than a member of the monocytic lineage
In our Indian rhesus macaques, we have evaluated age as a contributing factor to viremia by comparing the titers of DV when propagated in whole BM in vitro
Summary
Dengue Virus (DV), the causative agent of dengue fever (DF), is the most important vector-borne human pathogen, infecting between 50 and 100 million people annually (Who, 2012). A young suckling mouse model inoculated intracranially with DV that displayed mild disease was developed (Sabin and Schlesinger, 1945) This model was quite limited, with paralysis observed only after 3–4 weeks in 10–20% of the mice, but this provided a starting point for virus adaptation and lead to the first small animal infection model. The role of DV specific cell-mediated responses in NHP models has received relatively less attention, some studies reported recognition of non-structural proteins in addition to viral components by both CD4+ and CD8+ T cells (Koraka et al, 2007; Mladinich et al, 2012) Such responses have been difficult to detect in immunized monkeys, even in those that show protection from challenge (Chen et al, 2007; Porter et al, 2012).
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