Evaluation of sylvatic dengue virus isolates for their pathogenic potential in humans

PROJECT SUMMARY Four dengue viruses (DENV-1, 2, 3, 4) are endemic in humans and carried by mosquitoes. Dengue viruses (DENVs) also exist in a sylvatic cycle, a term derived from the Latin word silvaticus meaning "of the woods." The dengue virus sylvatic cycle exists in Southeast Asia and West Africa and is sustained by forest dwelling mosquitoes and non-human primates. Sylvatic DENVs are phylogenetically ancestral to human DENVs, suggesting that there were 4 spillover events from the sylvatic reservoir that gave birth to human DENV-1-4. Ongoing, sporadic human infections involving novel sylvatic dengue viruses indicate continuous spillover from the sylvatic reservoir. Although extensive knowledge exists about the biology of human DENV in both mosquitos and humans, our understanding of sylvatic dengue viruses remains strikingly limited. This is due in part to the dearth of sylvatic isolates available for study. Our hypothesis is that some (but not all) sylvatic viruses have the potential to replicate in human target cells and thus present a greater danger of future spillover occurrence. Here we create a diverse panel of sylvatic viruses, assess the ability of these viruses to enter and replicate in human target cells, and determine whether sylvatic isolates inactivate the human innate immune response in the same way that human isolates do. This research helps us understand the dengue virus reservoir and the zoonotic potential of these viruses.