Sylvatic dengue: evolution, emergence, and impact on human health
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Dengue viruses (DENV) are the most important arboviral pathogens in tropical and subtropical regions throughout the world. Transmission includes a sylvatic, enzootic cycle between nonhuman primates and arboreal mosquitoes of the genus Aedes, and an urban, endemic/epidemic cycle between Aedes aegypti, a mosquito with larval development in peridomestic water containers, and human reservoir hosts. All 4 serotypes of endemic DENV evolved independently from ancestral sylvatic viruses and have become both ecologically and evolutionarily distinct. The independent evolutionary events that resulted in the emergence of DENV were facilitated by the expansion of DENV progenitors’ host range in Asia to new vectors and hosts that occurred gradually over a period of several hundred years. Emerging viral pathogens often become human pathogens by changing their host range from another vertebrate organism. This study assessed the likelihood of current sylvatic DENV-2 strains to emerge into the human transmission cycle by investigating the factors that facilitate their emergence. My analysis of sylvatic and endemic DENV-2 strains’ ability to replicate in two surrogate human model hosts, determined that adaptation to humans is probably not a necessary component of sylvatic dengue emergence. Then, through an analysis of several sylvatic DENV-2, I demonstrated that both endemic and sylvatic DENV-2 share similar rates of evolutionary change and patterns of natural selection. These findings imply that the potential of future DENV re-emergence from the sylvatic cycle is high. Subsequently, phylogenetic analysis of virus genomes isolated from febrile patients in Nigeria during DENV-2 activity, demonstrated that unrecognized outbreaks of sylvatic DENV-2 in humans are possible. However, their re-emergence into the endemic cycle would be limited by homotypic immunity mediated by virus neutralizing antibodies.