The evolution of dengue virus type 3 in association with the emergence of dengue hemorrhagic fever in Sri Lanka

Dengue virus is a mosquito borne pathogen that occurs throughout the tropics and subtropics. Dengue virus infections can be asymptomatic, cause non-fatal dengue fever (DF), or cause dengue hemorrhagic fever (DHF), a frequently fatal condition characterized by internal hemorrhaging, significant fluid loss and shock. In some areas of the tropics, DHF has become entrenched, with annual epidemics of thousands of cases, while other regions experience DHF sporadically or not at all. The reasons for the emergence of DHF in a given region are not well understood. The island of Sri Lanka offers a unique opportunity to study DHF emergence. Though dengue virus has been endemic in Sri Lanka since at least 1966, DHF was very rare in Sri Lanka before 1989. However, since 1989, Sri Lanka has experienced annual DHF epidemics, with reported cases ranging from several hundred to more than one thousand. This sudden and persistent change in DHF incidence in Sri Lanka remains unexplained. Research presented here was done in the context of a disease model for DHF that combines aspects of dengue virus transmission and known and putative DHF risk factors. Using a large body of available data and samples, I test the hypothesis that the appearance of a novel virus genotype has lead to DHF emergence in Colombo, Sri Lanka. Specifically, in the context of the disease model, I establish that for Colombo, Sri Lanka, there have been no changes in weather, the size, age structure, nutritional status and genetic background of the Colombo population, virus transmission rate, population immune status, or relative abundance of dengue virus serotypes that could explain the emergence of DHF in Colombo, Sri Lanka. Through a detailed genetic analysis of dengue virus genomic sequences, I demonstrate that a new genotype of dengue virus emerged in Colombo at the same time that DHF emerged in Colombo. Furthermore, I demonstrate that a closely related virus has been associated with DHF outbreaks in Latin America. Finally, I propose a hypothesis for a biological basis for the observed difference in disease severity associated with the different virus genotypes.