Kathryn Hanley, PhD New Mexico State University khanley@mvar.nmsu.edu Phone:(505) 646-3611 Personal Website

Title: Evolutionary Consequences of Dengue Virus Emergence

Project Description:

Dengue virus, the causative agent of the disease dengue fever (DF) and its more severe form dengue hemorrhagic fever (DHF), is an emerging, mosquito-borne pathogen. Cases of both DF and DHF have shown a sharp increase in the past decades; currently an estimated 50-100 million cases of DF occur annually. One reason for this dramatic emergence is a rapid geographic spread of all four antigenically distinct serotypes of dengue virus (DEN1-4) and consequent increase in the degree of overlap among serotypes. Immune-mediated interactions between serotypes in the human host are known to enhance disease. Each serotype is comprised of multiple genetically distinct genotypes, and another reason for emergence is the spread of virulent genotypes into new areas, sometimes accompanied by the displacement of more benign endemic genotypes. As the range of dengue virus continues to expand, opportunities for interactions among genotypes and serotypes increase, particularly within the mosquito vector, in which infection is life-long. Yet little is known about how genotypes and serotypes interact within the vector and whether such interactions affect the evolution of the virus. Of particular importance for public health is whether competition within the vector selects for dengue virus variants that replicate to higher or lower levels, and thereby cause more or less severe disease, in humans. The proposed project will investigate within-vector competition between genotypes and serotypes of dengue virus using experimental co-infection of mosquitoes followed by quantification of the replication of different viruses. Viruses will then be serially passaged in mosquitoes to select for improved replication, after which the specific mutations that contribute to mosquito adaptation will be identified. Finally, the effect of such mutations on replication in mammalian cells, a model for replication in humans, will be measured. This research will help to predict the future progress of the dengue virus pandemic and will also contribute to the design of live-attenuated vaccines.