This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Dengue virus (genus Flavivirus) the most significant threat to public health among the arthropod-borne viruses, circulates in two distinct life cycles. Epidemic dengue viruses, which cause human dengue fever, cycle between humans and peridomestic Aedes mosquitoes. Sylvatic dengue viruses cycle in the forest canopies of Africa and Asia between sylvatic Aedes species and non-human primates. Endemic and sylvatic viruses show high sequence homology, but sylvatic viruses do not cause outbreaks in humans. Our initial hypothesis to explain this apparent paradox was that an 'adaptive barrier' prevents the emergence of sylvatic dengue virus, or more specifically that sylvatic dengue virus replicates poorly in either humans or in peridomestic Aedes species. However, in collaboration with INBRE mentor Scott Weaver (UTMB) and members of his lab, we have demonstrated that no such adaptive barrier exists, because sylvatic and endemic strains of DENV serotype 2 (DENV-2) are equally infectious for models of virus replication in humans (Vasilakis et al. 2007, Vaslakis et al. submitted, Vasilakis et al. in preparation) and for Ae. aegypti, the primary vector of endemic dengue (Hanley et al. in preparation).An alternative explanation for the restriction of sylvatic dengue to the forest cycle is that competition with endemic strains of DENV prevents emergence of sylvatic strains. Thus, our current research focuses on characterizing the strength and symmetry of competition between endemic and sylvatic DENV strains. Such competition could occur in either the host or vector, but may be more likely in the vector where infection persists for life. We have recently demonstrated that when mixed infections of DENV-2 and DENV-4 are introduced to cultured mosquito cells concurrently (co-infection) or with a designated interval between the introduction of the first and second serotype (superinfection), the replication of each serotype is decreased, as is the overall productivity of the infection (Pepin et al. in press, Pepin and Hanley in preparation). Moreover suppression is strongest for strains that infect second in superinfection treatments. These patterns are the hallmarks of competition. In the proposed research, patterns of competition between DENV-2 and DENV-4 will be tested in mosquitoes in vivo. Subsequently, we will use the same methods to measure competitive suppression of a panel of sylvatic and endemic DENV-2 isolates in vivo. Competitive suppression will be measured as the titer achieved by a particular isolate when it is co-infected with a common DENV-4 competitor versus when it infects alone. The relative competitive suppression of sylvatic and endemic isolates will be compared. If sylvatic isolates are poorer competitors against endemic DENV-4 than other endemic isolates, this will support the hypothesis that competition may contribute to the exclusion of sylvatic DENV from the endemic cycle.
Showing the most recent 10 out of 296 publications
