Linking vector, virus and immunity to the evolving fitness of dengue virus

Across pathogens, it remains unclear why some lineages persist while others die out. Population immunity pressure coupled with relative abilities to infect and disseminate in hosts are likely to play a critical role. There are key data and methodological gaps that prevent us from identifying and quantifying drivers of pathogen fitness. We need robust measures of fitness and be able to apply these measures to sequences from the same ecological disease system over many years. We also need to understand how an individual's immunity responds, if at all, to ongoing exposures by continuously changing pathogens. Finally, we need appropriate methods that can integrate candidate drivers of fitness within the same analytical framework. Using dengue virus as a model system, I will use annual sequence data from Thailand collected from 1973 to today alongside long term measurements of immune responses in the same individuals over 25 years apart to answer the following questions: - How does individual immunity change over decadal time frames? I will re-recruit individuals who were infected with dengue virus during participation in cohort studies in the 1990s. I will measure their antibody response today to viruses that have circulated over the past 58 years, including the specific virus that infected them in the 1990s. I will compare their responses today to those in stored samples from the original cohort study. - What are the drivers of fitness? I will quantify the changing fitness of circulating dengue viruses from 1973 to today. I will then explore how changes in viral dissemination in mosquitoes, changes in kinetics in human cells and the build up of strain-specific population immunity interact to determine viral fitness. By studying the dynamic interplay between pathogen fitness, host immunity and vector, this project will explore a fundamental concept of disease ecology, as well as providing insights into a major threat to global public health.