Spread and Evolution of West Nile virus in the United States

Since its emergence 20 years ago, West Nile virus (WNV) has become the most important mosquito-borne virus in the United States. Cycles of WNV outbreaks have led to an estimated 7 million human infections and have decimated certain bird populations. Even though there are expansive WNV surveillance and vector control systems in place, we critically lack a detailed understanding of how the virus is spreading and what drives outbreaks, which is integral to reducing the burden of disease. These knowledge gaps include: ( 1 ) how WNV spreads regionally and nationally, ( 2 ) what facilitates emergence and spread, ( 3 ) if WNV is evolving to local vector and host populations, and ( 4 ) how WNV genetic diversity influences virus phenotypes. We hypothesize that there are ecological, biological, and genetic barriers that determine endemic spread of WNV, leading to regional segregation of the virus. Furthermore, we predict that these factors and their impact on WNV genetic diversity contribute to the patterns of WNV outbreaks. Incorporating genomic approaches into traditional epidemiological and experimental investigations has the power to give us deep insights into how viruses emerge, spread, and evolve. Therefore, to test our hypotheses, and to uncover how virus movement and diversity contributes to outbreaks, we have established the "WestNile 4K Project" and will complete the following research: ( 1 ) generate and analyze an ultra large dataset of at least 8,000 new WNV genomes, by sequencing thousands of viruses from our large network of collaborating public health partners across the United States, and ( 2 ) directly examine the impact of WNV genetics on virus fitness and phenotype using a series of controlled laboratory experiments. The rationale is that by completion of our research goals, we will obtain a high definition reconstruction of WNV emergence, spread, and evolution, allowing us to define WNV transmission networks, investigate the role of virus diversity in outbreaks, and examine the impact of WNV genetics on virus phenotype. By sharing our data and analyses in real-time with our public health partners and the research community, our goal is to provide up-to-date resources to help inform WNV control.