Genetic causes and epigenetic consequences of infection in childhood.

Infection in children results in 3 million deaths annually. Designing better tools to control infection needs an improved understanding of why children develop invasive infection. Moreover, the burden of infection in children is largely framed through its immediate consequences, and the long-term sequelae of a high burden of infection in childhood is undefined. My recent work suggests a model in which genetic variation determines whether or not a child develops infection. In turn, episodes of infection affect genes through epigenetic changes, modifying risk of cancer in later life. I will test this model through the following experiments: 1. Genome-wide association studies in Kenyan and Ugandan children to identify genetic variation associated with infection risk. 2. Expression quantitative trait locus studies in immune cells during infection to understand the function of infection-associated genetic variation discovered by GWAS. These experiments will be performed in controlled human challenge models of infection. 3. Map epigenetic changes in Ugandan children throughout childhood, correlating these with burden of infection. We will then test if infection-associated epigenetic changes are associated with cancers in adulthood. Together these studies will help us understand why children develop invasive infection and what the consequences of those infections are for long-term health.