Host and pathogen genomics of severe pediatric infections

Infectious diseases are among the leading causes of human morbidity and mortality, with the greatest burden felt in the pediatric population. For any infectious disease, only a fraction of the exposed individuals develop clinical symptoms. These inter-individual differences can be due to variation in pathogen virulence or in host susceptibility. The recent advent of high-throughput sequencing (HTS) technology has enabled studies of both human and pathogen genetic factors that have the potential to influence infectious diseases pathogenesis and alter clinical presentation. In this thesis, I present a set of genomic studies that used HTS to dissect the genetic basis of life-threatening infections with Pseudomonas aeruginosa (P. aeruginosa) and respiratory syncytial virus (RSV). This work provides conclusive evidence for the role of rare human genetic variants in susceptibility to life-threatening P. aeruginosa and RSV infections in previously healthy children. Furthermore, in an attempt to determine the role of viral genetic factors in severe presentations of RSV infection, I established a framework for exploring RSV genetic variation using HTS technology and bioinformatic analysis. Together, theses studies demonstrate that current genomic technology, bioinformatic analysis and functional follow-up have the potential to give us novel insight into the molecular basis of host-pathogen interactions and infectious disease pathogenesis.