Genetic Variants of Immune Dysregulation and Thrombotic Microangiopathy in Severe Pediatric Sepsis Induced Organ Dysfunction

Sepsis results in 75,000 pediatric and one million adult hospital admissions per year, costing $20 billion dollars and 200,000 lives in the US annually. Risk for severe infection has a heritable component, and offspring of parents who suffer early death from infection have a 6-fold increased risk of infectious death even when adopted into other households. However, the specific sites of genetic variation that convey this are poorly understood. Here, I propose to use whole exome sequencing to identify septic individuals with shared genetic risk for heritable thrombotic microangiopathy and immune dysregulation, and determine if these genotypes associate with clinical, cytokine and organ injury patterns typical of these thrombotic microangiopathy and hyperinflammatory disorders during severe sepsis, phenotypes that have been associated with poor outcome. My overall objective in this career development award is to identify genotypes that confer risk for development of thrombotic microangiopathy and immune dysregulation in severe sepsis, and validate these findings in multiple sepsis cohorts. My central hypothesis is that immunologically active variants that cause primary immunologic disorders characterized by thrombotic microangiopathy and hyperinflammation will be linked to the development of related phenotypes and organ failure patterns in severe sepsis. I will test my central hypothesis in three specific aims: 1) Confirm the link between thrombotic microangiopathy-related variants and complement hyperactivation in severe sepsis by direct measurement of complement activation products and archetypal organ injury biomarkers, 2) Explore the relationships between immune dysregulation genotype and clinical, immunologic and organ injury patterns typical for cytotoxic defects and dysfunctional macrophage and T-cell interaction and 3) externally validate our previous IEI genotype-phenotype associations in novel cohorts. This approach may allow for identification of specific genetic risk variants, as well as outcome-associated disease mechanisms as targets for further study in severe sepsis. Closely mentored by experts in pediatric sepsis, immune dysregulation, genomic medicine, bioinformatics and data science, this award will provide essential training in coding, genetic epidemiology, statistical assessment of genomic data, and prospective clinical trials. As the foundation for a career, this project will hone my skills in genomic research design and analysis necessary to study precision approaches to pediatric critical care.