Dennis Ko, MD, PhD
Box 3053 DUMC
Durham, NC 27710
Human genetic variation regulating infection and inflammation
Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, individuals demonstrate a large variability in the severity of infection. The long-term goal of the lab is to understand the genetic basis for differences in susceptibility to infection and related inflammatory disorders. We approach this question through a combination of experimental and computational approaches that combine high-throughput cell biology with quantitative human genetics. The identified genetic differences serve as the starting point for exploring new cell biology and human disease susceptibility genes.
Using hundreds of genotyped cell lines from different people, we measure inter-individual variation in host-pathogen traits and identify associated genetic differences with a cellular genome-wide association study (GWAS) approach called Hi-HOST (High-throughput Human in vitrO Susceptibility Testing). Importantly, Hi-HOST serves as a platform for both identification of SNPs associated with cellular traits and experimental dissection of how they affect those traits. To connect these cellular traits to human disease susceptibility, we have developed a computational framework called CPAG (Cross-Phenotype Analysis of GWAS) to identify cellular traits that can explain a portion of the genetic risk for human diseases based on similarity of GWAS hits. In this way, genetic variants that modulate complex human diseases can be connected to experimentally tractable cellular models to study mechanisms. Using this experimental and analytic platform, the ultimate goal is to reveal critical genes and pathways involved in the pathophysiology of disease to enable development of new therapeutic targets.
We have accumulated screening data for nine different pathogens, which are now being studied to reveal basic mechanisms of host-pathogen interactions. Current research efforts are focused on genetic variants that impact:
- Invasion of cells by Salmonellato reveal basic mechanisms of cellular uptake and relevance to risk of typhoid fever
- Inflammatory cell death (pyroptosis) in response to Salmonellaand development of metabolites as biomarkers for sepsis outcomes
- Cytokine response to Salmonellato elucidate novel host-pathogen signaling pathways and their relevance to risk and severity of infection and autoimmunity
- Chlamydia trachomatis invasion, replication, and cytokine-induction as a means of understanding susceptibility and severity of this common sexually transmitted infection
- Intracellular replication of Yersinia pestis, one of the most feared pathogens in human history, which we suspect has left lasting evolutionary consequences in humans
In characterizing variation in these traits, the first goal is to understand the molecular/cellular mechanism of how the identified genetic variants intersect with known pathways. The second goal is to use our findings to guide clinical association studies and experiments with animal models to determine the relevance in disease. Thus our lab employs experimental, computational, and translational approaches to understand the consequences of human genetic variation and welcomes enthusiastic individuals interested in any or all of these approaches. We hope that the knowledge gained in these studies will help explain why some individuals are resistant to different infections and in developing therapies to decrease the mortality and morbidity of susceptible individuals.