|Faculty and Research
Dennis Ko, MD, PhD
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 novel cellular genome-wide association approach that combines high-throughput cell biology with quantitative human genetics. The identified genetic differences serve as the starting point for exploring new cell biology and new human disease susceptibility genes.
The Hi-HOST Discovery Framework
We perform genome-wide association of cellular traits of host-pathogen interactions using a screening approach called Hi-HOST (high-throughput human in vitro susceptibility testing). Using cells derived from hundreds of normal individuals, we have measured the naturally occurring variation for several intermediate phenotypes of susceptibility. Family-based association analyses are being used to correlate values from these assays with SNPs on a genome-wide scale. The traits that are currently the focus of our research efforts are:
- Inflammatory cell death (pyroptosis) in response to Salmonella as a probe for the caspase-1 inflammatory response
- Invasion of cells by Salmonella as a measure for actin/Rho GTPase signaling during macropinocytosis
- Cytokine response to Salmonella as a measure of cytokine expression and release likely important for both infection and inflammatory disease
- 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 compare our findings with clinical association studies and mouse models to determine the relevance in disease. Thus our lab employs both experimental and computational approaches to understand the consequences of human genetic variation and welcomes enthusiastic individuals interested in either or both. 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.