Human Susceptibility to Bacteria

 

The goals of this project, titled Hi-HOST for human in vitro susceptibility testing, are to

1) identify aspects of bacterial infection in human cells that exhibit heritable variation,

2) determine the genetic changes that are responsible, and

3) assess the relevance of this variation on the fitness of whole organisms.

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. Causation of the identified SNPs is being established by a combination of expression analysis, RNA interference, overexpression experiments, pharmacologic inhibition, and mechanistic studies tailored to the individual SNPs. Finally, relevance to health and disease is being measured using association analysis of clinical phenotypes and phenotypic measurements of knockout and transgenic mice.

The Hi-HOST Discovery Framework

Proof of concept article:

  • Ko DC, Shukla KP, Fong C, Wasnick M, Brittnacher MJ, Wurfel MM, Holden TD, O’Keefe GE, Van Yserloo B, Akey JM, Miller SI. (2009) A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am J Hum Genet. 85(2):214-27.

Bioinformatics tool developed for analysis:

  • Fong C, Ko DC, Wasnick M, Radey M, Miller SI, Brittnacher M. (2010) GWAS Analyzer: integrating genotype, phenotype and public annotation data for genome-wide association study analysis. Bioinformatics. 26(4):560-4.