An integrative platform for cell-resolution analysis of the acute-to-chronic transition in bacterial pathogens
Prof. J. Christian Ray, Department of Molecular Biosciences
Center for Computational Biology
University of Kansas
Project dates: 2016-2017
This pilot project will develop a new method to understand how pathogens form chronic infections. Many experiments in model bacterial organisms, especially Escherichia coli, have provided tantalizing clues about how bacteria can resist the assaults of antibiotic treatment. In our emerging picture of bacterial robustness, it appears that colonies can transition into a slow-growing state that creates a stubborn infection. Recently, researchers have discovered that cellular lineage (that is, non-genetic inheritance of cellular contents) and the interaction of many different similar growth-regulating systems at once together create specific statistical patterns of heterogeneous robustness to antibiotic treatment. Ultimately, researchers believe that these factors are contributing to the acceleration of antibiotic resistance, among the most dangerous of emerging medical crises today. One of the worst offenders of antibiotic resistance is the most common cause of urinary tract infections, known as uropathogenic E. coli, or UPEC. The goal of our pilot project is to test the feasibility of a new, integrative method for understanding how heterogeneity in UPEC colonies contributes to its ability to form chronic infections. Our strategy is to create a microfluidic device that allows us to monitor, and capture, lineages of UPEC that can be subjected to global gene expression analysis with next-generation sequencing techniques (Aim 1). Because UPEC is closely related to the laboratory E. coli strain, which has had many valuable molecular tools and strains created for it, we will also use our transcriptomic analysis in conjunction with a comparative regulatory network approach to identify targets in UPEC that control its ability to maintain robust chronic infections (Aim 2).