Jonathan Hansen

Associate Professor of Medicine

Research Interests

A widely accepted hypothesis is that inflammatory bowel diseases (IBD) including Crohn’s disease and ulcerative colitis are caused by overly-aggressive, T cell-mediated immune responses to bacterial products in genetically susceptible hosts. Bacterial components, including some bacterial stress-response proteins, promote inflammation by stimulating both innate and adaptive host immune systems. While the host response to bacterial products has been extensively studied, little is known about the subsequent effects of host inflammation on bacterial properties. Until this is better understood, it will not be possible to design new therapeutic strategies for IBD that target this interaction. In preliminary data, we have shown that selective colonization with a commensal strain of Escherichia coli (NC101) causes colitis in IL-10-deficient (IL-10-/-), but not wild-type (wt), mice, and that intestinal inflammation triggers NC101 to upregulate bacterial stress-response genes, including ibpB. IbpB is a small heat shock protein that helps bacteria tolerate heat stress and potentially lethal levels of reactive oxygen species (ROS) such as those found in the inflamed intestine and macrophage phagolysosomes. We have preliminary evidence that E. coli ibpB is upregulated by secreted and intracellular factors, inhibits uptake of bacteria by macrophages, and increases intracellular survival. We HYPOTHESIZE that the host inflammatory milieu upregulates bacterial ibpB, which in turn allows bacteria to adapt to the environment and perpetuate inflammation by increasing their survival and virulence. We will test this hypothesis in the following SPECIFIC AIMS: 1) Determine how immune cells upregulate E. coli ibpB and consequent effects on mechanisms of bacterial clearance in vitro We will study the roles of inflammatory cytokines and ROS in upregulating E. coli ibpB using ibpB-eGFP reporter bacteria. We will also determine mechanisms by which E. coli IbpB inhibits bacterial uptake by macrophages using gentamicin protection assays with NC101 lacking or overexpressing ibpB. 2) Examine the biological relevance of E. coli IbpB in the initiation and perpetuation of chronic experimental colitis in E. coli monoassociated IL-10-/- mice. We will measure histological inflammation, bacterial distribution, innate and adaptive immune responses in wt and IL-10-/- mice monoassociated for various lengths of time with NC101 or ibpB-deficient NC101. Collectively, these studies will establish the importance of E. coli ibpB in the perpetuation of chronic colitis and will stimulate the development of novel pharmacologic agents to treat IBD. At the same time, these studies will yield a fundamentally new paradigm regarding bacterial stress responses to inflammation and bacterial/host crosstalk during inflammation that will advance the general field of host-microbial interactions.