Grant: Operating Grant

Microbial antibiotic resistance is rapidly becoming wide spread, making infections that were once easily treated difficult, or impossible, to eradicate. Our need for new therapies is more pressing than ever. In order to develop new therapies that short-circuit the infectious process, a detailed understanding of how bacteria cause infection is required. To cause infection, microbes must produce specialized factors called virulence determinants after entering our bodies. For example, diarrhea-causing Escherichia coli must assemble hair-like structures called pili on the bacterial cell surface that allow adherence to intestinal cells. Next, a more intimate attachment is formed between human and bacterial cells and a bacterial secretion system injects virulence determinants directly into intestinal cells. This ultimately causes diarrhea and the symptoms of E. coli infection. Bacteria use special regulatory proteins or pathways to control expression of virulence determinants so that they are only produced when needed (i.e. inside our bodies). My lab has evidence that one such regulatory pathway, the Cpx envelope stress response, is capable of shutting off the pili and secretion system required for E. coli to cause diarrhea. This effect is also observed in other microbes that cause diarrhea. Accordingly, it is our hypothesis that multiple disease-causing bacteria use the Cpx response to shut down expression of virulence determinants when they are not needed or are detrimental to the microbe. Our goal is to characterize the mechanism by which the Cpx response accomplishes this task in E. coli, with the hope that this knowledge will be exploited in the future to develop new treatments for infection.