Type 1 Fimbriae, a Colonization Factor of Uropathogenic Escherichia coli, Are Controlled by the Metabolic Sensor CRP-cAMP

Abstract

Type 1 fimbriae are a crucial factor for the virulence of uropathogenic Escherichia coli during the first steps of infection by mediating adhesion to epithelial cells. They are also required for the consequent colonization of the tissues and for invasion of the uroepithelium. Here, we studied the role of the specialized signal transduction system CRP-cAMP in the regulation of type 1 fimbriation. Although initially discovered by regulating carbohydrate metabolism, the CRP-cAMP complex controls a major regulatory network in Gram-negative bacteria, including a broad subset of genes spread into different functional categories of the cell. Our results indicate that CRP-cAMP plays a dual role in type 1 fimbriation, affecting both the phase variation process and fimA promoter activity, with an overall repressive outcome on fimbriation. The dissection of the regulatory pathway let us conclude that CRP-cAMP negatively affects FimB-mediated recombination by an indirect mechanism that requires DNA gyrase activity. Moreover, the underlying studies revealed that CRP-cAMP controls the expression of another global regulator in Gram-negative bacteria, the leucine-responsive protein Lrp. CRP-cAMP-mediated repression is limiting the switch from the non-fimbriated to the fimbriated state. Consistently, a drop in the intracellular concentration of cAMP due to altered physiological conditions (e.g. growth in presence of glucose) increases the percentage of fimbriated cells in the bacterial population. We also provide evidence that the repression of type 1 fimbriae by CRP-cAMP occurs during fast growth conditions (logarithmic phase) and is alleviated during slow growth (stationary phase), which is consistent with an involvement of type 1 fimbriae in the adaptation to stress conditions by promoting biofilm growth or entry into host cells. Our work suggests that the metabolic sensor CRP-cAMP plays a role in coupling the expression of type 1 fimbriae to environmental conditions, thereby also affecting subsequent attachment and colonization of host tissues. Attachment of bacteria to the surface of host tissues is a crucial initial step in the establishment of bacterial infections. This process is mediated by adhesins, such as the type 1 fimbriae of Escherichia coli, which play a key role during urinary tract infections by mediating adhesion to the uroepithelium. The expression of type 1 fimbriae is finely regulated attending to environmental signals and is under phase variation control, which determines the percentage of fimbriated cells in the population. In this report, we show that the expression of type 1 fimbriae is repressed by a metabolic sensor of the cell, the global regulatory complex CRP-cAMP. We demonstrate that CRP-cAMP affects the switching outcome by selectively inhibiting the recombination process in one direction only, resulting in a lower percentage of fimbriated cells. Such a switch to the non-fimbriated state after successful adhesion might be advantageous in the urinary tract, where the immune mechanisms of the host favor the removal of bacteria expressing immunogenic surface structures. Understanding the regulatory networks that govern regulation of virulence and colonization factors is both of basic interest and might help to develop novel strategies to treat bacterial infections.