Proteus mirabilis swarming: Initiation and role during urinary tract infection

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Catheter-associated urinary tract infection (CAUTI) is the most common hospital-acquired infection, largely due to Proteus mirabilis. This species has the unique ability to differentiate into swarm cells that migrate across catheter surfaces and gain entry to the urinary tract, where P. mirabilis can persist despite antibiotic treatment and frequently results in formation of painful urinary stones. P. mirabilis swarming is therefore a fascinating and medically-relevant problem that has perplexed scientists since its discovery. There is a fundamental gap in understanding of the specific cues and conditions that trigger P. mirabilis swarming motility, as well as the role of swarm cells during UTI. Addressing this gap has the potential to guide design of catheters or coatings that prevent entry of P. mirabilis into the urinary tract and provide new targets for disruption of persistent and severe infections, reducing the burden of CAUTI and associated complications. The central hypothesis is that Proteus mirabilis swarm cell differentiation and swarming motility are initiated in response to specific environmental cues and influence the establishment, persistence, and severity of UTI. Guided by substantial preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify specific factors and conditions that trigger swarming and determine how these factors are sensed by the bacterial population, and 2) Define the role of swarm cell differentiation and swarming triggers in the persistence and severity of UTI. Under the first aim, factors that trigger swarming by the well-characterized P. mirabilis strain HI4320 are already being identified by the candidate, based on the ability to promote swarming under normally non-permissive conditions. Media formulations in which carbon source, nitrogen source, and pH are varied are being used to determine the optimal conditions and minimal requirements for initiation of swarming motility. A transposon library has also been created and will be screened to identify mutants that have lost the ability to swarm in response to triggers, allowing for identification of genes and pathways involved in sensing and responding to the triggers. Under the second aim, the established CBA/J model of ascending UTI and biophotonic imaging will be utilized to determine the frequency and distribution of swarm cells during UTI. The contribution of swarm cells and swarming triggers to the establishment, persistence, and severity of UTI will also be addressed using the CBA/J model and mutants constructed in the first aim. The proposed research is significant because it will provide insight into how bacteria decide to perform coordinated multicellular functions, both on an agar surface and during infection of a host. This research will also contribute to a general understanding of how bacteria sense and interact with their environment, and how bacterial metabolism impacts pathogenesis. Ultimately, such knowledge has the potential to inform catheter design and therapeutic strategies for reducing the burden of CAUTI. PUBLIC HEALTH RELEVANCE: Catheter-associated urinary tract infections (CAUTI) are the most common hospital-acquired infections and are largely caused by Proteus mirabilis. Once in the urinary tract, P. mirabilis can persist despite extensive antibiotic treatment and catheter changes and frequently results in the formation of painful urinary stones, demonstrating the importance of approaches that prevent initial migration of P. mirabilis from the catheter surface to the urinary tract. Understanding the conditions that allow for migration and defining the role o this unique form of motility in the establishment, persistence, and severity of urinary tract infection has the potential to guide catheter design and provide new targets for therapeutic intervention in CAUTI.