Patrick Seed, MD, PhD
Assistant Professor
Department of Pediatrics
Department of Molecular Genetics and Microbiology

Uropathogenic Escherichia coli (UPEC) are the leading cause of community-acquired urinary tract infections (UTIs). Over 100 million UTIs occur annually throughout the world including more than 7 million in U.S. adolescents and adults and result in billions of health care dollars. UTIs in younger children are associated with greater risk of morbidity and mortality than in older children and adults. Neonates have increased risk of urosepsis and meningitis. Febrile UTIs in children under five years frequently represent pyelonephritis which results in renal scarring in 2%7 to 64% cases in the absence of underlying urinary tract anomalies and can lead to hypertension and chronic renal failure.

Recurrent UTI causes additional morbidity. Over 25% of women with an initial UTI experience recurrent infections, and most occur within the first six months after the initial infection. Up to 70% of young children with UTI develop at least one recurrence, putting them at a higher risk for renal scarring. Most studies have shown that over 40-60% of the recurrent UPEC are the sa me isolate as caused the initial UTI.

The pathogenesis of UPEC in a mouse model of bladder infection (cystitis) is illustrated in Figure 1. UPEC adhere, invade, and amass in the superficial epithelial cells of the bladder. The biomasses of bacteria, called intracellular bacterial communities (IBC), have biofilm-like characteristics, making this a great model of in vivo biofilm formation. These first three steps in pathogenesis rely on the adhesive pilus structure called type 1 pili. After IBC formation, the bacteria disperse and flux from infected cells where they re-adhere and invade new epithelial cells. In mice, we observe that bacteria can also enter into a chronic persistent state and reemerge to produce further episodes of bacteruria months later.

Figure 1. A model of cystitis pathogenesis. Bacteria enter the normally sterile urinary tract and initiate an infection with adherence to the bladder epithelium.  Bacteria invade and form IBCs. Mature IBCs disperse and introduce bacteria back into the bladder lumen starting a new round of adherence, invasion, and IBC formation. After several rounds and intervention by the host innate immunity, the cycle is broken leaving a quiescent reservoir that may recrudesce at a later time.

Using a cutting-edge combination of microbial genetics, molecular biology, advanced microscopy, biochemistry, immunology, and animal modeling, we are exploring how UPEC interacts with the bladder epithelium to persist during acute and chronic infections. We have shown that intracellular proliferation in IBC is a key step in pathogenesis and, as a consequence, are exploring the regulation and contribution of key virulence factors in the initiation and development of the IBC state. We are also exploring how discrete members of bacterial populations enter into productive niches while other subpopulations fail to persist resulting in profound population bottlenecks. Last, we are mapping the ligand-receptor bacterial-host temporal spatial changes that occur as a consequence of bladder infections. Perhaps most importantly, we are collaborating with clinical experts in urinary tract infections to create a reciprocal exchange of ideas and observations. Through these collaborations, we aim to use key clinical observations and human specimens to shape our molecular research (bedside to bench) and translate some of the molecular details of UTI discovered in the laboratory into new diagnostics and therapies (bench to bedside).