Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host-pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

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Urinary tract infections: epidemiology, mechanisms of infection and treatment options

http://www.dzumenvis.nic.in/Physiology/pdf/Biofilms%20the%20matrix%20revisited.pdf

Biofilms: the matrix revisited

Urinary tract infections (UTIs) are among the most common bacterial infections acquired in the community and in hospitals. In individuals without anatomical or functional abnormalities, UTIs are generally self limiting, but have a propensity to recur. Uropathogens have specialized characteristics, such as the production of adhesins, siderophores and toxins that enable them to colonize and invade the urinary tract, and are transmitted between individuals both through person-to-person contact and possibly via food or water. Although generally self limiting, treatment of UTIs with antibiotics leads to a more rapid resolution of symptoms and is more likely to clear bacteriuria, but also selects for resistant uropathogens and commensal bacteria and adversely affects the gut and vaginal microbiota. As uropathogens are increasingly becoming resistant to currently available antibiotics, it may be time to explore alternative strategies for managing UTI.

The epidemiology of urinary tract infection

Escherichia coli entry into the bladder is met with potent innate defenses, including neutrophil influx and epithelial exfoliation. Bacterial subversion of innate responses involves invasion into bladder superficial cells. We discovered that the intracellular bacteria matured into biofilms, creating pod-like bulges on the bladder surface. Pods contained bacteria encased in a polysaccharide-rich matrix surrounded by a protective shell of uroplakin. Within the biofilm, bacterial structures interacted extensively with the surrounding matrix, and biofilm associated factors had regional variation in expression. The discovery of intracellular biofilm-like pods explains how bladder infections can persist in the face of robust host defenses.

http://science.sciencemag.org/content/sci/301/5629/105.full.pdf

Intracellular bacterial biofilm-like pods in urinary tract infections

Noise has many roles in biological function, including generation of errors in DNA replication leading to mutation and evolution, noise-driven divergence of cell fates, noise-induced amplification of signals, and maintenance of the quantitative individuality of cells. Yet there is order to the behaviour and development of cells. They operate within strict parameters and in many cases this behaviour seems robust, implying that noise is largely filtered by the system. How can we explain the use, rejection and sensitivity to noise that is found in biological systems? An exploration of the sources and consequences of noise calls for the use of stochastic models.

/pdf/control-exploitation-and-tolerance-of-intracellular-noise-4jcv4xt5vt.pdf

Control, exploitation and tolerance of intracellular noise

Most strains of uropathogenic Escherichia coli (UPEC) encode filamentous adhesive organelles called type 1 pili. We have determined that the type 1 pilus adhesin, FimH, mediates not only bacterial adherence, but also invasion of human bladder epithelial cells. In contrast, adherence mediated by another pilus adhesin, PapG, did not initiate bacterial internalization. FimH-mediated invasion required localized host actin reorganization, phosphoinositide 3-kinase (PI 3-kinase) activation and host protein tyrosine phosphorylation, but not activation of Src-family tyrosine kinases. Phosphorylation of focal adhesin kinase (FAK) at Tyr397 and the formation of complexes between FAK and PI 3-kinase and between α-actinin and vinculin were found to correlate with type 1 pilus-mediated bacterial invasion. Inhibitors that prevented bacterial invasion also blocked the formation of these complexes. Our results demonstrate that UPEC strains are not strictly extracellular pathogens and that the type 1 pilus adhesin FimH can directly trigger host cell signaling cascades that lead to bacterial internalization.

/pdf/type-1-pilus-mediated-bacterial-invasion-of-bladder-dg8vtvynhd.pdf

Type 1 pilus‐mediated bacterial invasion of bladder epithelial cells

Strains of uropathogenic Escherichia coli (UPEC) are the causative agents in the vast majority of all urinary tract infections. Upon entering the urinary tract, UPEC strains face a formidable array of host defenses, including the flow of urine and a panoply of antimicrobial factors. To gain an initial foothold within the bladder, most UPEC strains encode filamentous surface adhesive organelles called type 1 pili that can mediate bacterial attachment to, and invasion of, bladder epithelial cells. Invasion provides UPEC with a protective environment in which bacteria can either replicate or persist in a quiescent state. Infection with type 1-piliated E. coli can trigger a number of host responses, including cytokine production, inflammation, and the exfoliation of infected bladder epithelial cells. Despite numerous host defenses and even antibiotic treatments that can effectively sterilize the urine, recent studies demonstrate that uropathogens can persist within the bladder tissue. These bacteria may serve as a reservoir for recurrent infections, a common problem affecting millions each year.

http://www.pnas.org/content/97/16/8829.full.pdf

Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses.

Bacterial pili: molecular mechanisms of pathogenesis

Bladder infections caused by uropathogenic Escherichia coli (UPEC) depends on the ability of E. coli to express type 1 pili. The adhesive component of the pilus, FimH, mediates the invasion of E. coli into the bladder epithelium, a mechanism that facilitates the survival and persistence of E. coli in the bladder. The invasion mechanism requires actin polymerization, focal adhesion kinase phosphorylation and PI 3-kinase activation as well as the formation of FAK/PI 3-kinase and downstream vinculin/alpha-actinin complexes. In this study, we report a role for Rho-GTPase family members, namely RhoA, Cdc42 and Rac1, in the invasion process. Internalization of type 1-piliated E. coli (fimH+) and FimH-coated micro-spheres was inhibited by compactin, a pan-Rho-GTPase inhibitor and dominant negative isoforms of Rac1 and Cdc42. Expression of active Rac1 induced an internalization of E. coli that was insensitive to wortmannin and genistein. Expression of constitutively active Cdc42 induced the formation of FAK/PI 3-kinase and vinculin/alpha-actinin complexes whereas active Rac1 induced only a vinculin/alpha-actinin complex. Taken together, these data suggest that FimH-mediated invasion is dependent on GTP-binding protein activity that involves Cdc42 and PI 3-kinase activation probably upstream of Rac1.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1462-5822.2002.00166.x

Juan J. Martinez

Papers

Type 1 pilus‐mediated bacterial invasion of bladder epithelial cells

Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses.

Bacterial pili: molecular mechanisms of pathogenesis

Requirement of Rho-family GTPases in the invasion of Type 1-piliated uropathogenic Escherichia coli.