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      Uropathogenic Escherichia coli P and Type 1 Fimbriae Act in Synergy in a Living Host to Facilitate Renal Colonization Leading to Nephron Obstruction

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          Abstract

          The progression of a natural bacterial infection is a dynamic process influenced by the physiological characteristics of the target organ. Recent developments in live animal imaging allow for the study of the dynamic microbe-host interplay in real-time as the infection progresses within an organ of a live host. Here we used multiphoton microscopy-based live animal imaging, combined with advanced surgical procedures, to investigate the role of uropathogenic Escherichia coli (UPEC) attachment organelles P and Type 1 fimbriae in renal bacterial infection. A GFP + expressing variant of UPEC strain CFT073 and genetically well-defined isogenic mutants were microinfused into rat glomerulus or proximal tubules. Within 2 h bacteria colonized along the flat squamous epithelium of the Bowman's capsule despite being exposed to the primary filtrate. When facing the challenge of the filtrate flow in the proximal tubule, the P and Type 1 fimbriae appeared to act in synergy to promote colonization. P fimbriae enhanced early colonization of the tubular epithelium, while Type 1 fimbriae mediated colonization of the center of the tubule via a mechanism believed to involve inter-bacterial binding and biofilm formation. The heterogeneous bacterial community within the tubule subsequently affected renal filtration leading to total obstruction of the nephron within 8 h. Our results reveal the importance of physiological factors such as filtration in determining bacterial colonization patterns, and demonstrate that the spatial resolution of an infectious niche can be as small as the center, or periphery, of a tubule lumen. Furthermore, our data show how secondary physiological injuries such as obstruction contribute to the full pathophysiology of pyelonephritis.

          Author Summary

          When bacteria such as uropathogenic Escherichia coli (UPEC) infect a living kidney, they face numerous physiological challenges such as the flow of urine. Bacteria need to attach themselves to the epithelial linings of the kidney to withstand this flow. In this work we use a live animal imaging model to study how UPEC colonize a living kidney despite the physiological challenges they face. We show that P and Type 1 fimbriae, two of the most well described UPEC adhesion factors, work together to promote successful bacterial colonization. P fimbriae mediate binding between the bacteria and the epithelial cells lining the tubules, while Type 1 appears to play a role in inter-bacterial binding and biofilm formation in the center parts of the lumen. The heterogeneous bacterial community which filled the tubule was subsequently shown to effect nephron filtration and resulted in a total loss of filtrate flow i.e. obstruction. This work demonstrates the interplay between the bacterial and host aspects, indicating how factors such as filtration may affect bacterial adhesion and vice versa. It also highlights the multifactorial basis of kidney infection, demonstrating how physiological injuries such as obstruction may contribute towards the full pathophysiology of pyelonephritis.

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          Most cited references48

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          Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli.

          We present the complete genome sequence of uropathogenic Escherichia coli, strain CFT073. A three-way genome comparison of the CFT073, enterohemorrhagic E. coli EDL933, and laboratory strain MG1655 reveals that, amazingly, only 39.2% of their combined (nonredundant) set of proteins actually are common to all three strains. The pathogen genomes are as different from each other as each pathogen is from the benign strain. The difference in disease potential between O157:H7 and CFT073 is reflected in the absence of genes for type III secretion system or phage- and plasmid-encoded toxins found in some classes of diarrheagenic E. coli. The CFT073 genome is particularly rich in genes that encode potential fimbrial adhesins, autotransporters, iron-sequestration systems, and phase-switch recombinases. Striking differences exist between the large pathogenicity islands of CFT073 and two other well-studied uropathogenic E. coli strains, J96 and 536. Comparisons indicate that extraintestinal pathogenic E. coli arose independently from multiple clonal lineages. The different E. coli pathotypes have maintained a remarkable synteny of common, vertically evolved genes, whereas many islands interrupting this common backbone have been acquired by different horizontal transfer events in each strain.
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            Genetic analysis of Escherichia coli biofilm formation: roles of flagella, motility, chemotaxis and type I pili.

            We have used Escherichia coli as a model system to investigate the initiation of biofilm formation. Here, we demonstrate that E. coli forms biofilms on multiple abiotic surfaces in a nutrient-dependent fashion. In addition, we have isolated insertion mutations that render this organism defective in biofilm formation. One-half of these mutations was found to perturb normal flagellar function. Using defined fli, flh, mot and che alleles, we show that motility, but not chemotaxis, is critical for normal biofilm formation. Microscopic analyses of these mutants suggest that motility is important for both initial interaction with the surface and for movement along the surface. In addition, we present evidence that type I pili (harbouring the mannose-specific adhesin, FimH) are required for initial surface attachment and that mannose inhibits normal attachment. In light of the observations presented here, a working model is discussed that describes the roles of both motility and type I pili in biofilm development.
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              Bacterial adhesion to target cells enhanced by shear force.

              Surface adhesion of bacteria generally occurs in the presence of shear stress, and the lifetime of receptor bonds is expected to be shortened in the presence of external force. However, by using Escherichia coli expressing the lectin-like adhesin FimH and guinea pig erythrocytes in flow chamber experiments, we show that bacterial attachment to target cells switches from loose to firm upon a 10-fold increase in shear stress applied. Steered molecular dynamics simulations of tertiary structure of the FimH receptor binding domain and subsequent site-directed mutagenesis studies indicate that shear-enhancement of the FimH-receptor interactions involves extension of the interdomain linker chain under mechanical force. The ability of FimH to function as a force sensor provides a molecular mechanism for discrimination between surface-exposed and soluble receptor molecules.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                February 2011
                February 2011
                24 February 2011
                : 7
                : 2
                : e1001298
                Affiliations
                [1 ]Department of Neuroscience, Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden
                [2 ]Division of Nephrology, Department of Medicine, Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [3 ]Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                Yale University School of Medicine, United States of America
                Author notes

                ¤: Current address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

                Conceived and designed the experiments: KM BAM ARD. Performed the experiments: KM RMS AK LJ GAT. Analyzed the data: KM RMS GAT ARD. Contributed reagents/materials/analysis tools: BAM. Wrote the paper: KM ARD.

                Article
                10-PLPA-RA-4148R2
                10.1371/journal.ppat.1001298
                3044688
                21383970
                8f99adb5-6123-446c-ad7d-a2e031571c3c
                Melican et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 8 September 2010
                : 18 January 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Microbiology
                Microbiology/Cellular Microbiology and Pathogenesis
                Nephrology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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