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      CdrA Interactions within the Pseudomonas aeruginosa Biofilm Matrix Safeguard It from Proteolysis and Promote Cellular Packing

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          Abstract

          Pseudomonas aeruginosa forms multicellular aggregates or biofilms using both exopolysaccharides and the CdrA matrix adhesin. We showed for the first time that P. aeruginosa can use CdrA to build biofilms that do not require known matrix exopolysaccharides. It is appreciated that biofilm growth is protective against environmental assaults. However, little is known about how the interactions between individual matrix components aid in this protection. We found that interactions between CdrA and the exopolysaccharide Psl fortify the matrix by preventing CdrA proteolysis. When both components—CdrA and Psl—are part of the matrix, robust aggregates form that are tightly packed and protease resistant. These findings provide insight into how biofilms persist in protease-rich host environments.

          ABSTRACT

          Biofilms are robust multicellular aggregates of bacteria that are encased in an extracellular matrix. Different bacterial species have been shown to use a range of biopolymers to build their matrices. Pseudomonas aeruginosa is a model organism for the laboratory study of biofilms, and past work has suggested that exopolysaccharides are a required matrix component. However, we found that expression of the matrix protein CdrA, in the absence of biofilm exopolysaccharides, allowed biofilm formation through the production of a CdrA-rich proteinaceous matrix. This represents a novel function for CdrA. Similar observations have been made for other species such as Escherichia coli and Staphylococcus aureus, which can utilize protein-dominant biofilm matrices. However, we found that these CdrA-containing matrices were susceptible to both exogenous and self-produced proteases. We previously reported that CdrA directly binds the biofilm matrix exopolysaccharide Psl. Now we have found that when CdrA bound to Psl, it was protected from proteolysis. Together, these results support the idea of the importance of multibiomolecular components in matrix stability and led us to propose a model in which CdrA-CdrA interactions can enhance cell-cell packing in an aggregate that is resistant to physical shear, while Psl-CdrA interactions enhance aggregate integrity in the presence of self-produced and exogenous proteases.

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          Most cited references33

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          The EPS matrix: the "house of biofilm cells".

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            Biofilm infections, their resilience to therapy and innovative treatment strategies.

            Biofilm formation of microorganisms causes persistent tissue and foreign body infections resistant to treatment with antimicrobial agents. Up to 80% of human bacterial infections are biofilm associated; such infections are most frequently caused by Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus and Enterobacteria such as Escherichia coli. The accurate diagnosis of biofilm infections is often difficult, which prevents the appropriate choice of treatment. As biofilm infections significantly contribute to patient morbidity and substantial healthcare costs, novel strategies to treat these infections are urgently required. Nucleotide second messengers, c-di-GMP, (p)ppGpp and potentially c-di-AMP, are major regulators of biofilm formation and associated antibiotic tolerance. Consequently, different components of these signalling networks might be appropriate targets for antibiofilm therapy in combination with antibiotic treatment strategies. In addition, cyclic di-nucleotides are microbial-associated molecular patterns with an almost universal presence. Their conserved structures sensed by the eukaryotic host have a widespread effect on the immune system. Thus, cyclic di-nucleotides are also potential immunotherapeutic agents to treat antibiotic-resistant bacterial infections. © 2012 The Association for the Publication of the Journal of Internal Medicine.
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              Pseudomonas aeruginosa biofilms in cystic fibrosis.

              The persistence of chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients is due to biofilm-growing mucoid (alginate-producing) strains. A biofilm is a structured consortium of bacteria, embedded in a self-produced polymer matrix consisting of polysaccharide, protein and DNA. In CF lungs, the polysaccharide alginate is the major part of the P. aeruginosa biofilm matrix. Bacterial biofilms cause chronic infections because they show increased tolerance to antibiotics and resist phagocytosis, as well as other components of the innate and the adaptive immune system. As a consequence, a pronounced antibody response develops, leading to immune complex-mediated chronic inflammation, dominated by polymorphonuclear leukocytes. The chronic inflammation is the major cause of the lung tissue damage in CF. Biofilm growth in CF lungs is associated with an increased frequency of mutations, slow growth and adaptation of the bacteria to the conditions in the lungs, and to antibiotic therapy. Low bacterial metabolic activity and increase of doubling times of the bacterial cells in CF lungs are responsible for some of the tolerance to antibiotics. Conventional resistance mechanisms, such as chromosomal β-lactamase, upregulated efflux pumps, and mutations of antibiotic target molecules in the bacteria, also contribute to the survival of P. aeruginosa biofilms. Biofilms can be prevented by early aggressive antibiotic prophylaxis or therapy, and they can be treated by chronic suppressive therapy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                25 September 2018
                Sep-Oct 2018
                : 9
                : 5
                : e01376-18
                Affiliations
                [a ]Department of Microbiology, University of Washington, Seattle, Washington, USA
                [b ]Departments of Microbial Infection and Immunity, Microbiology, The Ohio State University, Columbus, Ohio, USA
                Emory University School of Medicine
                Author notes
                Address correspondence to Matthew R. Parsek, parsem@ 123456u.washington.edu .
                Article
                mBio01376-18
                10.1128/mBio.01376-18
                6156197
                30254118
                55c022b2-b147-4895-b0ad-7e7e4086da6d
                Copyright © 2018 Reichhardt et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 22 June 2018
                : 13 August 2018
                Page count
                supplementary-material: 9, Figures: 7, Tables: 0, Equations: 0, References: 55, Pages: 12, Words: 8353
                Funding
                Funded by: CFF;
                Award ID: REICHH17F0
                Award Recipient :
                Funded by: HHS | National Institutes of Health (NIH), https://doi.org/10.13039/100000002;
                Award ID: R01AI34895
                Award ID: R01AI077628
                Award ID: R01AI097511
                Award Recipient : Award Recipient :
                Categories
                Research Article
                Molecular Biology and Physiology
                Custom metadata
                September/October 2018

                Life sciences
                cdra,pseudomonas aeruginosa,psl,biofilm,elastase,exopolysaccharides
                Life sciences
                cdra, pseudomonas aeruginosa, psl, biofilm, elastase, exopolysaccharides

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