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      Modulation of Haemophilus influenzae interaction with hydrophobic molecules by the VacJ/MlaA lipoprotein impacts strongly on its interplay with the airways

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          Abstract

          Airway infection by nontypeable Haemophilus influenzae (NTHi) associates to chronic obstructive pulmonary disease (COPD) exacerbation and asthma neutrophilic airway inflammation. Lipids are key inflammatory mediators in these disease conditions and consequently, NTHi may encounter free fatty acids during airway persistence. However, molecular information on the interplay NTHi-free fatty acids is limited, and we lack evidence on the importance of such interaction to infection. Maintenance of the outer membrane lipid asymmetry may play an essential role in NTHi barrier function and interaction with hydrophobic molecules. VacJ/MlaA-MlaBCDEF prevents phospholipid accumulation at the bacterial surface, being the only system involved in maintaining membrane asymmetry identified in NTHi. We assessed the relationship among the NTHi VacJ/MlaA outer membrane lipoprotein, bacterial and exogenous fatty acids, and respiratory infection. The vacJ/mlaA gene inactivation increased NTHi fatty acid and phospholipid global content and fatty acyl specific species, which in turn increased bacterial susceptibility to hydrophobic antimicrobials, decreased NTHi epithelial infection, and increased clearance during pulmonary infection in mice with both normal lung function and emphysema, maybe related to their shared lung fatty acid profiles. Altogether, we provide evidence for VacJ/MlaA as a key bacterial factor modulating NTHi survival at the human airway upon exposure to hydrophobic molecules.

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          Most cited references56

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          Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential.

          Amongst the diverse and potent biological activities of free fatty acids (FFAs) is the ability to kill or inhibit the growth of bacteria. The antibacterial properties of FFAs are used by many organisms to defend against parasitic or pathogenic bacteria. Whilst their antibacterial mode of action is still poorly understood, the prime target of FFA action is the cell membrane, where FFAs disrupt the electron transport chain and oxidative phosphorylation. Besides interfering with cellular energy production, FFA action may also result from the inhibition of enzyme activity, impairment of nutrient uptake, generation of peroxidation and auto-oxidation degradation products or direct lysis of bacterial cells. Their broad spectrum of activity, non-specific mode of action and safety makes them attractive as antibacterial agents for various applications in medicine, agriculture and food preservation, especially where the use of conventional antibiotics is undesirable or prohibited. Moreover, the evolution of inducible FFA-resistant phenotypes is less problematic than with conventional antibiotics. The potential for commercial or biomedical exploitation of antibacterial FFAs, especially for those from natural sources, is discussed.
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            Cell-PLoc: a package of Web servers for predicting subcellular localization of proteins in various organisms.

            Information on subcellular localization of proteins is important to molecular cell biology, proteomics, system biology and drug discovery. To provide the vast majority of experimental scientists with a user-friendly tool in these areas, we present a package of Web servers developed recently by hybridizing the 'higher level' approach with the ab initio approach. The package is called Cell-PLoc and contains the following six predictors: Euk-mPLoc, Hum-mPLoc, Plant-PLoc, Gpos-PLoc, Gneg-PLoc and Virus-PLoc, specialized for eukaryotic, human, plant, Gram-positive bacterial, Gram-negative bacterial and viral proteins, respectively. Using these Web servers, one can easily get the desired prediction results with a high expected accuracy, as demonstrated by a series of cross-validation tests on the benchmark data sets that covered up to 22 subcellular location sites and in which none of the proteins included had > or =25% sequence identity to any other protein in the same subcellular-location subset. Some of these Web servers can be particularly used to deal with multiplex proteins as well, which may simultaneously exist at, or move between, two or more different subcellular locations. Proteins with multiple locations or dynamic features of this kind are particularly interesting, because they may have some special biological functions intriguing to investigators in both basic research and drug discovery. This protocol is a step-by-step guide on how to use the Web-server predictors in the Cell-PLoc package. The computational time for each prediction is less than 5 s in most cases. The Cell-PLoc package is freely accessible at http://chou.med.harvard.edu/bioinf/Cell-PLoc.
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              An ABC transport system that maintains lipid asymmetry in the gram-negative outer membrane.

              The outer membranes (OMs) of gram-negative bacteria have an asymmetric lipid distribution with lipopolysaccharides at the outer leaflet and phospholipids (PLs) at the inner leaflet. This lipid arrangement is essential for the barrier function of the OM and for the viability of most gram-negative bacteria. Cells with OM assembly defects or cells exposed to harsh chemical treatments accumulate PLs in the outer leaflet of the OM and this disrupts lipopolysaccharide organization and increases sensitivity to small toxic molecules. We have identified an ABC transport system in Escherichia coli with predicted import function that serves to prevent PL accumulation in the outer leaflet of the OM. This highly conserved pathway, which we have termed the Mla pathway for its role in preserving OM lipid asymmetry, is composed of at least 6 proteins and contains at least 1 component in each cellular compartment. We propose that the Mla pathway constitutes a bacterial intermembrane PL trafficking system.
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                Author and article information

                Contributors
                juncal.garmendia@csic.es
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                2 May 2018
                2 May 2018
                2018
                : 8
                : 6872
                Affiliations
                [1 ]Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno, Navarra, Spain
                [2 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), ; Madrid, Spain
                [3 ]Departamento Microbiología, Hospital Universitari Bellvitge, University of Barcelona, IDIBELL, Barcelona, Spain
                [4 ]ISNI 0000 0001 0627 4262, GRID grid.411325.0, Servicio Microbiología, , Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), ; Santander, Spain
                [5 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Red Española de Investigación en Patología Infecciosa (REIPI), ISCIII, ; Madrid, Spain
                [6 ]ISNI 0000 0004 0374 7521, GRID grid.4777.3, Wellcome-Wolfson Institute for Experimental Medicine, , Queen’s University Belfast, ; Belfast, UK
                [7 ]ISNI 0000000419370271, GRID grid.5924.a, Laboratory of Preclinical Models and Analytical Tools, , Division of Solid Tumors and Biomarkers, Center for Applied Medical Research, ; Pamplona, Spain
                [8 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro de Investigación Biomédica en Red de Enfermedades Oncológicas (CIBERONC), ; Madrid, Spain
                [9 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro Nacional de Microbiología, , Instituto de Salud Carlos III (ISCIII), ; Madrid, Spain
                [10 ]ISNI 0000000419370271, GRID grid.5924.a, Instituto de Salud Tropical, , Instituto de Investigación Sanitaria de Navarra and Dpto. Microbiología y Parasitología, Universidad de Navarra, Edificio de Investigación, ; Pamplona, Spain
                Author information
                http://orcid.org/0000-0002-9677-8751
                Article
                25232
                10.1038/s41598-018-25232-y
                5932069
                29720703
                cb9ea9e9-b6ac-4fe4-b089-934660ec0564
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 November 2017
                : 13 April 2018
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