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      Quorum sensing modulates the formation of virulent Legionella persisters within infected cells

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          Abstract

          The facultative intracellular bacterium Legionella pneumophila replicates in environmental amoebae and in lung macrophages, and causes Legionnaires’ disease. Here we show that L. pneumophila reversibly forms replicating and nonreplicating subpopulations of similar size within amoebae. The nonreplicating bacteria are viable and metabolically active, display increased antibiotic tolerance and a distinct proteome, and show high virulence as well as the capacity to form a degradation-resistant compartment. Upon infection of naïve or interferon-γ-activated macrophages, the nonreplicating subpopulation comprises ca. 10% or 50%, respectively, of the total intracellular bacteria; hence, the nonreplicating subpopulation is of similar size in amoebae and activated macrophages. The numbers of nonreplicating bacteria within amoebae are reduced in the absence of the autoinducer synthase LqsA or other components of the Lqs quorum-sensing system. Our results indicate that virulent, antibiotic-tolerant subpopulations of L. pneumophila are formed during infection of evolutionarily distant phagocytes, in a process controlled by the Lqs system.

          Abstract

          The pathogenic bacterium Legionella pneumophila infects lung macrophages and environmental amoebae. Here, Personnic et al. show that the pathogen reversibly forms virulent, antibiotic-tolerant subpopulations during infection of macrophages and amoebae, in a process regulated by the Lqs quorum-sensing system.

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          Most cited references55

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          Bacterial persistence as a phenotypic switch.

          A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microfluidic devices. Persistence was linked to preexisting heterogeneity in bacterial populations because phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates. Quantitative measurements led to a simple mathematical description of the persistence switch. Inherent heterogeneity of bacterial populations may be important in adaptation to fluctuating environments and in the persistence of bacterial infections.
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            A functional perspective on phenotypic heterogeneity in microorganisms.

            Most microbial communities consist of a genetically diverse assembly of different organisms, and the level of genetic diversity plays an important part in community properties and functions. However, biological diversity also arises at a lower level of biological organization, between genetically identical cells that reside in the same microenvironment. In this Review, I outline the molecular mechanisms responsible for phenotypic heterogeneity and discuss how phenotypic heterogeneity allows genotypes to persist in fluctuating environments. I also describe how it promotes interactions between phenotypic subpopulations in clonal groups, providing microbial groups with new functionality.
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              Modulation of host cell function by Legionella pneumophila type IV effectors.

              Macrophages and protozoa ingest bacteria by phagocytosis and destroy these microbes using a conserved pathway that mediates fusion of the phagosome with lysosomes. To survive within phagocytic host cells, bacterial pathogens have evolved a variety of strategies to avoid fusion with lysosomes. A virulence strategy used by the intracellular pathogen Legionella pneumophila is to manipulate host cellular processes using bacterial proteins that are delivered into the cytosolic compartment of the host cell by a specialized secretion system called Dot/Icm. The proteins delivered by the Dot/Icm system target host factors that play evolutionarily conserved roles in controlling membrane transport in eukaryotic cells, which enables L. pneumophila to create an endoplasmic reticulum-like vacuole that supports intracellular replication in both protozoan and mammalian host cells. This review focuses on intracellular trafficking of L. pneumophila and describes how bacterial proteins contribute to modulation of host processes required for survival within host cells.
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                Author and article information

                Contributors
                npersonnic@imm.uzh.ch
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                18 November 2019
                18 November 2019
                2019
                : 10
                : 5216
                Affiliations
                [1 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Institute for Medical Microbiology, , University of Zürich, ; Gloriastrasse 30, 8006 Zürich, Switzerland
                [2 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, Proteomics Core Facility, Biozentrum, , University of Basel, ; Klingelbergstrasse 50/70, 4056 Basel, Switzerland
                [3 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Max von Pettenkofer Institute, , Ludwig-Maximilians University Munich, ; Pettenkoferstrasse 9a, 80336 Munich, Germany
                Author information
                http://orcid.org/0000-0003-4180-8260
                http://orcid.org/0000-0001-7575-8965
                http://orcid.org/0000-0002-4756-7907
                http://orcid.org/0000-0002-3149-2381
                http://orcid.org/0000-0002-5462-9301
                Article
                13021
                10.1038/s41467-019-13021-8
                6861284
                31740681
                58598bfc-0cf8-4ebb-bccf-931457fed65a
                © The Author(s) 2019

                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
                : 19 March 2019
                : 14 October 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation);
                Award ID: PZ00P3_161492
                Award ID: PZ00P3_161492_185529
                Award ID: 31003A_153200
                Award ID: 31003A_175557
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004359, Vetenskapsrådet (Swedish Research Council);
                Award ID: 2014-396
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: SPP 1617
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                antimicrobial resistance,bacteria,cellular microbiology,pathogens
                Uncategorized
                antimicrobial resistance, bacteria, cellular microbiology, pathogens

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