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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 10 January 2014, Vol.343(6167), pp.204-8
    Description: Many bacterial pathogens cause persistent infections despite repeated antibiotic exposure. Bacterial persisters are antibiotic-tolerant cells, but little is known about their growth status and the signals and pathways leading to their formation in infected tissues. We used fluorescent single-cell analysis to identify Salmonella persisters during infection. These were part of a nonreplicating population formed immediately after uptake by macrophages and were induced by vacuolar acidification and nutritional deprivation, conditions that also induce Salmonella virulence gene expression. The majority of 14 toxin-antitoxin modules contributed to intracellular persister formation. Some persisters resumed intracellular growth after phagocytosis by naïve macrophages. Thus, the vacuolar environment induces phenotypic heterogeneity, leading to either bacterial replication or the formation of nonreplicating persisters that could provide a reservoir for relapsing infection.
    Keywords: Macrophages -- Microbiology ; Salmonella Infections -- Immunology ; Salmonella Typhimurium -- Growth & Development
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 February 2010, Vol.107(8), pp.3746-51
    Description: Several important pathogens cause disease by surviving and replicating within host cells. Bacterial proliferation is the product of both replication and killing undergone by the population. However, these processes are difficult to distinguish, and are usually assessed together by determination of net bacterial load. In addition, measurement of net load does not reveal heterogeneity within pathogen populations. This is particularly important in persistent infections in which slow or nongrowing bacteria are thought to have a major impact. Here we report the development of a reporter system based on fluorescence dilution that enables direct quantification of the replication dynamics of Salmonella enterica serovar Typhimurium (S. Typhimurium) in murine macrophages at both the population and single-cell level. We used this technique to demonstrate that a major S. Typhimurium virulence determinant, the Salmonella pathogenicity island 2 type III secretion system, is required for bacterial replication but does not have a major influence on resistance to killing. Furthermore, we found that, upon entry into macrophages, many bacteria do not replicate, but appear to enter a dormant-like state. These could represent an important reservoir of persistent bacteria. The approach could be extended to other pathogens to study the contribution of virulence and host resistance factors to replication and killing, and to identify and characterize nonreplicating bacteria associated with chronic or latent infections.
    Keywords: Flow Cytometry -- Methods ; Macrophages -- Microbiology ; Salmonella Typhimurium -- Growth & Development
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Current Opinion in Microbiology, April 2013, Vol.16(2), pp.184-191
    Description: ► Net bacterial growth rate does not necessarily reflect replication rate. ► Bacterial replication can be quantified directly by dilution methods. ► Single cell analysis of intracellular bacterial replication reveals heterogeneity. ► Heterogeneity of intracellular replication is caused by both host and pathogen. ► Non-replicating bacterial subpopulations illustrate the benefits of heterogeneity. Intracellular growth of bacterial pathogens is usually measured at the whole population level, which masks potential cell-to-cell variation. More direct measurements of replication using microscopy and Flow Cytometry have revealed extensive heterogeneity among populations of intracellular bacteria. Heterogeneity could result from differential exposure to nutritional deprivation and host cell antimicrobial activities, as well as variability in production or efficacy of virulence molecules. Furthermore, bacteria have evolved specific mechanisms to generate epigenetic variation. These include unequal partitioning of proteins during cell division, genetic phase variation and activation of toxin/antitoxin systems. An important aspect of heterogeneity concerns the generation of viable, non-replicating bacteria. These are predicted to confer tolerance to host-induced stress and antibiotics, and to be sources of persistent infection.
    Keywords: Biology
    ISSN: 1369-5274
    E-ISSN: 1879-0364
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  • 4
    Language: English
    In: Trends in Microbiology, July 2014, Vol.22(7), pp.417-424
    Description: Persisters are multidrug-tolerant bacteria that could account for the relapse of infections. For a long time, persisters have been assumed to be nonreplicating dormant bacteria, but the growth status of these recalcitrant cells is still debated. Toxin–antitoxin (TA) modules have an important role in the formation of persisters and several studies show that they can form in response to different triggers. These findings, together with the invention of new tools to study persisters, could have important implications for the development of novel therapeutics to eradicate persisting subpopulations.
    Keywords: Bacteria ; Persisters ; Pathogens ; Infection ; Antibiotic Tolerance ; Biology
    ISSN: 0966-842X
    E-ISSN: 1878-4380
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  • 5
    Language: English
    In: Science (New York, N.Y.), 07 December 2018, Vol.362(6419), pp.1156-1160
    Description: Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
    Keywords: Drug Resistance, Bacterial ; Host-Pathogen Interactions -- Immunology ; Macrophages -- Immunology ; Salmonella Infections -- Drug Therapy ; Salmonella Typhimurium -- Metabolism ; Type III Secretion Systems -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 6
    Language: English
    In: Toxicon, July 2018, Vol.149, pp.99-99
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology
    ISSN: 0041-0101
    E-ISSN: 1879-3150
    Source: ScienceDirect Journals (Elsevier)
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 02 October 2007, Vol.104(40), pp.15888-93
    Description: Type IV pili (Tfp) are widespread filamentous bacterial organelles that mediate multiple virulence-related phenotypes. They are composed mainly of pilin subunits, which are processed before filament assembly by dedicated prepilin peptidases. Other proteins processed by these peptidases, whose molecular nature and mode of action remain enigmatic, play critical roles in Tfp biology. We have performed a detailed structure/function analysis of one such protein, PilX from Neisseria meningitidis, which is crucial for formation of bacterial aggregates and adhesion to human cells. The x-ray crystal structure of PilX reveals the alpha/beta roll fold shared by all pilins, and we show that this protein colocalizes with Tfp. These observations suggest that PilX is a minor, or low abundance, pilin that assembles within the filaments in a similar way to pilin. Deletion of a PilX distinctive structural element, which is predicted to be exposed on the filament surface, abolishes aggregation and adhesion. Our results support a model in which surface-exposed motifs in PilX subunits stabilize bacterial aggregates against the disruptive force of pilus retraction and illustrate how a minor pilus component can enhance the functional properties of pili of rather simple composition and structure.
    Keywords: Bacterial Proteins -- Chemistry ; Fimbriae Proteins -- Chemistry ; Fimbriae, Bacterial -- Ultrastructure ; Neisseria Gonorrhoeae -- Pathogenicity
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 8
    In: Infection and Immunity, 2010, Vol. 78(7), p.3053
    Description: Type IV pili (Tfp), which mediate multiple phenotypes ranging from adhesion to motility, are one of the most widespread virulence factors in bacteria. However, the molecular mechanisms of Tfp biogenesis and associated functions remain poorly understood. One of the underlying reasons is that the roles played by the numerous genes involved in Tfp biology are unclear because corresponding mutants have been studied on a case-by-case basis, in different species, and using different assays, often generating heterogeneous results. Therefore, we have recently started a systematic functional analysis of the genes involved in Tfp biology in a well-characterized clinical isolate of the human pathogen Neisseria meningitidis. After previously studying 16 genes involved in Tfp biogenesis, here we report the characterization of 7 genes that are dispensable for piliation and potentially involved in Tfp biology. Using a battery of assays, we assessed piliation and each of the Tfp-linked functions in single mutants, double mutants in which filament retraction is abolished by a concurrent mutation in pilT, and strains overexpressing the corresponding proteins. This showed that each of the seven genes actually fine-tunes a Tfp-linked function(s), which brings us one step closer to a global view of Tfp biology in the meningococcus.
    Keywords: Fimbriae, Bacterial -- Genetics ; Genes, Bacterial -- Genetics ; Neisseria Meningitidis -- Genetics;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 9
    Language: English
    In: Journal of bacteriology, October 2014, Vol.196(20), pp.3527-33
    Description: The third Young Microbiologists Symposium took place on the vibrant campus of the University of Dundee, Scotland, from the 2nd to 3rd of June 2014. The symposium attracted over 150 microbiologists from 17 different countries. The significant characteristic of this meeting was that it was specifically aimed at providing a forum for junior scientists to present their work. The meeting was supported by the Society for General Microbiology and the American Society for Microbiology, with further sponsorship from the European Molecular Biology Organization, the Federation of European Microbiological Societies, and The Royal Society of Edinburgh. In this report, we highlight some themes that emerged from the many exciting talks and poster presentations given by the young and talented microbiologists in the area of microbial gene expression, regulation, biogenesis, pathogenicity, and host interaction.
    Keywords: Bacterial Physiological Phenomena ; Bacteria -- Metabolism ; Biomedical Research -- Trends ; Microbiology -- Organization & Administration
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 10
    Language: English
    Description: Several bacterial pathogens and viruses interfere with the cell cycle of their host cells to enhance virulence. This is especially apparent in bacteria that colonize the gut epithelium, where inhibition of the cell cycle of infected cells enhances the intestinal colonization. We found that intracellular Salmonella enterica serovar Typhimurium induced the binucleation of a large proportion of epithelial cells by 14 h postinvasion and that the effect was dependent on an intact Salmonella pathogenicity island 2 (SPI-2) type 3 secretion system. The SPI-2 effectors SseF and SseG were required to induce binucleation. SseF and SseG are known to maintain microcolonies of Salmonella-containing vacuoles close to the microtubule organizing center of infected epithelial cells. During host cell division, these clustered microcolonies prevented the correct localization of members of the chromosomal passenger complex and mitotic kinesin-like protein 1 and consequently prevented cytokinesis. Tetraploidy, arising from a cytokinesis defect, is known to have a deleterious effect on subsequent cell divisions, resulting in either chromosomal instabilities or cell cycle arrest. In infected mice, proliferation of small intestinal epithelial cells was compromised in an SseF/SseG-dependent manner, suggesting that cytokinesis failure caused by S. Typhimurium delays epithelial cell turnover in the intestine.
    Keywords: Cellular Microbiology ; Pathogen-Host Cell Molecular ; Interactions
    ISSN: 0019-9567
    E-ISSN: 10985522
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