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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 05 October 2012, Vol.287(41), pp.34844-55
    Description: RegIIIβ is a member of the C-type lectin family called RegIII. It is known to bind peptidoglycan, and its bactericidal activity shapes the interactions with commensal and pathogenic gut bacteria. However, little is known about its carbohydrate recognition specificity and the bactericidal mechanism, particularly against Gram-negative bacteria. Here, we show that RegIIIβ can bind directly to LPS by recognizing the carbohydrate moiety of lipid A via a novel motif that is indispensable for its bactericidal activity. This bactericidal activity of RegIIIβ could be inhibited by preincubation with LPS, lipid A, or gentiobiose. The latter is a disaccharide composed of two units of β-(1→6)-linked d-glucose and resembles the carbohydrate moiety of lipid A. Therefore, this structural element may form a key target site recognized by RegIIIβ. Using point-mutated RegIIIβ proteins, we found that amino acid residues in two structural motifs termed "loop 1" and "loop 2," are important for peptidoglycan and lipid A binding (Arg-135, Asp-142) and for the bactericidal activity (Glu-134, Asn-136, Asp-142). Thus, the ERN motif and residue Asp-142 in the loop 2 are of critical importance for RegIIIβ function. This provides novel insights into the carbohydrate recognition specificity of RegIIIβ and explains its bactericidal activity against Gram-negative bacteria.
    Keywords: Anti-Bacterial Agents -- Chemistry ; Gram-Negative Bacteria -- Chemistry ; Lectins, C-Type -- Chemistry ; Lipid A -- Chemistry ; Proteins -- Chemistry
    E-ISSN: 1083-351X
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  • 2
    In: Nature, 2015, Vol.527(7578), p.309
    Keywords: Antibiotics -- Dosage And Administration ; Microbial Drug Resistance -- Risk Factors ; Staphylococcus Aureus Infections -- Drug Therapy ; Staphylococcus Aureus Infections -- Patient Outcomes;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Article
    Article
    Language: English
    In: Nature, 11/2015, Vol.527(7578), pp.309-310
    Description: The pathogenic bacterium Staphylococcus aureus causes thousands of deaths each year. Therapy is sometimes unsuccessful, partly because antibiotic-resistance genes are spreading worldwide. However, even strains of S. aureus that lack resistance genes are often difficult to kill with available antibiotics; it has been suggested that the bacteria 'hide' inside host cells. This hypothesis inspired Lehar et al.1, who, on page 323 of this issue, present a construct in which an antibiotic is linked to an antibody that binds to the pathogen's surface. Alone, this 'prodrug' is inactive, but when prodrug-coated bacteria enter host cells, enzymatic activity releases the antibiotic. In mouse models of S. aureus infection, this strategy was strikingly more potent than standard antibiotic treatment.
    Keywords: Bacteriology ; Bacterial Infections ; Pathogens ; Bacteria ; Antibiotics ; Staphylococcus Infections ; Medical Research ; Enzymes;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Nature Publishing Group (via CrossRef)
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(7), p.e69901
    Description: The C-type lectin RegIIIβ can kill certain Gram-positive and Gram-negative bacteria. The susceptibility of S. Typhimurium depends on the bacterial growth phase, i.e., bacteria from the logarithmic growth phase do bind RegIIIβ and are subsequently killed. Lipid A is one of the bacterial targets for RegIIIβ. However, at the molecular level, it is not understood how RegIIIβ interacts with and kills Gram-negative bacteria. Here, we show that RegIIIβ interacts with Gram-negative bacteria in two distinct steps. Initially, it binds to surface-exposed lipid A. The lipid A can be shielded by the O-antigen of lipopolysaccharide (LPS), as indicated by the exquisite susceptibility of wbaP mutants to RegIIIβ-mediated killing. Increased cell viability after incubation with an anti-lipid A antibody also supports this conclusion. This RegIIIβ-binding permeabilizes the outer membrane to hydrophobic dyes like Ethidium bromide or to bulky bacteriolytic enzymes like lysozyme. Conversely, compromising the outer membrane integrity by the mild detergent Triton X-100 enhances the antibacterial effect of RegIIIβ. Based on our observations, we conclude that RegIIIβ interacts with Gram-negative bacteria in two subsequent steps. Initially, it binds to the outer membrane thus leading to outer membrane permeabilization. This initial step is necessary for RegIIIβ to reach a second, still not well understood target site (presumably localized in the periplasm or the cytoplasmic membrane), thereby triggering bacterial death. This provides novel insights into the outer membrane-step of the bactericidal mechanism of RegIIIβ.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 25 March 2014, Vol.111(12), pp.4548-53
    Description: Systematic genetic perturbation screening in human cells remains technically challenging. Typically, large libraries of chemically synthesized siRNA oligonucleotides are used, each designed to degrade a specific cellular mRNA via the RNA interference (RNAi) mechanism. Here, we report on data from three genome-wide siRNA screens, conducted to uncover host factors required for infection of human cells by two bacterial and one viral pathogen. We find that the majority of phenotypic effects of siRNAs are unrelated to the intended "on-target" mechanism, defined by full complementarity of the 21-nt siRNA sequence to a target mRNA. Instead, phenotypes are largely dictated by "off-target" effects resulting from partial complementarity of siRNAs to multiple mRNAs via the "seed" region (i.e., nucleotides 2-8), reminiscent of the way specificity is determined for endogenous microRNAs. Quantitative analysis enabled the prediction of seeds that strongly and specifically block infection, independent of the intended on-target effect. This prediction was confirmed experimentally by designing oligos that do not have any on-target sequence match at all, yet can strongly reproduce the predicted phenotypes. Our results suggest that published RNAi screens have primarily, and unintentionally, screened the sequence space of microRNA seeds instead of the intended on-target space of protein-coding genes. This helps to explain why previously published RNAi screens have exhibited relatively little overlap. Our analysis suggests a possible way of identifying "seed reagents" for controlling phenotypes of interest and establishes a general strategy for extracting valuable untapped information from past and future RNAi screens.
    Keywords: Antimicrobials ; High-Throughput Rnai Screening ; RNA Interference ; Brucella Abortus -- Drug Effects ; Bunyaviridae -- Drug Effects ; Micrornas -- Genetics ; Oligonucleotides -- Pharmacology ; Salmonella Typhimurium -- Drug Effects
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 January 2012, Vol.109(4), pp.1269-74
    Description: The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ~100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.
    Keywords: Biological Evolution ; Colitis -- Microbiology ; Enterobacteriaceae -- Genetics ; Gene Transfer, Horizontal -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    Language: English
    In: Applied and Environmental Microbiology, 2011, Vol. 77(5), p.1816
    Description: Most large-scale biological processes, like global element cycling or decomposition of organic matter, are mediated by microbial consortia. Commonly, the different species in such consortia exhibit mutual metabolic dependencies that include the exchange of nutrients. Despite the global importance, surprisingly little is known about the metabolic interplay between species in particular subpopulations. To gain insight into the intracellular fluxes of subpopulations and their interplay within such mixed cultures, we developed here a ... flux analysis approach based on affinity purification of the recombinant fusion glutathione S-transferase (GST) and green fluorescent protein (GFP) as a reporter protein. Instead of detecting the ... labeling patterns in the typically used amino acids from the total cellular protein, our method detects these ... patterns in amino acids from the reporter protein that has been expressed in only one species of the consortium. As a proof of principle, we validated our approach by mixed-culture experiments of an Escherichia coli wild type with two metabolic mutants. The reporter method quantitatively resolved the expected mutant-specific metabolic phenotypes down to subpopulation fractions of about 1%. (ProQuest: ... denotes formulae/symbols omitted.)
    Keywords: Microbiology ; Nonnative Species ; Nonlethal Weapons ; Cell Culture ; Fluorescence ; Bacterial Proteins ; Amino Acids ; Gene Expression ; Genotype & Phenotype;
    ISSN: 0099-2240
    ISSN: 00992240
    E-ISSN: 10985336
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  • 8
    Article
    Article
    In: Nature, 2009, Vol.459(7249), p.893
    Description: The gut immune system can distinguish between harmless commensal microorganisms and dangerous pathogens, and attenuates its response to the former to avoid dangerous chronic inflammation.
    Keywords: Immunology ; Rodents ; Infections ; Inflammatory Diseases;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 9
    In: Nature, 2013, Vol.494(7437), p.353
    Description: Pathogens often infect hosts through collective actions: they secrete growth-promoting compounds or virulence factors, or evoke host reactions that fuel the colonization of the host. Such behaviours are vulnerable to the rise of mutants that benefit from the collective action without contributing to it; how these behaviours can be evolutionarily stable is not well understood1. We address this question using the intestinal pathogen Salmonella enterica serovar Typhimurium (hereafter termed S. typhimurium), which manipulates its host to induce inflammation, and thereby outcompetes the commensal microbiota2,3. Notably, the virulence factors needed for host manipulation are expressed in a bistable fashion, leading to a slowgrowing subpopulation that expresses virulence genes, and a fastgrowing subpopulation that is phenotypically avirulent4,5. Here we show that the expression of the genetically identical but phenotypically avirulent subpopulation is essential for the evolutionary stability of virulence in this pathogen. Using a combination of mathematical modelling, experimental evolution and competition experiments we found that within-host evolution leads to the emergence of mutants that are genetically avirulent and fast-growing. These mutants are defectors that exploit inflammation without contributing to it. In infection experiments initiated with wild-type S. typhimurium, defectors increase only slowly in frequency. In a genetically modified S. typhimurium strain in which the phenotypically avirulent subpopulation is reduced in size, defectors rise more rapidly, inflammation ceases prematurely, and S. typhimurium is quickly cleared from the gut. Our results establish that host manipulation by S. typhimurium is a cooperative trait that is vulnerable to the rise of avirulent defectors; the expression of a phenotypically avirulent subpopulation that grows as fast as defectors slows down this process, and thereby promotes the evolutionary stability of virulence. This points to a key role of bistable virulence gene expression in stabilizing cooperative virulence and may lead the way to new approaches for controlling pathogens. [PUBLICATION ]
    Keywords: Animals–Microbiology ; Biological Evolution–Pathology ; Host-Pathogen Interactions–Microbiology ; Inflammation–Microbiology ; Inflammation–Prevention & Control ; Intestines–Transmission ; Mice–Genetics ; Mice, Inbred C57bl–Growth & Development ; Mutation–Pathogenicity ; Phenotype–Genetics ; Salmonella Infections–Physiology ; Salmonella Infections–Genetics ; Salmonella Infections–Metabolism ; Salmonella Typhimurium–Metabolism ; Salmonella Typhimurium–Metabolism ; Salmonella Typhimurium–Metabolism ; Virulence–Metabolism ; Virulence–Metabolism ; Virulence Factors–Metabolism ; Virulence Factors–Metabolism ; Food Safety ; Mutation ; Salmonella ; Experiments ; Bacteria ; Infections ; Cloning ; Genetic Engineering ; Competition ; Mathematical Models ; Gene Expression ; Genotype & Phenotype ; Virulence Factors;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    Language: English
    In: Journal of Molecular Biology, 19 January 2018, Vol.430(2), pp.193-206
    Description: Inflammasome signaling impinges on the activation of inflammatory caspases (i.e., caspase-1 and caspase-4/5/11) and endows host cells with a sentinel system to sense microbial intrusion and thereby initiate appropriate immune responses. Lately, it has become evident that mammalian inflammasome-dependent responses to infection are not confined solely to cells of hematopoietic origin. Epithelial cells that line the body's mucosal surfaces use inflammasome signaling to sense and counteract pathogenic microorganisms that compromise barrier integrity. Many of the molecular mechanisms of epithelial inflammasome signaling remain unexplored. However, it now seems clear that epithelial inflammasome activation has a profound impact both on the infected cell itself and on its ability to communicate with other cell types of the mucosa. Here, we summarize current knowledge regarding the output of epithelial inflammasome activation during bacterial infection. Well-established downstream effects include epithelial cell death, release of soluble mediators, and subsequent recruitment of effector cell types, including NK cells, mast cells, and neutrophils, to sites of mucosal infection. We discuss the implications of recent findings for antibacterial defense in the mucosa and sketch out areas for future exploration.
    Keywords: Epithelium ; Inflammasomes ; Nlrc4 ; Nlrp3 ; Interleukin-18 ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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