TY - JOUR A1 - Biju, Joseph A1 - Schwarz, Roland A1 - Linke, Burkhard A1 - Blom, Jochen A1 - Becker, Anke A1 - Claus, Heike A1 - Goesmann, Alexander A1 - Frosch, Matthias A1 - Müller, Tobias A1 - Vogel, Ulrich A1 - Schoen, Christoph T1 - Virulence Evolution of the Human Pathogen Neisseria meningitidis by Recombination in the Core and Accessory Genome JF - PLoS One N2 - Background Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. Principal Findings We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin- and two-partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. Conclusions Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence. KW - population genetics KW - DNA recombination KW - meningococcal disease KW - recombinant proteins KW - genomic databases KW - comparative genomics KW - neisseria meningitidis KW - homologous recombination Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137960 VL - 6 IS - 4 ER - TY - JOUR A1 - Schwerk, Christian A1 - Papandreou, Thalia A1 - Schuhmann, Daniel A1 - Nickol, Laura A1 - Borkowski, Julia A1 - Steinmann, Ulrike A1 - Quednau, Natascha A1 - Stump, Carolin A1 - Weiss, Christel A1 - Berger, Jürgen A1 - Wolburg, Hartwig A1 - Claus, Heike A1 - Vogel, Ulrich A1 - Ishikawa, Hiroshi A1 - Tenenbaum, Tobias A1 - Schroten, Horst T1 - Polar Invasion and Translocation of Neisseria meningitidis and Streptococcus suis in a Novel Human Model of the Blood-Cerebrospinal Fluid Barrier JF - PLoS One N2 - Acute bacterial meningitis is a life-threatening disease in humans. Discussed as entry sites for pathogens into the brain are the blood-brain and the blood-cerebrospinal fluid barrier (BCSFB). Although human brain microvascular endothelial cells (HBMEC) constitute a well established human in vitro model for the blood-brain barrier, until now no reliable human system presenting the BCSFB has been developed. Here, we describe for the first time a functional human BCSFB model based on human choroid plexus papilloma cells (HIBCPP), which display typical hallmarks of a BCSFB as the expression of junctional proteins and formation of tight junctions, a high electrical resistance and minimal levels of macromolecular flux when grown on transwell filters. Importantly, when challenged with the zoonotic pathogen Streptococcus suis or the human pathogenic bacterium Neisseria meningitidis the HIBCPP show polar bacterial invasion only from the physiologically relevant basolateral side. Meningococcal invasion is attenuated by the presence of a capsule and translocated N. meningitidis form microcolonies on the apical side of HIBCPP opposite of sites of entry. As a functionally relevant human model of the BCSFB the HIBCPP offer a wide range of options for analysis of disease-related mechanisms at the choroid plexus epithelium, especially involving human pathogens. KW - gene expression KW - plexus epithelial-cells KW - central-nervous-system KW - microvascular endothelial-cells KW - choroid-plexus KW - in vitro KW - brain barrier KW - tight junctions KW - meningococcal disease KW - bacterial meningitis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131459 VL - 7 IS - 1 ER - TY - JOUR A1 - Taha, Muhamed-Kheir A1 - Claus, Heike A1 - Lappann, Martin A1 - Veyrier, Frédéric J. A1 - Otto, Andreas A1 - Becher, Dörte A1 - Deghmane, Ala-Eddine A1 - Frosch, Matthias A1 - Hellenbrand, Wiebke A1 - Hong, Eva A1 - du Châtelet, Isabelle Parent A1 - Prior, Karola A1 - Harmsen, Dag A1 - Vogel, Ulrich T1 - Evolutionary Events Associated with an Outbreak of Meningococcal Disease in Men Who Have Sex with Men JF - PLoS ONE N2 - Meningococci spread via respiratory droplets, whereas the closely related gonococci are transmitted sexually. Several outbreaks of invasive meningococcal disease have been reported in Europe and the United States among men who have sex with men (MSM). We recently identified an outbreak of serogroup C meningococcal disease among MSM in Germany and France. In this study, genomic and proteomic techniques were used to analyze the outbreak isolates. In addition, genetically identical urethritis isolates were recovered from France and Germany and included in the analysis. Genome sequencing revealed that the isolates from the outbreak among MSM and from urethritis cases belonged to a clade within clonal complex 11. Proteome analysis showed they expressed nitrite reductase, enabling anaerobic growth as previously described for gonococci. Invasive isolates from MSM, but not urethritis isolates, further expressed functional human factor H binding protein associated with enhanced survival in a newly developed transgenic mouse model expressing human factor H, a complement regulatory protein. In conclusion, our data suggest that urethritis and outbreak isolates followed a joint adaptation route including adaption to the urogenital tract. KW - nitrites KW - genome sequencing KW - men who have sex with men KW - meningococcal disease KW - Neisseria meningitidis KW - Neisseria gonorrhoeae KW - mammalian genomics KW - mouse models Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179870 VL - 11 IS - 5 ER -