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ESCMID Online Lecture Library @ by Author Declaration of Conflicts of Interest 25th ECCMID Copenhagen, 25-28 April 2015 Bacterial genomics: usefulness to identify virulence factors and antibiotic resistance markers Pierre-Edouard Fournier ESCMID Online Lecture Library @ by author Declaration of conflicts of interest I certify that I do not have any conflict of interest in relation to the topic of this presentation ESCMID Online Lecture Library @ by author History of bacterial genome sequencing 20000 18000 17208 16000 High throughput Next generation Sanger sequencing Sequencing sequencing 14000 4,000th 12000 1,000th Staph. Escherichia aureus coli genome genome 10000 8000 7823 Real- time genomics 6000 Introduction Sequencing of of high th th 30,000th 4000 Haemophilus 100 throughput 1,000 4019 genome sequencing genome genome influenzae Number of annually sequenced bacterial genomes genomes bacterial sequenced of annually Number 2000 2218 830 ESCMID Online Lecture 326Library 0 2 2 4 5 4 13 25 29 48 60 77 139 172 177 226 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 @ by author A previously unsuspected biodiversity Candidatus ‘’Tremblaya princeps’’ 0.139 Mb Sorangium cellulosum 14.78 Mb ESCMID Online Lecture Library @ by author Many applications ESCMID Online Lecture Library @ by author Fournier et al. Annu. Rev. Microbiol. 2011;65:169-188 Detection of virulence ESCMID Online Lecture Library @ by author Dectecting virulence factors in a pathogen, a necessity? Essential: • In understanding pathogenesis • To identify targets for novel drugs • To identify targets for vaccine design • To optimize patient management ESCMID Online Lecture Library @ by author Detecting virulence in routine microbiology Toxin-encoding genes • To limit person-to-person spread (C. difficile 027) • To avoid antibiotic-induced deleterious effects - Oxacillin in PVL-producing S. aureus - -lactams, sulfonamides and fluoroquinolones in Shiga toxin-producing E. coli - Fluoroquinolones in R. conorii • To optimize the antibiotic therapy ClindamycinESCMID in PVL-producing Online S. aureus Lecture Library @ by author Bacterial virulence factors • Membrane proteins: role in adhesion, colonization, invasion, resistance to antimicrobials • Polysaccharide capsules: anti-phagocytic properties • Secretory proteins: toxins, type I-V secretion systems • Cell wall and outer membrane components: LPS,c lipoteichoic acids c • Biofilm forming proteins ESCMID Online Lecture Library • Siderophores c @ by author Wu et al. Curr. Opin. Chem. Biol. 2008;12:93-101 Predicting virulence from a genomic sequence « Pathogenomics » (Pallen et al. Nature. 2007.449;835-842) • 1) Search for homology with known virulence genes (toxins ++) Homology in DNA or amino acid sequence and/or phylogenetic profile • 2) Identification of LGT-acquired genes Pathogenicity islands? • ESCMID3) Comparison of Online a pathogenic Lecture strain with a Librarynonpathogenic strain or the metagenome of healthy subjects (Belda-Ferre et al. PLoS One. 2011;6:e24975)@ by author 1) Mining virulence gene databases • VFDB database (http://www.mgc.ac.cn/VFs/main.htm) 2,505 virulence-associated genes (Chen et al. Nucleic Acids Res.2012;D641-D645) - A. baumannii LCA-4: 5 types of IS, 12 genomic islands, 3 transposons, 615 hits in VFDB, incl. a heme utilization cluster (Ou H.Y. et al. Scientific Rep. 2015;5:8643) - Asian M. tuberculosis isolates => SNPs in 3 virulence genes (Pardieu et al. Infect. Immu. 2015;epub) • Virulence Searcher (http://www.hpa-bioinfotools.org.uk/pise/virfactfind_small.html) Based on the PRINTS database -S. aureus MW2: 91 virulence factors (Underwood A.P. et al. Clin. Microbiol. Infect. 2005; 11:770- 772) • Victors (http://www.phidias.us/victors/intro.phpirulence) 5,713 virulence-associated genes from 125 pathogens (bacteria, parasites and viruses) • VirulenceESCMID finder (http://cge.cbs.dtu.dk/services/VirulenceFinder/) Online Lecture Library Virulence genes from E. coli, Enterococcus sp. and S. aureus (Joensen K.G. et al. J. Clin. Microbiol. 2014;52:1501-1510) @ by author Virulence gene databases • VirulentPred (http://203.92.44.117/virulent/submit.html) Uses VFDB and Swissprot virulence protein sequences (Garg A. & Gupta G. BMC Bioinformatics. 2008; 9:62) • Virulent-GO Combines VirulentPred and gene ontology annotation (Tsai C.T. et al. Int. J. Biol. Life Sci. 2009;5:80-87) • PathogenFinder (http://cge.cbs.dtu.dk/services/PathogenFinder/) Differenciates virulent from avirulent strains (Cosentino S. et al. PLoS One. 2013;8(12) ESCMID Online Lecture Library @ by author Multi-criteria search tools • MvirDB (http://mvirdb.llnl.gov/) Combines several databases Enables searching virulence factors (incl.toxins) and antibiotic resistance markers (Zhou C.E. et al. Nucleic Acids Res. 2007; 35:D391-D394) • PATRIC: Pathosystems Resource Integration Center (https://www.patricbrc.org/portal/portal/patric/HPITool) Combines VFDB, Victors and Patric VF (1,572 genes) to identify virulence factors and host-pathogen protein-protein interactions • PHI-base: pathogen-host interaction database (http://www.phi-base.org/) 2,875ESCMID virulence genes and Online 4,102 host-pathogen Lecture Library Interactions (Urban M. et al. Nucleic Acids Res. 2015;43:D645-655) @ by author Specialized virulence gene databases Toxins • BTXpred: bacterial toxin prediction server (http://www.imtech.res.in/raghava/btxpred) Uses SVM, HMM and PSI-BLAST (Saha S. & raghava G.P. In Silico Biol. 2007;7:405-412) • T3db: toxin and toxin target database (http://www.t3db.ca/) >15,000 genes for >3,500 toxins (Wishart D. et al. Nucleic Acids Res. 2015; 43:D928-934) • DBETH: database of bacterial exotoxins for human (http://www.hpppi.iicb.res.in/btox/) 229 exotoxins from 26 bacterial genera (Chakraborty A. et al. Nucleic Acids Res. 2012;40:D615-620) • PanDaTox: pangenomic database for genomic elements toxic for bacteria (http://exploration.weizmann.ac.il/pandatox/1_0/home.html) IdentifiesESCMID genes and intergenic Online regions unclonable Lecture in E. coli. >Library 40,000 genes (Amitai G. & Sorek R. Bioengineered. 2012; 3:218-221) @ by author Specialized virulence gene databases Adhesins • SPAAN (ftp://203.195.151.45) Combination of 105 compositional properties to identify adhesins (Sachdeva G. et al. Bioinformatics. 2005; 21:483-491) Vaccine targets • Virmugen DB: database of virulent genes used for development of live attenuated vaccines (http://www.violinet.org/virmugendb/) (RaczESCMID R. et al. Vaccine. 2013; 31:797 -805)Online Lecture Library @ by author Ready? Test! Streptococcus pyogenes strain G673 - Community-acquired endocarditis - 1.948 Mb - 1,886 predicted genes • VFDB => 24, 31 or 46 virulence genes • MvirDB => 51 • Virulentpred => 516 • T3db => 3 toxins • PanDaTox => 32 • DBETHESCMID Online=> 1,381 Lecture Library @ by author 2) Searching LGT-acquired genes Pathogenicity islands (Che D. et al. Pathogens. 2014; 3:3656) • PAIDB: Pathogenicity island database (http://www.paidb.re.kr/about_paidb.php) 233 bacterial PAIs (Yoon S.H. et al. Nucleic Acids Res. 2011;35:D395-400) • Island viewer (http://www.pathogenomics.sfu.ca/islandviewer2/resources.php) Combines the SIGI-HMM, IslandPath and IslandPickgenome island prediction tools (Langille et al. BMC Bioinformatics. 2008; 9:329) ESCMID Online Lecture Library @ by author 3) Comparison of virulent and non pathogenic strains • E. coli O157:H7 EDL933 vs K-12 MG1655 (Perna N.T. et al. Nature. 2001;409:529-533) 1,387 genes specific for O157:H7 (26%) are in genomic islands, incl. ~30 additional virulence genes • 7 E. faecium strains vs E. faecalis (Van Schalk W. et al. BMC Genomics. 2010;11:239) 64 – 104 kb pathogenicity islands incl. the esp gene involved in urinary tract invasion ESCMID Online Lecture Library @ by author Comparison of virulent strains and the metagenomes from healthy subjects VS dental plaque metagenomedental plaque gut metagenome VS ESCMID Online Lecture Library @ by author(Belda-Ferre et al. PLoS One. 2011;6:e24975) Virulence linked to genome reduction • Reductive genomic evolution of Rickettsia species • The most virulent species (R. prowazekii) has the smallest genome • Loss of regulatory genes (Fournier et al. BMC Genomics.2009;10:166) ESCMID Online Lecture Library @ by author An isolated phenomenon ? Species genome size (bp) GC (%) coding % ORFs pseudogenes phylum order/family M. leprae 3, 268, 203 57% 49% 1605 1115 Actinobacteria Mycobacteria M. avium 5, 475, 491 68% 88% 5120 1143 Actinobacteria Mycobacteria M. tuberculosis 4, 411, 532 65% 90% 3988 8 Actinobacteria Mycobacteria M. smegmatis 6, 988, 209 67% 90% 6716 168 Actinobacteria Mycobacteria R. prowazekii 1, 111, 523 29% 75% 835 0 Proteobacteria Rickettsiae R. africae 1, 278, 540 32% 72% 1030 87 Proteobacteria Rickettsiae C. diphtheriae 2, 488, 635 53% 87% 2272 48 Actinobacteria Corynebacteria C. glutamicum 3, 314, 179 54% 86% 3052 0 Actinobacteria Corynebacteria T. pallidum 1, 139, 457 52% 93% 1028 9 Spirochetes Spirochaetaceae T. denticola 2, 843, 201 37% 91% 2767 19 Spirochetes Spirochaetaceae Y. pestis 4, 600, 755 47% 82% 4048 54 Proteobacteria γ-enterobacteria Y. pseudotuberculosis 4, 744, 671 47% 82% 3901 73 Proteobacteria γ-enterobacteria B. pertussis 4, 086, 189 67% 82% 3436 358 Proteobacteria β-enterobacteria B. bronchiseptica 5, 339, 179 68% 91% 4994 12 Proteobacteria β-enterobacteria S. pneumoniae 2, 078, 953 39% 85% 2115 0 Firmicutes Lactobacillales S. agalactiae 2, 160, 267 35% 86% 2124 0 Firmicutes Lactobacillales S. pyogenes 1, 852, 442 38% 83% 1696 35 Firmicutes Lactobacillales S. suis 2, 096, 309 41% 86% 2186 0 Firmicutes
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