title: A functional genomics catalogue of activated transcription factors during pathogenesis of pneumococcal disease.
abstract: BACKGROUND
  Streptococcus pneumoniae (the pneumococcus) is the world's foremost microbial pathogen, killing more people each year than HIV, TB or malaria. The capacity to penetrate deeper host tissues contributes substantially to the ability of this organism to cause disease. Here we investigated, for the first time, functional genomics modulation of 3 pneumococcal strains (serotype 2 [D39], serotype 4 [WCH43] and serotype 6A [WCH16]) during transition from the nasopharynx to lungs to blood and to brain of mice at both promoter and domain activation levels.
  
  
  RESULTS
  We found 7 highly activated transcription factors (TFs) [argR, codY, hup, rpoD, rr02, scrR and smrC] capable of binding to a large number of up-regulated genes, potentially constituting the regulatory backbone of pneumococcal pathogenesis. Strain D39 showed a distinct profile in employing a large number of TFs during blood infection. Interestingly, the same highly activated TFs used by D39 in blood are also used by WCH16 and WCH43 during brain infection. This indicates that different pneumococcal strains might activate a similar set of TFs and regulatory elements depending on the final site of infection. Hierarchical clustering analysis showed that all the highly activated TFs, except rpoD, clustered together with a high level of similarity in all 3 strains, which might suggest redundancy in the regulatory roles of these TFs during infection. Discriminant function analysis of the TFs in various niches highlights differential regulatory backgrounds of the 3 strains, and pathogenesis data confirms codY as the most significant predictor discriminating between these strains in various niches, particularly in the blood. Moreover, the predicted TF and domain activation profiles of the 3 strains correspond with their distinct pathogenicity characteristics.
  
  
  CONCLUSIONS
  Our findings suggest that the pneumococcus changes the short binding sites in the promoter regions of genes in a niche-specific manner to enhance its ability to disseminate from one host niche to another. This study provides a framework for an improved understanding of the dynamics of pneumococcal pathogenesis, and opens a new avenue into similar investigations in other pathogenic bacteria.
authors.forename: Layla K
authors.initials: LK
authors.lastname: Mahdi
authors.forename: Tahereh
authors.initials: T
authors.lastname: Deihimi
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Zamansani
authors.forename: Mario
authors.initials: M
authors.lastname: Fruzangohar
authors.forename: David L
authors.initials: DL
authors.lastname: Adelson
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia. david.ogunniyi@adelaide.edu.au.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Ebrahimie
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D016000:Cluster Analysis; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D056084:Genetic Fitness; D023281:Genomics; D051379:Mice; D011008:Pneumococcal Infections / Q000382:microbiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D040901:Proteomics; D013296:Streptococcus pneumoniae / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors