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Global transcription pattern of virulent S. pneumoniae strain D39 (NCTC) compared to that of strains R6 and D39 (Lilly)

ABSTRACT: Streptococcus pneumoniae (pneumococcus) is a leading human respiratory pathogen that causes a variety of serious mucosal and invasive diseases. D39 is an historically important serotype 2 strain that was used in experiments by Avery and coworkers to demonstrate that DNA is the genetic material. Although isolated nearly a century ago, D39 remains extremely virulent in murine infection models and is perhaps the strain used most frequently in current studies of pneumococcal pathogenicity. To date, the complete genome sequences have been reported for only two S. pneumoniae strains; TIGR4, a recent serotype 4 clinical isolate, and laboratory strain R6, an avirulent, unencapsulated derivative of strain D39. We report herein the genome sequences of two different isolates of strain D39 and the corrected sequence and updated annotation of strain R6. Comparisons of these three related sequences allowed deduction of the likely sequence of the D39 progenitor and mutations that arose in each isolate. Despite its numerous repeated sequences and IS elements, the serotype 2 genome has remained remarkably stable during cultivation, and one of the D39 isolates contains only 5 relatively minor mutations compared to the deduced D39 progenitor. In contrast, laboratory strain R6 contains 71 single base pair changes, 6 deletions, 4 insertions, and has lost the cryptic pDP1 plasmid compared to the D39 progenitor strain. Many of these mutations are in or affect the expression of genes that play important roles in regulation, metabolism, and virulence. The nature of the mutations that arose spontaneously in these three strains, relative global transcription patterns determined by microarray analyses, and the implications of the D39 genome sequences to studies of pneumococcal physiology and pathogenesis are presented and discussed. Keywords: bacterial strain comparison, bacterial isolate comparison

ORGANISM(S): Streptococcus pneumoniae

PROVIDER: GSE5375 | GEO | 2006/10/09

SECONDARY ACCESSION(S): PRJNA96277

REPOSITORIES: GEO

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Project description:Infection of the human host by Streptococcus pneumoniae begins with colonization of the nasopharynx, which is mediated by adherence of bacteria to respiratory epithelium. Several studies have indicated an important role for the pneumococcal capsule in this process. Here, we used microarrays to characterize the in vitro transcriptional response of human nasopharyngeal epithelial Detroit 562 cells to adherence of serotype 2-encapsulated strain D39, serotype 19F-encapsulated strain G54, serotype 4-encapsulated strain TIGR4, and their nonencapsulated derivatives (delta-cps). In total, 322 genes were found to be upregulated in response to adherent pneumococci. Twenty-two genes were commonly induced, including those encoding several cytokines (e.g., IL-1-beta, IL-6), chemokines (e.g., IL-8, CXCL1/2), and transcriptional regulators (e.g., FOS), consistent with an innate immune response mediated by Toll-like receptor signaling. Interestingly, 85% of genes was induced specifically by one or more encapsulated strains, suggestive of a capsule-dependent response. Importantly, purified capsular polysaccharides alone had no effect. Over a third of these loci encoded products predicted to be involved in transcriptional regulation and signal transduction, in particular MAPK signaling pathways. Real-time PCR of a subset of ten genes confirmed microarray data and showed a time-dependent upregulation of especially innate immunity genes. Downregulation of epithelial genes was most pronounced upon adherent D39delta-cps, as 68% of the 161 genes identified was only repressed using this nonencapsulated strain. In conclusion, we identified a subset of host genes specifically induced by encapsulated strains during in vitro adherence, and have demonstrated the complexity of interactions occurring during the initial stages of pneumococcal infection. Experiment Overall Design: We used three different pneumococcal strains and their isogenic nonencapsulated derivatives (delta-cps): serotype 2-encapsulated strain D39, serotype 19F-encapsulated strain G54, and serotype 4-encapsulated strain TIGR4. All experiments were performed in triplicate (3 independent biological replicates) and compared to uninfected control Detroit 562 cells. Bacteria were allowed to adhere to the epithelial cells for 2 hours, after which the transcriptional response of the Detroit cells was analyzed using Affymetrix Human U133 Plus GeneChips. In addition to the 6 strains mentioned above, we included transcriptional analysis of the epithelial cell response to low-dose D39delta-cps (giving adherence equivalent to wild-type D39) and purified type 2 capsular polysaccharides.

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Global transcription pattern of virulent S. pneumoniae strain D39 (NCTC) compared to that of strains R6 and D39 (Lilly)

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