Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A biphasic epigenetic switch controls immunoevasion, virulence and niche adapatation in non-typeable Haemophilus influenzae

ABSTRACT: Non-typeable Haemophilus influenzae (NTHi) contains an N6-adenine DNA-methyltransferase (ModA), that is subject to phase variable expression (random ON/OFF switching). Five modA alleles, modA2, 4, 5, 9 and 10, account for over two-thirds of clinical otitis media isolates surveyed. Single Molecule Real Time (SMRT) methylome analysis identified the DNA recognition motifs for all five of these modA alleles. Phase variation of these alleles regulated multiple proteins, including vaccine candidates. ON/OFF switching of modA alleles resulted in differential regulation of key virulence phenotypes, such as antibiotic resistance (modA2, 5, 10), biofilm formation (modA2) and immunoevasion (modA4). Analysis of the modA2 strain, 723, in the chinchilla model of otitis media showed a clear selection for switching from modA2OFF to ON in the middle ear. This is the first report of a biphasic epigenetic switch controlling bacterial virulence, immunoevasion and niche adaptation in an animal model system Direct comparison of biological triplicates of wild type and mutant strains

ORGANISM(S): Haemophilus influenzae

SUBMITTER: Sean Grimmond

PROVIDER: E-GEOD-69831 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Gram-positive bacterium Listeria monocytogenes is widely distributed in the environment and capable of causing food-borne infections in susceptible individuals. In this study, we investigated the cell envelope stress response in L. monocytogenes. Whole-genome transcriptional profiling was performed to investigate the response upon exposure to the cell wall antibiotic cefuroxime. Differential expression (≥ 2-fold difference) of 558 genes was observed, corresponding to 20% of the L. monocytogenes genome. The majority of genes strongly induced by cefuroxime exposure have cell envelope-related functions, including the dlt-operon, genes encoding penicillin-binding proteins, and members from the LiaRS regulon. The virulence-associated genes dacA and lmo2714 were up-regulated upon cefuroxime exposure, whereas PrfA-regulated virulence genes, required for invasion and intracellular replication, were repressed. A large overlap was observed between the cefuroxime stimulon and genes known to be induced in L. monocytogenes in blood and during intracellular infection, indicating that the cell envelope stress response is active at various stages of the infectious process. Genes involved in stress tolerance (htrA, ctc) and signal transduction (lisRK) were also found among the highly up-regulated genes. We analysed the roles of the two-component systems LisRK and CesRK, showing that activation of the most highly cefuroxime-induced genes was LisR- and CesR-dependent. Using genetic analyses, we showed that several genes of the cefuroxime stimulon contribute to the innate resistance of L. monocytogenes to cefuroxime and tolerance to other cell envelope-perturbing conditions. Collectively, these findings demonstrate central roles for LisRK and CesRK in orchestrating the cell envelope stress response in L. monocytogenes. Cefuroxime induced expression was measured in the wildtype, lisR deletion mutant and, cesR deletion mutant after 60 minutes of exposure and compared to unexposed control samples. Multiple technical and biological replicates where analyzed with or without the dyes-swapped.

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A biphasic epigenetic switch controls immunoevasion, virulence and niche adapatation in non-typeable Haemophilus influenzae

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