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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

ORGANISM(S): Haemophilus influenzae

PROVIDER: GSE69831 | GEO | 2015/06/12

SECONDARY ACCESSION(S): PRJNA286882

REPOSITORIES: GEO

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

Project description: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

2015-06-12 | E-GEOD-69831 | biostudies-arrayexpress

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Oligopeptide Importers AliC and AliD of Nonencapsulated Streptococcus pneumoniae Facilitate Mucosal Infections and Mediate Persistence during Invasive Disease

Project description:Nonencapsulated Streptococcus pneumoniae (NESp) is an emerging human pathogen that colonizes the nasopharynx and is associated with noninvasive disease such as otitis media (OM), conjunctivitis, and nonbacteremic pneumonia. For decades, expression of a polysaccharide capsule appeared to be necessary for establishment of colonization and development of invasive pneumococcal disease (IPD). Accordingly, the currently licensed pneumococcal vaccines target the polysaccharide capsule. However, NESp expressing the novel oligopeptide importer proteins AliC and AliD have been isolated during IPD. Our study reveals that NESp expressing AliC and AliD have intensified virulence compared to isogenic mutants, and we provide insight about how this pneumococcal population has become associated with IPD. Our data demonstrates that AliC and AliD enhance murine nasopharyngeal colonization and are required for OM in a chinchilla model. Furthermore, AliC and AliD increase pneumococcal survival in chinchilla whole blood and decrease deposition of human C3b on the bacterial surface. As NESp become an increasing threat to public health, our study exposes specific virulence factors to possibly target for a broadened prevention of IPD through vaccination.

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Expression analysis of a full SlrV locus 1 knockout in Haemophilus influenzae strain PittII

Project description:Investigation of whole genome gene expression differences between a full (four-gene) SlrV locus 1 deletion compared to the WT PittII strain. Removal of the four SlrV genes (aka macrophage survival factors : ?msf) results in a competetive defect with the WT strain in in vitro biofilms and in the otitis media chinchilla model. It also results in an inability to persist within macrophages long-term in vitro and to escape from the middle-ear space and infect other sites in the chinchilla model. WT and ?msf strains were grown in a chemically defined media (CDM) to early stationary phase (OD ~1.0). RNA was extracted from two separate cultures (biological replicates). 3-13 probes represent each subcluster(gene) and two replicate probe sets are included on each custom NTHi supragenome chip (technical replicates) thus under each sampling condition 4 separate values are obtained per strain and used for WT:Msf-KO comparisons.

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Beta- lactam antibiotics stimulate biofilm formation in non-typeable Haemophilus influenzae by up-regulating carbohydrate metabolism

Project description:Non-typeable Haemophilus influenzae (NTHi) is a common acute otitis media pathogen, with an incidence that is increased by previous antibiotic treatment. NTHi is also an emerging causative agent of other chronic infections in humans, some linked to morbidity, and all of which impose substantial treatment costs. In this study we explore the possibility that antibiotic exposure may stimulate biofilm formation by NTHi bacteria. We discovered that sub-inhibitory concentrations of beta-lactam antibiotic (i.e., amounts that partially inhibit bacterial growth) stimulated the biofilm-forming ability of NTHi strains, an effect that was strain and antibiotic dependent. When exposed to sub-inhibitory concentrations of beta-lactam antibiotics NTHi strains produced tightly packed biofilms with decreased numbers of culturable bacteria but increased biomass. The ratio of protein per unit weight of biofilm decreased as a result of antibiotic exposure. Antibiotic-stimulated biofilms had altered ultrastructure, and genes involved in glycogen production and transporter function were up regulated in response to antibiotic exposure. Down-regulated genes were linked to multiple metabolic processes but not those involved in stress response. Antibiotic-stimulated biofilm bacteria were more resistant to a lethal dose (10M-BM-5g/mL) of cefuroxime. Our results suggest that beta-lactam antibiotic exposure may act as a signaling molecule that promotes transformation into the biofilm phenotype. Loss of viable bacteria, increase in biofilm biomass and decreased protein production coupled with a concomitant up-regulation of genes involved with glycogen production might result in a biofilm of sessile, metabolically inactive bacteria sustained by stored glycogen. These biofilms may protect surviving bacteria from subsequent antibiotic challenges, and act as a reservoir of viable bacteria once antibiotic exposure has ended. 12 samples

2014-06-04 | E-GEOD-58213 | biostudies-arrayexpress

Beta- lactam antibiotics stimulate biofilm formation in non-typeable Haemophilus influenzae by up-regulating carbohydrate metabolism

Project description:Non-typeable Haemophilus influenzae (NTHi) is a common acute otitis media pathogen, with an incidence that is increased by previous antibiotic treatment. NTHi is also an emerging causative agent of other chronic infections in humans, some linked to morbidity, and all of which impose substantial treatment costs. In this study we explore the possibility that antibiotic exposure may stimulate biofilm formation by NTHi bacteria. We discovered that sub-inhibitory concentrations of beta-lactam antibiotic (i.e., amounts that partially inhibit bacterial growth) stimulated the biofilm-forming ability of NTHi strains, an effect that was strain and antibiotic dependent. When exposed to sub-inhibitory concentrations of beta-lactam antibiotics NTHi strains produced tightly packed biofilms with decreased numbers of culturable bacteria but increased biomass. The ratio of protein per unit weight of biofilm decreased as a result of antibiotic exposure. Antibiotic-stimulated biofilms had altered ultrastructure, and genes involved in glycogen production and transporter function were up regulated in response to antibiotic exposure. Down-regulated genes were linked to multiple metabolic processes but not those involved in stress response. Antibiotic-stimulated biofilm bacteria were more resistant to a lethal dose (10µg/mL) of cefuroxime. Our results suggest that beta-lactam antibiotic exposure may act as a signaling molecule that promotes transformation into the biofilm phenotype. Loss of viable bacteria, increase in biofilm biomass and decreased protein production coupled with a concomitant up-regulation of genes involved with glycogen production might result in a biofilm of sessile, metabolically inactive bacteria sustained by stored glycogen. These biofilms may protect surviving bacteria from subsequent antibiotic challenges, and act as a reservoir of viable bacteria once antibiotic exposure has ended.

2014-06-04 | GSE58213 | GEO

RNA-seq of Moraxella catarrhalis CCRI-195ME ModM3 ON and ModM3 OFF phase variants

Project description:Moraxella catarrhalis contains an N6-adenine DNA-methyltransferase (ModM3), that is subject to phase variable expression (random ON/OFF switching). Phase-variable switching of DNA methyltransferase activity results in the presence or absence of methylation at a specific target sequence, leading to co-ordinated, epigenetically-regulated switching of expression of multiple genes across the genome. The suite of genes thus regulated are known as a phasevarion (phase-variable regulon). Phase variation of modM is mediated at the translational level by a 5′-(CAAC)n-3′ tetranucleotide repeat tract present within its open reading frame (ORF). Analysis of the genomes of 51 M. catarrhalis strains identified six modM alleles (modM1-6) that vary in their target recognition domains. The modM3 allele is also overrepresented in middle ear isolates of M. catarrhalis from children with OM. Here we characterise the genes regulated in the ModM3 phasevarion and show that phase variation of the M.catarrhalis CCRI-195ME ModM3 epigenetically regulates the expression of a phasevarion containing multiple genes that are potentially important in the progression of otitis media.

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