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

Atack JM, Srikhanta YN, Fox KL, Jurcisek JA, Brockman KL, Clark TA, Boitano M, Power PM, Jen FE, McEwan AG, Grimmond SM, Smith AL, Barenkamp SJ, Korlach J, Bakaletz LO, Jennings MP - Nat Commun (2015)

Bottom Line: Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles.Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4).Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

View Article: PubMed Central - PubMed

Affiliation: Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.

ABSTRACT
Non-typeable Haemophilus influenzae contains an N(6)-adenine DNA-methyltransferase (ModA) that is subject to phase-variable expression (random ON/OFF switching). Five modA alleles, modA2, modA4, modA5, modA9 and modA10, account for over two-thirds of clinical otitis media isolates surveyed. Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles. Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4). Analyses of a modA2 strain in the chinchilla model of otitis media show a clear selection for ON switching of modA2 in the middle ear. Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

No MeSH data available.


Related in: MedlinePlus

Analysis of NTHi strain collections to ascertain the proportion of isolates containing phase variable modA alleles.(a–d) Presents the four separate strain collections that were analysed to ascertain the distribution of phase variable modA alleles in NTHi populations; (a) collection containing a broad selection of NTHi isolates from a variety of sources (for example, culture collections, OM-prone individuals)6; (b) samples of paired isolates of NTHi isolated from patients presenting with chronic/recurrent OM17; (c) sample collection of NTHi isolates taken from OM-prone individuals18; (d) NTHi isolates from the nasopharynx of healthy children (collected as part of this study); and (e) the five modA alleles most commonly associated with OM—modA2, modA4, modA5, modA9 and modA10. Each modA gene is represented as a white arrow, with the DRD represented by a coloured box that matches the colour in panels a–d. The black box to the right of each gene represents the 5′ region of the downstream gene (an inactive restriction endonuclease). The blue arrow to the left of each modA gene represents the 3′ end of the gene upstream of each modA (in all the cases, a ribonuclease, rnhB). Details of the strain collections used in c and d are presented in Supplementary Table 1.
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f1: Analysis of NTHi strain collections to ascertain the proportion of isolates containing phase variable modA alleles.(a–d) Presents the four separate strain collections that were analysed to ascertain the distribution of phase variable modA alleles in NTHi populations; (a) collection containing a broad selection of NTHi isolates from a variety of sources (for example, culture collections, OM-prone individuals)6; (b) samples of paired isolates of NTHi isolated from patients presenting with chronic/recurrent OM17; (c) sample collection of NTHi isolates taken from OM-prone individuals18; (d) NTHi isolates from the nasopharynx of healthy children (collected as part of this study); and (e) the five modA alleles most commonly associated with OM—modA2, modA4, modA5, modA9 and modA10. Each modA gene is represented as a white arrow, with the DRD represented by a coloured box that matches the colour in panels a–d. The black box to the right of each gene represents the 5′ region of the downstream gene (an inactive restriction endonuclease). The blue arrow to the left of each modA gene represents the 3′ end of the gene upstream of each modA (in all the cases, a ribonuclease, rnhB). Details of the strain collections used in c and d are presented in Supplementary Table 1.

Mentions: The variable central region of Mod methyltransferases contains the DNA-recognition domain (DRD; see Fig. 1e) that dictates methylation-sequence specificity111213. In H. influenzae strain Rd, our previous work has demonstrated that random switching of the modA1 gene controls expression of multiple genes via differential methylation of the genome in the modA1 ON and OFF states10. This novel genetic system, termed the phasevarion (phase-variable regulon) regulates gene expression in four other important human pathogens: Neisseria gonorrhoeae, Neisseria meningitidis7, Helicobacter pylori9 and Moraxella catarrhalis14. Differences in the DRD have previously been observed in a genetically diverse collection of H. influenzae strains and these differences define 20 distinct mod alleles (modA1 to modA20)615. Different DRDs are proposed to recognize and methylate different target sequences. Our studies with pathogenic Neisseria, which also contains modA, confirmed that different modA alleles methylate different target sequences and thereby regulate different sets of genes, that is, have distinct phasevarions. Conversely, strains that harbour the same modA allele regulate the same phasevarion of genes716.


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

Atack JM, Srikhanta YN, Fox KL, Jurcisek JA, Brockman KL, Clark TA, Boitano M, Power PM, Jen FE, McEwan AG, Grimmond SM, Smith AL, Barenkamp SJ, Korlach J, Bakaletz LO, Jennings MP - Nat Commun (2015)

Analysis of NTHi strain collections to ascertain the proportion of isolates containing phase variable modA alleles.(a–d) Presents the four separate strain collections that were analysed to ascertain the distribution of phase variable modA alleles in NTHi populations; (a) collection containing a broad selection of NTHi isolates from a variety of sources (for example, culture collections, OM-prone individuals)6; (b) samples of paired isolates of NTHi isolated from patients presenting with chronic/recurrent OM17; (c) sample collection of NTHi isolates taken from OM-prone individuals18; (d) NTHi isolates from the nasopharynx of healthy children (collected as part of this study); and (e) the five modA alleles most commonly associated with OM—modA2, modA4, modA5, modA9 and modA10. Each modA gene is represented as a white arrow, with the DRD represented by a coloured box that matches the colour in panels a–d. The black box to the right of each gene represents the 5′ region of the downstream gene (an inactive restriction endonuclease). The blue arrow to the left of each modA gene represents the 3′ end of the gene upstream of each modA (in all the cases, a ribonuclease, rnhB). Details of the strain collections used in c and d are presented in Supplementary Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525171&req=5

f1: Analysis of NTHi strain collections to ascertain the proportion of isolates containing phase variable modA alleles.(a–d) Presents the four separate strain collections that were analysed to ascertain the distribution of phase variable modA alleles in NTHi populations; (a) collection containing a broad selection of NTHi isolates from a variety of sources (for example, culture collections, OM-prone individuals)6; (b) samples of paired isolates of NTHi isolated from patients presenting with chronic/recurrent OM17; (c) sample collection of NTHi isolates taken from OM-prone individuals18; (d) NTHi isolates from the nasopharynx of healthy children (collected as part of this study); and (e) the five modA alleles most commonly associated with OM—modA2, modA4, modA5, modA9 and modA10. Each modA gene is represented as a white arrow, with the DRD represented by a coloured box that matches the colour in panels a–d. The black box to the right of each gene represents the 5′ region of the downstream gene (an inactive restriction endonuclease). The blue arrow to the left of each modA gene represents the 3′ end of the gene upstream of each modA (in all the cases, a ribonuclease, rnhB). Details of the strain collections used in c and d are presented in Supplementary Table 1.
Mentions: The variable central region of Mod methyltransferases contains the DNA-recognition domain (DRD; see Fig. 1e) that dictates methylation-sequence specificity111213. In H. influenzae strain Rd, our previous work has demonstrated that random switching of the modA1 gene controls expression of multiple genes via differential methylation of the genome in the modA1 ON and OFF states10. This novel genetic system, termed the phasevarion (phase-variable regulon) regulates gene expression in four other important human pathogens: Neisseria gonorrhoeae, Neisseria meningitidis7, Helicobacter pylori9 and Moraxella catarrhalis14. Differences in the DRD have previously been observed in a genetically diverse collection of H. influenzae strains and these differences define 20 distinct mod alleles (modA1 to modA20)615. Different DRDs are proposed to recognize and methylate different target sequences. Our studies with pathogenic Neisseria, which also contains modA, confirmed that different modA alleles methylate different target sequences and thereby regulate different sets of genes, that is, have distinct phasevarions. Conversely, strains that harbour the same modA allele regulate the same phasevarion of genes716.

Bottom Line: Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles.Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4).Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

View Article: PubMed Central - PubMed

Affiliation: Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.

ABSTRACT
Non-typeable Haemophilus influenzae contains an N(6)-adenine DNA-methyltransferase (ModA) that is subject to phase-variable expression (random ON/OFF switching). Five modA alleles, modA2, modA4, modA5, modA9 and modA10, account for over two-thirds of clinical otitis media isolates surveyed. Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles. Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance (modA2, modA5, modA10), biofilm formation (modA2) and immunoevasion (modA4). Analyses of a modA2 strain in the chinchilla model of otitis media show a clear selection for ON switching of modA2 in the middle ear. Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system.

No MeSH data available.


Related in: MedlinePlus