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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

Results from chinchilla middle ear samples.(a) Heat map showing fragment analysis results from animals challenged with either NTHi 723 modA2(22)ON or modA2(24)OFF. The time of sampling is indicated at the top of the figure by days after initial infection, for example, day 0=initial inoculum, day 4=4 days after initial infection and so on. All fragment analysis data are presented in Supplementary Table 4; (b) middle ear exudate (MEE) bacterial CFU mean counts from animals infected with modA2(22)ON and modA2(24)OFF. Error bars represent s.d.; and (c) survival of animals infected with modA2(22)ON and modA2(24)OFF.
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f5: Results from chinchilla middle ear samples.(a) Heat map showing fragment analysis results from animals challenged with either NTHi 723 modA2(22)ON or modA2(24)OFF. The time of sampling is indicated at the top of the figure by days after initial infection, for example, day 0=initial inoculum, day 4=4 days after initial infection and so on. All fragment analysis data are presented in Supplementary Table 4; (b) middle ear exudate (MEE) bacterial CFU mean counts from animals infected with modA2(22)ON and modA2(24)OFF. Error bars represent s.d.; and (c) survival of animals infected with modA2(22)ON and modA2(24)OFF.

Mentions: The ON/OFF status of the repeat tracts in both the modA2(22)ON and modA2(24)OFF infected cohorts from the starting inoculum (day 0) and subsequent days 4, 7, 10, 14, 18 and 22 after challenge were verified by fragment analysis (Fig. 5a; full data set presented in Supplementary Table 4). No gross difference in colony-forming units (c.f.u.) number or mortality was observed (Fig. 5b,c). Figure 5a shows a heat map of the modA2ON status of the inoculum, and the bacteria isolated from both middle ears. Animals challenged with the predominantly modA2ON variant (green) remained ON, whereas those animals challenged with the predominantly modA2OFF variant (red) showed a consistent switch from the OFF to the ON state during the course of the experimental OM study (Fig. 5a). This observation suggests that selection for modA2ON over modA2OFF occurred during overt infection of the middle ear.


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)

Results from chinchilla middle ear samples.(a) Heat map showing fragment analysis results from animals challenged with either NTHi 723 modA2(22)ON or modA2(24)OFF. The time of sampling is indicated at the top of the figure by days after initial infection, for example, day 0=initial inoculum, day 4=4 days after initial infection and so on. All fragment analysis data are presented in Supplementary Table 4; (b) middle ear exudate (MEE) bacterial CFU mean counts from animals infected with modA2(22)ON and modA2(24)OFF. Error bars represent s.d.; and (c) survival of animals infected with modA2(22)ON and modA2(24)OFF.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Results from chinchilla middle ear samples.(a) Heat map showing fragment analysis results from animals challenged with either NTHi 723 modA2(22)ON or modA2(24)OFF. The time of sampling is indicated at the top of the figure by days after initial infection, for example, day 0=initial inoculum, day 4=4 days after initial infection and so on. All fragment analysis data are presented in Supplementary Table 4; (b) middle ear exudate (MEE) bacterial CFU mean counts from animals infected with modA2(22)ON and modA2(24)OFF. Error bars represent s.d.; and (c) survival of animals infected with modA2(22)ON and modA2(24)OFF.
Mentions: The ON/OFF status of the repeat tracts in both the modA2(22)ON and modA2(24)OFF infected cohorts from the starting inoculum (day 0) and subsequent days 4, 7, 10, 14, 18 and 22 after challenge were verified by fragment analysis (Fig. 5a; full data set presented in Supplementary Table 4). No gross difference in colony-forming units (c.f.u.) number or mortality was observed (Fig. 5b,c). Figure 5a shows a heat map of the modA2ON status of the inoculum, and the bacteria isolated from both middle ears. Animals challenged with the predominantly modA2ON variant (green) remained ON, whereas those animals challenged with the predominantly modA2OFF variant (red) showed a consistent switch from the OFF to the ON state during the course of the experimental OM study (Fig. 5a). This observation suggests that selection for modA2ON over modA2OFF occurred during overt infection of the middle ear.

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