ModM DNA methyltransferase methylome analysis reveals a potential role for
            <i>Moraxella catarrhalis</i>
            phasevarions in otitis media

Blakeway, Luke V.; Power, Peter M.; Jen, Freda E.-C.; Worboys, Sam R.; Boitano, Matthew; Clark, Tyson A.; Korlach, Jonas; Jennings, Michael P.; Peak, Ian R.; Seib, Kate L.

doi:10.1096/fj.14-256578

Cited by 71 publications

(122 citation statements)

References 53 publications

(66 reference statements)

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…Phasevarions are increasingly being recognized as playing an important role in hostadapted pathogens. In H. influenzae (ModA) (21), N. gonorrhoeae and N. meningitidis (ModA, ModB, and ModD) (22,23), M. catarrhalis (ModM) (25), and H. pylori (ModH) (24), phasevarions control expression of surface antigens and virulence factors, leading to altered phenotypes between Mod ON and OFF variants. For example, the gonococcal ModA13 ON/OFF variants have distinct phenotypes for biofilm formation, resistance to antimicrobials, and survival in primary human cervical epithelial cells (22).…”

Section: Discussionmentioning

confidence: 99%

“…These phase variable regulons, or phasevarions, control expression of surface antigens and virulence factors, leading to altered phenotypes between Mod ON and OFF variants (where ON indicates in frame for expression and OFF indicates out of frame). Phasevarions have been studied in Haemophilus influenzae (ModA [21]), Neisseria gonorrhoeae and Neisseria meningitidis (ModA, ModB, and ModD [22,23]), Helicobacter pylori (ModH [24]), and Moraxella catarrhalis (ModM [25]). The ModA, -B, -D, -H, and -M proteins have different alleles based on amino acid differences in their central DNA recognition domain (20,22,(24)(25)(26), and each mod allele methylates different DNA sequences.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

et al. 2017

View full text Add to dashboard Cite

Kingella kingae is a common etiological agent of pediatric osteoarticular infections. While current research has expanded our understanding of K. kingae pathogenesis, there is a paucity of knowledge about host-pathogen interactions and virulence gene regulation. Many host-adapted bacterial pathogens contain phase variable DNA methyltransferases (mod genes), which can control expression of a regulon of genes (phasevarion) through differential methylation of the genome. Here, we identify a phase variable type III mod gene in K. kingae, suggesting that phasevarions operate in this pathogen. Phylogenetic studies revealed that there are two active modK alleles in K. kingae. Proteomic analysis of secreted and surfaceassociated proteins, quantitative PCR, and a heat shock assay comparing the wildtype modK1 ON (i.e., in frame for expression) strain to a modK1 OFF (i.e., out of frame) strain revealed three virulence-associated genes under ModK1 control. These include the K. kingae toxin rtxA and the heat shock genes groEL and dnaK. Cytokine expression analysis showed that the interleukin-8 (IL-8), IL-1␤, and tumor necrosis factor responses of THP-1 macrophages were lower in the modK1 ON strain than in the modK1::kan mutant. This suggests that the ModK1 phasevarion influences the host inflammatory response and provides the first evidence of this phase variable epigenetic mechanism of gene regulation in K. kingae.KEYWORDS Kingella kingae, gene regulation, phase variation, type III restrictionmodification systems, phasevarion K ingella kingae is a Gram-negative bacterial pathogen belonging to the Neisseriaceae family. While often carried asymptomatically in the respiratory tract, K. kingae is associated with invasive infections, including bacteremia, osteoarticular infections, meningitis, lower respiratory tract infections, and keratitis. Diagnostic advances have resulted in its recognition as a leading cause of osteoarticular infections in young children (1-3). Importantly, it is a member of the HACEK group, associated with infective endocarditis. However, unlike other HACEK organisms, K. kingae-mediated infective endocarditis can progress very rapidly (4-6) and is associated with serious complications, with an overall mortality rate of 16% (1, 6). Adults with invasive infections usually have predisposing medical ailments.Transmission occurs via close personal contact, and clusters of invasive infections have been reported among day care center attendees (7,8). Invasive disease begins with colonization of the oropharynx and is often preceded by an upper respiratory tract infection (8, 9). The disrupted respiratory mucosa may then facilitate invasion and hematogenous dissemination to the bones, joints, and heart (10).

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

et al. 2017

View full text Add to dashboard Cite

show abstract

“…These phase variable regulons, or phasevarions [7], control expression of surface antigens and virulence factors, leading to altered phenotypes between Mod ON and OFF variants. Phasevarions have been studied in H. influenzae (ModA; [8,9], N. gonorrhoeae and N. meningitidis (ModA, ModB and ModD; (40-42); H. pylori (ModH; [13] and M. catarrhalis (ModM [14]). The structure of each class of Mod proteins (ModA, B, D, H, and M) are highly conserved, apart from the central DNA recognition domain (DRD) that dictates methylation specificity [15].…”

Section: Introductionmentioning

confidence: 99%

The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits

VanWagoner

Atack

Nelson

et al. 2016

Microbial Pathogenesis

Self Cite

View full text Add to dashboard Cite

Non-typeable Haemophilus influenzae (NTHi) is a human restricted commensal and pathogen that elicits inflammation by adhering to and invading airway epithelia cells: transcytosis across these cells can result in systemic infection. NTHi strain R2866 was isolated from the blood of a normal 30-month old infant with meningitis, and is unusual for NTHi in that it is able to cause systemic infection. Strain R2866 is able to replicate in normal human serum due to expression of lgtC which mimics human blood group pk. R2866 contains a phase-variable DNA methyltransferase, modA10 which switches ON and OFF randomly and reversibly due to polymerase slippage over a long tetrameric repeat tract located in its open reading frame. Random gain or loss of repeats during replication can results in expressed (ON), or not expressed (OFF) states, the latter due to a frameshift or transcriptional termination at a premature stop codon. We sought to determine if the unusual virulence of R2866 was modified by modA10 phase-variation. A modA10 knockout mutant was found to have increased adherence to, and invasion of, human ear and airway monolayers in culture, and increased invasion and transcytosis of polarized human bronchial epithelial cells. Intriguingly, the rate of bacteremia was lower in the infant rat model of infection than a wild-type R2866 strain, but the fatality rate was greater. Transcriptional analysis comparing the modA10 knockout to the R2866 wild-type parent strain showed increased expression of genes in the modA10 knockout whose products mediate cellular adherence. We conclude that loss of ModA10 function in strain R2866 enhances colonization and invasion by increasing expression of genes that allow for increased adherence, which can contribute to the increased virulence of this strain.

show abstract

“…Such changes, the scale of which far outstrips that of base-by-base mutation, enable bacteria to quickly respond to environmental changes and to exploit new ecological niches [43–45]. With regard to bacteria such as B .…”

Section: Discussionmentioning

confidence: 99%

“…However, it is becoming increasingly apparent that specific methylation marks can affect bacterial gene expression, and therefore can affect cellular processes not obviously connected to restriction-modification. Well known examples include the orphan MTases Dam in Gamma-Proteobacteria [46] and CcrM in Alpha-Proteobacteria [47], and more recent work has shown that MTases within R-M systems can also have consequential transcriptional effects [43, 44, 48]. Therefore, changes in the activity of any given MTase may, through resulting changes in the methylome, have unknown, pleiotropic effects.…”

Section: Discussionmentioning

confidence: 99%

Comparative Methylome Analysis of the Occasional Ruminant Respiratory Pathogen Bibersteinia trehalosi

et al. 2016

View full text Add to dashboard Cite

We examined and compared both the methylomes and the modification-related gene content of four sequenced strains of Bibersteinia trehalosi isolated from the nasopharyngeal tracts of Nebraska cattle with symptoms of bovine respiratory disease complex. The methylation patterns and the encoded DNA methyltransferase (MTase) gene sets were different between each strain, with the only common pattern being that of Dam (GATC). Among the observed patterns were three novel motifs attributable to Type I restriction-modification systems. In some cases the differences in methylation patterns corresponded to the gain or loss of MTase genes, or to recombination at target recognition domains that resulted in changes of enzyme specificity. However, in other cases the differences could be attributed to differential expression of the same MTase gene across strains. The most obvious regulatory mechanism responsible for these differences was slipped strand mispairing within short sequence repeat regions. The combined action of these evolutionary forces allows for alteration of different parts of the methylome at different time scales. We hypothesize that pleiotropic transcriptional modulation resulting from the observed methylomic changes may be involved with the switch between the commensal and pathogenic states of this common member of ruminant microflora.

show abstract

ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media

Cited by 71 publications

References 53 publications

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

The modA10 phasevarion of nontypeable Haemophilus influenzae R2866 regulates multiple virulence-associated traits

Comparative Methylome Analysis of the Occasional Ruminant Respiratory Pathogen Bibersteinia trehalosi

Contact Info

Product

Resources

About