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

被引:61
作者
Blakeway, Luke V. [1 ]
Power, Peter M. [1 ]
Jen, Freda E. -C. [1 ]
Worboys, Sam R. [1 ]
Boitano, Matthew [3 ]
Clark, Tyson A. [3 ]
Korlach, Jonas [3 ]
Bakaletz, Lauren O. [4 ]
Jennings, Michael P. [1 ]
Peak, Ian R. [1 ,2 ]
Seib, Kate L. [1 ]
机构
[1] Griffith Univ, Inst Glyc, Southport, Qld 4215, Australia
[2] Griffith Univ, Sch Med Sci, Southport, Qld 4215, Australia
[3] Pacific Biosci, Menlo Pk, CA USA
[4] Nationwide Childrens Hosp, Ctr Microbial Pathogenesis, Res Inst, Columbus, OH USA
基金
英国医学研究理事会;
关键词
epigenetic regulation; middle ear infection; phase variation; single-molecule; real-time genome sequencing; SMRT; NASOPHARYNGEAL BACTERIAL-COLONIZATION; PHASE VARIATION; EPIDEMIOLOGY; RESTRICTION; EXPRESSION; INFECTION; PATHOGENS; CHILDREN; SEQUENCE; VACCINE;
D O I
10.1096/fj.14-256578
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Moraxella catarrhalis is a significant cause of otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we characterize a phase-variable DNA methyltransferase (ModM), which contains 5'-CAAC-3' repeats in its open reading frame that mediate high-frequency mutation resulting in reversible on/off switching of ModM expression. Three modM alleles have been identified (modM1-3), with modM2 being the most commonly found allele. Using single-molecule, real-time (SMRT) genome sequencing and methylome analysis, we have determined that the ModM2 methylation target is 5'-GAR(m6)AC-3', and 100% of these sites are methylated in the genome of the M. catarrhalis 25239 ModM2 on strain. Proteomic analysis of ModM2 on and off variants revealed that ModM2 regulates expression of multiple genes that have potential roles in colonization, infection, and protection against host defenses. Investigation of the distribution of modM alleles in a panel of M. catarrhalis strains, isolated from the nasopharynx of healthy children or middle ear effusions from patients with otitis media, revealed a statistically significant association of modM3 with otitis media isolates. The modulation of gene expression via the ModM phase-variable regulon (phasevarion), and the significant association of the modM3 allele with otitis media, suggests a key role for ModM phasevarions in the pathogenesis of this organism.
引用
收藏
页码:5197 / 5207
页数:11
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