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.
机构:
SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14260 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Davie, Jeremiah J.
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Earl, Josh
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Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Earl, Josh
;
de Vries, Stefan P. W.
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Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
de Vries, Stefan P. W.
;
Ahmed, Azad
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Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Ahmed, Azad
;
Hu, Fen Z.
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Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USA
Drexel Univ, Coll Med, Dept Microbiol & Immunol, Pittsburgh, PA USA
Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hu, Fen Z.
;
Bootsma, Hester J.
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Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Bootsma, Hester J.
;
Stol, Kim
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Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Stol, Kim
;
Hermans, Peter W. M.
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Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hermans, Peter W. M.
;
Wadowsky, Robert M.
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Univ Pittsburgh, Grad Sch Publ Hlth, Sch Med, Dept Pathol, Pittsburgh, PA USA
Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA
Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Wadowsky, Robert M.
;
Ehrlich, Garth D.
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机构:
Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USA
Drexel Univ, Coll Med, Dept Microbiol & Immunol, Pittsburgh, PA USA
Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Ehrlich, Garth D.
;
Hays, John P.
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Erasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hays, John P.
;
Campagnari, Anthony A.
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机构:
SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14260 USA
SUNY Buffalo, Dept Med, Div Infect Dis, Buffalo, NY 14260 USA
SUNY Buffalo, Witebsky Ctr Microbial Pathogenesis & Immunol, Buffalo, NY 14260 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
机构:
SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14260 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Davie, Jeremiah J.
;
Earl, Josh
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h-index: 0
机构:
Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Earl, Josh
;
de Vries, Stefan P. W.
论文数: 0引用数: 0
h-index: 0
机构:
Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
de Vries, Stefan P. W.
;
Ahmed, Azad
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h-index: 0
机构:
Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Ahmed, Azad
;
Hu, Fen Z.
论文数: 0引用数: 0
h-index: 0
机构:
Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USA
Drexel Univ, Coll Med, Dept Microbiol & Immunol, Pittsburgh, PA USA
Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hu, Fen Z.
;
Bootsma, Hester J.
论文数: 0引用数: 0
h-index: 0
机构:
Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Bootsma, Hester J.
;
Stol, Kim
论文数: 0引用数: 0
h-index: 0
机构:
Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Stol, Kim
;
Hermans, Peter W. M.
论文数: 0引用数: 0
h-index: 0
机构:
Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hermans, Peter W. M.
;
Wadowsky, Robert M.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Pittsburgh, Grad Sch Publ Hlth, Sch Med, Dept Pathol, Pittsburgh, PA USA
Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA
Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Wadowsky, Robert M.
;
Ehrlich, Garth D.
论文数: 0引用数: 0
h-index: 0
机构:
Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USA
Drexel Univ, Coll Med, Dept Microbiol & Immunol, Pittsburgh, PA USA
Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Ehrlich, Garth D.
;
Hays, John P.
论文数: 0引用数: 0
h-index: 0
机构:
Erasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, NetherlandsErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands
Hays, John P.
;
Campagnari, Anthony A.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14260 USA
SUNY Buffalo, Dept Med, Div Infect Dis, Buffalo, NY 14260 USA
SUNY Buffalo, Witebsky Ctr Microbial Pathogenesis & Immunol, Buffalo, NY 14260 USAErasmus Univ, Med Ctr, Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands