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Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners.

ABSTRACT: Lactobacillus iners is a common constituent of the human vaginal microbiota. This species was only recently characterized due to its fastidious growth requirements and has been hypothesized to play a role in the pathogenesis of bacterial vaginosis. Here we present the identification and molecular characterization of a protein toxin produced by L. iners. The L. iners genome encodes an open reading frame with significant primary sequence similarity to intermedilysin (ILY; 69.2% similarity) and vaginolysin (VLY; 68.4% similarity), the cholesterol-dependent cytolysins from Streptococcus intermedius and Gardnerella vaginalis, respectively. Clinical isolates of L. iners produce this protein, inerolysin (INY), during growth in vitro, as assessed by Western analysis. INY is a pore-forming toxin that is activated by reducing agents and inhibited by excess cholesterol. It is active across a pH range of 4.5 to 6.0 but is inactive at pH 7.4. At sublytic concentrations, INY activates p38 mitogen-activated protein kinase and allows entry of fluorescent phalloidin into the cytoplasm of epithelial cells. Unlike VLY and ILY, which are human specific, INY is active against cells from a broad range of species. INY represents a new target for studies directed at understanding the role of L. iners in states of health and disease at the vaginal mucosal surface.

SUBMITTER: Rampersaud R

PROVIDER: S-EPMC3067590 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners.

Rampersaud Ryan R Planet Paul J PJ Randis Tara M TM Kulkarni Ritwij R Aguilar Jorge L JL Lehrer Robert I RI Ratner Adam J AJ

Journal of bacteriology 20101217 5

Lactobacillus iners is a common constituent of the human vaginal microbiota. This species was only recently characterized due to its fastidious growth requirements and has been hypothesized to play a role in the pathogenesis of bacterial vaginosis. Here we present the identification and molecular characterization of a protein toxin produced by L. iners. The L. iners genome encodes an open reading frame with significant primary sequence similarity to intermedilysin (ILY; 69.2% similarity) and vag ...[more]

PMID: 21169489

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Project description:Lactobacillus iners is often associated with vaginal dysbiosis and bacterial vaginosis (BV), which are risk factors for adverse gynecological and obstetric outcomes. To discover natural inhibitors of L. iners, cell-free culture supernatants (CFSs) from 77 vaginal human Lactobacillus strains and 1 human intestinal strain were screened for inhibitory activity. Three active strains were identified, and Lactobacillus paragasseri K7 (K7), a human intestinal strain, produced the most potent L. iners-inhibitory activity. The active material was purified from the K7 CFS and yielded three active peptides, identified as components of two different class IIb, two-peptide bacteriocins, gassericin K7A (GasK7A) and gassericin K7B (GasK7B). The peptides corresponded to the GasK7A α peptide and the GasK7B α and β peptides. While all three peptides exhibited individual activity against L. iners, GasK7B α was the most potent, with an MIC of 23 ng/ml (4 nM). When combined in equal amounts, the GasK7B α and β peptides showed synergistic inhibition, with an MIC of 2 ng/ml (each peptide at 0.4 nM). Among the four major vaginal Lactobacillus species, the K7 bacteriocins selectively inhibited L. iners All 21 strains of L. iners tested (100%) were inhibited by the K7 bacteriocins, whereas <20% of the vaginal Lactobacillus crispatus, L. jensenii, and L. gasseri strains were inhibited. The combination of the BV treatment metronidazole and K7 bacteriocins completely killed both L. iners and Gardnerella vaginalis in a coculture experiment to mimic BV conditions. In contrast, this treatment did not inhibit L. crispatus cultures.IMPORTANCE Lactobacillus iners is a prevalent species of the vaginal microbiome, but unlike other major vaginal Lactobacillus species, it is not considered protective against BV and can coexist with BV-associated bacteria. L. iners is generally the first Lactobacillus species to emerge following the treatment of BV with metronidazole, and mounting evidence suggests that it may contribute to the onset and maintenance of vaginal dysbiosis. The discovery of highly potent bacteriocins that selectively kill L. iners while sparing protective vaginal lactobacilli may provide novel pharmacological tools to better understand the roles of this enigmatic bacterium in vaginal ecology and potentially lead to new and improved therapies for dysbiosis-related conditions such as BV.

Dataset Information

Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners.

Publications

Inerolysin, a cholesterol-dependent cytolysin produced by Lactobacillus iners.

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