Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models

Morrill, Sydney R.; Gilbert, Nicole M.; Lewis, Amanda L.

doi:10.3389/fcimb.2020.00168

Cited by 89 publications

(76 citation statements)

References 151 publications

(237 reference statements)

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“…Progress has been made in developing animal models for BV. For example, it was possible to model some of the clinical characteristics of BV, such as epithelial exfoliation and clue cells, upon infection of mice with Gardnerella [ 47 ]. However, it has not been possible so far to model the increase in pH and the diverse microbiome composition of human BV in animals.…”

Section: Discussionmentioning

confidence: 99%

Engineered Phage Endolysin Eliminates Gardnerella Biofilm without Damaging Beneficial Bacteria in Bacterial Vaginosis Ex Vivo

et al. 2021

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Bacterial vaginosis is characterized by an imbalance of the vaginal microbiome and a characteristic biofilm formed on the vaginal epithelium, which is initiated and dominated by Gardnerella bacteria, and is frequently refractory to antibiotic treatment. We investigated endolysins of the type 1,4-beta-N-acetylmuramidase encoded on Gardnerella prophages as an alternative treatment. When recombinantly expressed, these proteins demonstrated strong bactericidal activity against four different Gardnerella species. By domain shuffling, we generated several engineered endolysins with 10-fold higher bactericidal activity than any wild-type enzyme. When tested against a panel of 20 Gardnerella strains, the most active endolysin, called PM-477, showed minimum inhibitory concentrations of 0.13–8 µg/mL. PM-477 had no effect on beneficial lactobacilli or other species of vaginal bacteria. Furthermore, the efficacy of PM-477 was tested by fluorescence in situ hybridization on vaginal samples of fifteen patients with either first time or recurring bacterial vaginosis. In thirteen cases, PM-477 killed the Gardnerella bacteria and physically dissolved the biofilms without affecting the remaining vaginal microbiome. The high selectivity and effectiveness in eliminating Gardnerella, both in cultures of isolated strains as well as in clinically derived samples of natural polymicrobial biofilms, makes PM-477 a promising alternative to antibiotics for the treatment of bacterial vaginosis, especially in patients with frequent recurrence.

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Section: Discussionmentioning

confidence: 99%

Engineered Phage Endolysin Eliminates Gardnerella Biofilm without Damaging Beneficial Bacteria in Bacterial Vaginosis Ex Vivo

et al. 2021

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“…Progress has been made in developing animal models for BV. For example, it was possible to model some of the clinical characteristics of BV, such as epithelial exfoliation and clue cells upon infection of mice with Gardnerella 50 . However, it was not possible so far to model the increase in pH and the diverse microbiome composition of human BV in animals.…”

Section: Discussionmentioning

confidence: 99%

Engineered phage endolysin eliminates Gardnerella in bacterial vaginosis without damaging the healthy vaginal microbiome

Landlinger¹,

Tišáková²,

Oberbauer³

et al. 2020

Preprint

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Background: Bacterial vaginosis is characterized by an imbalance of the vaginal microbiome in which the normally predominant lactobacilli are replaced by other bacterial species. Initiated by strains of the bacterium Gardnerella, a characteristic biofilm forms on the vaginal epithelium, explaining the typical presence of clue cells. This biofilm contributes to the resilience of the bacteria to antibiotic treatment, which may explain the frequent recurrence of BV. Objective: In this study, we investigate whether a therapy based on bacteriophage endolysins which specifically lyse Gardnerella, in particular the drug candidate PM-477, might be a promising alternative to broad-spectrum antibiotics and antiseptics. Study design: To identify Gardnerella specific endolysins, we searched for endolysin-encoding sequences in regions of Gardnerella genomes that are of prophage origin. This search identified fourteen homologous genes predicted to encode 1,4-beta-N-acetylmuramidase-type endolysins. When expressed in Escherichia coli and purified, the recombinant proteins demonstrated strong bactericidal activity against four different Gardnerella species. By shuffling the N-terminal catalytic domains and C-terminal cell wall-binding domains between the homologues, we produced 81 chimeric endolysins. These endolysins were tested for their activity and specificity in vitro and ex-vivo on vaginal samples from fifteen BV positive patients. Fluorescence in situ hybridization was used for visualization. Results: Several engineered endolysins were 10-fold more active than the most active wild-type enzymes. When tested against a panel of 20 Gardnerella strains, the most active endolysin, called PM-477, showed minimum inhibitory concentrations of 0.13-8 ug/ml. PM-477 had no effect on Lactobacillus strains or other species of vaginal bacteria. Furthermore, the efficacy of PM-477 was tested on vaginal samples from fifteen patients with either first time or recurring bacterial vaginosis. In fourteen cases, PM-477 killed the Gardnerella bacteria and physically dissolved the biofilms without affecting the remaining vaginal microbiome. Conclusion: The high selectivity and effectiveness in eliminating Gardnerella, both in cultures of isolated strains as well as in clinically derived samples of natural polymicrobial biofilms, makes PM-477 a promising drug candidate and an alternative to antibiotics for the treatment of bacterial vaginosis, especially in patients with frequent recurrence.

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“…However, S. intermedius can cause brain and liver abscesses [290], and S. mitis can cause endocarditis, septicemia, and other complications [291]. G. vaginalis is more directly associated with bacterial vaginosis [292]. Most clinical isolates of G. vaginalis from bacterial vaginosis patients express VLY [20].…”

Section: Intermedilysin (Ily) and Vaginolysin (Vly)mentioning

confidence: 99%

Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival

Thapa

Ray

Keyel

2020

Toxins

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Cholesterol-dependent cytolysins (CDCs) are key virulence factors involved in many lethal bacterial infections, including pneumonia, necrotizing soft tissue infections, bacterial meningitis, and miscarriage. Host responses to these diseases involve myeloid cells, especially macrophages. Macrophages use several systems to detect and respond to cholesterol-dependent cytolysins, including membrane repair, mitogen-activated protein (MAP) kinase signaling, phagocytosis, cytokine production, and activation of the adaptive immune system. However, CDCs also promote immune evasion by silencing and/or destroying myeloid cells. While there are many common themes between the various CDCs, each CDC also possesses specific features to optimally benefit the pathogen producing it. This review highlights host responses to CDC pathogenesis with a focus on macrophages. Due to their robust plasticity, macrophages play key roles in the outcome of bacterial infections. Understanding the unique features and differences within the common theme of CDCs bolsters new tools for research and therapy.

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Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models

Cited by 89 publications

References 151 publications

Engineered Phage Endolysin Eliminates Gardnerella Biofilm without Damaging Beneficial Bacteria in Bacterial Vaginosis Ex Vivo

Engineered Phage Endolysin Eliminates Gardnerella Biofilm without Damaging Beneficial Bacteria in Bacterial Vaginosis Ex Vivo

Engineered phage endolysin eliminates Gardnerella in bacterial vaginosis without damaging the healthy vaginal microbiome

Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival

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