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Extracellular vesicles from vaginal Gardnerella vaginalis and Mobiluncus mulieris contain distinct proteomic cargo
Andrea Joseph1,2, Lauren Anton3, Yuxia Guan3
1Women's Biomedical Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA. andrea.joseph@mssm.edu.
Abstract:
Colonization of the vaginal space with bacteria such as Gardnerella vaginalis and Mobiluncus mulieris is associated with increased risk for STIs, bacterial vaginosis, and preterm birth, while Lactobacillus crispatus is associated with optimal reproductive health. Although host-microbe interactions are hypothesized to contribute to reproductive health and disease, the bacterial mediators that are critical to this response remain unclear. Bacterial extracellular vesicles (bEVs) are proposed to participate in host-microbe communication by providing protection of bacterial cargo, delivery to intracellular targets, and ultimately induction of immune responses from the host. We evaluated the proteome of bEVs produced in vitro from G. vaginalis, M. mulieris, and L. crispatus, identifying specific proteins of immunologic interest. We found that bEVs from each bacterial species internalize within cervical and vaginal epithelial cells, and that epithelial and immune cells express a multi-cytokine response when exposed to bEVs from G. vaginalis and M. mulieris but not L. crispatus. Further, we demonstrate that the inflammatory response induced by G. vaginalis and M. mulieris bEVs is TLR2-specific. Our results provide evidence that vaginal bacteria communicate with host cells through secreted bEVs, revealing a mechanism by which bacteria lead to adverse reproductive outcomes associated with inflammation. Elucidating host-microbe interactions in the cervicovaginal space will provide further insight into the mechanisms contributing to microbiome-mediated adverse outcomes and may reveal new therapeutic targets.
Insights
Bacterial extracellular vesicles (bEVs) from harmful vaginal bacteria like Gardnerella vaginalis trigger inflammatory responses, unlike those from beneficial Lactobacillus crispatus. This reveals a key mechanism in adverse reproductive outcomes linked to the vaginal microbiome.
Area of Science:
- Microbiology
- Immunology
- Reproductive Health
Background:
- The vaginal microbiome's composition influences reproductive health, with certain bacteria linked to STIs, bacterial vaginosis, and preterm birth.
- Host-microbe interactions are crucial, but the specific bacterial mediators driving these responses remain largely unknown.
- Bacterial extracellular vesicles (bEVs) are emerging as key mediators of inter-kingdom communication, delivering bacterial cargo and modulating host immunity.
Purpose of the Study:
- To investigate the role of bacterial extracellular vesicles (bEVs) in cervicovaginal host-microbe communication.
- To analyze the proteome of bEVs from key vaginal bacterial species: Gardnerella vaginalis, Mobiluncus mulieris, and Lactobacillus crispatus.
- To determine the immune response elicited by these bEVs in host epithelial and immune cells.
Main Methods:
- In vitro production and proteomic analysis of bEVs from G. vaginalis, M. mulieris, and L. crispatus.
- Internalization assays of bEVs in human cervical and vaginal epithelial cells.
- Measurement of multi-cytokine responses in epithelial and immune cells upon exposure to bEVs.
- Assessment of Toll-like receptor 2 (TLR2) involvement in the inflammatory response to bEVs.
Main Results:
- Proteomic analysis identified proteins of immunologic interest within bEVs from all three bacterial species.
- bEVs from G. vaginalis, M. mulieris, and L. crispatus were internalized by vaginal epithelial cells.
- Exposure to bEVs from G. vaginalis and M. mulieris induced a significant multi-cytokine inflammatory response, while L. crispatus bEVs did not.
- The inflammatory response to G. vaginalis and M. mulieris bEVs was dependent on TLR2 activation.
Conclusions:
- Vaginal bacteria communicate with host cells via secreted bEVs, mediating inflammatory responses.
- bEVs from pathobionts like G. vaginalis and M. mulieris contribute to adverse reproductive outcomes through TLR2-mediated inflammation.
- Understanding bEV-mediated communication offers insights into microbiome-associated pathologies and potential therapeutic targets.
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