Understanding how the vaginal microbiota modulates the maternal innate immune environment to promote health or disease

Pregnancy is a balancing act for the maternal immune system where it must tolerate the foreign foetus while maintaining protection against infection. Undue activation of the immune system leads to a broad range of women’s reproductive health disorders. Our aim is to understand how the maternal immune system is regulated and how the vaginal microbiota can tip the immunological balance toward health and disease.

Project Summary

The vaginal microbiota plays a key role in women’s health. Low diversity microbiota dominated by Lactobacillus crispatus is considered as the hallmark of health. Conversely, a high diversity microbiota, leading to inflammation, is associated with adverse women’s reproductive health outcomes such as bacterial vaginosis, increase susceptibility to sexually transmitted infections and adverse pregnancy outcomes such as infertility and preterm birth. Inflammation is a key driver of women’s health and disease. Interestingly, we identified a subset of anti-inflammatory lectins, innate immune receptors specialised in detecting glycan motifs, interacting specifically with the commensal bacterium L. crispatus; however, the consequences of these interactions remain unknown.

The aim of this project is to identify the bacterial ligands of these anti-inflammatory receptors, characterise the immune response triggered and develop chemical mimetics with improved anti-inflammatory properties.

The results of these project will not only help to better understand how the beneficial vs detrimental bacteria modulate the maternal immune system but will also open new ways to develop synthetic glyco-molecules mimicking the anti-inflammatory effect of the lactobacilli to prevent a broad range of women’s health diseases.

Methodology

The immunomodulatory glycans will be purified from Lactobacillus crispatus according to protocols established in the host laboratory. Briefly, L. crispatus will be grown and the glycans will be extracted and purified by size exclusion and affinity chromatography. The isolated glycans will then be analysed for binding to plant lectins as a proxy to determine glycan composition and by mass spectrometry.

The glycans identified as ligands of will then be tested for their ability to activate HEK reporter cell lines and monocyte derived dendritic cells. Signalling will be assessed by ELISA, Western Blot, flow cytometry and microscopy.

Finally, the bacterial glycans will be coupled to multivalent scaffolds and their biological activity will be assessed.

Enquiries

Speak to our postgraduate research team at wms.rdcoord@warwick.ac.uk