One-third of women in the U.S. have bacterial vaginosis (BV), a condition characterized by loss of lactobacilli and overgrowth of diverse potential pathogens. BV is associated with greater risks of intrauterine infection and preterm birth. Antibiotic treatment temporarily alleviates BV; however, most women develop the condition again within weeks or months. Break down of mucosal barriers is thought to play an important role in the causes and complications of BV. However, little is known about how degradation of mucosal barriers by individual bacterial species predisposes women to the clinical features and/or adverse events associated with BV. This proposal examines how sialidase-mediated mucosal damage by the bacterium Gardnerella vaginalis, one of the most common bacteria found to overgrow in BV, participates in the molecular pathogenesis of vaginal and intrauterine infection. Sialic acids are carbohydrate molecules found at high levels on cell surfaces and in mucus secretions. Vaginal sialidase enzyme activity (cleaves sialic acid residues) is found in nearly all women with BV and correlates with findings of 'thin' mucus secretions and a higher risk of preterm birth. In contrast, sialidase is rarely found in secretionsof those with a 'healthy' vaginal microbiota. We have shown that mucus sialic acids are degraded and depleted in women with BV compared to healthy women. In vitro studies showed that G. vaginalis liberates and consumes host sialic acids and was also sufficient to cause vaginal sialic acid depletion in our established mouse model (the first animal model to capture clinical features of BV). In three specific aims, this proposal will use a combination of isogenic bacterial strains and small molecule inhibitors to test several hypotheses about the molecular mechanism of G. vaginalis sialidase in the causes and complications of BV.
In Aim 1, we will examine the role of sialidase in vaginal colonization, and in particular, the degradation of sialic acids on th surfaces of vaginal epithelial cells, leading to exposure of underlying sites for bacterial adhesion.
In Aim 2, we will explore the use of sialic acids as a source of bacterial nutrition in te vagina, both for G. vaginalis, as well as other BV-associated bacteria that are predicted to consume sialic acids, but not to express sialidase. Finally, Aim 3 will use experimental models, as well as analyses of human specimens to examine the working hypothesis that sialidase-mediated attack on the barrier function of mucus reduces protection against intrauterine infection. The successful completion of these aims will have an important positive impact on this field by establishing the role of sialidase-mediated mucus barrier degradation in BV and BV-associated complications. Studies with small molecule inhibitors of sialidase and sialic acid foraging should also establish proof-of-principle for whether interference in these processes has therapeutic potential in the prevention of bacterial colonization and/or disease-causing potential.
Bacterial vaginosis is an imbalance of the vaginal flora that occurs in 1/3 of U.S. women and is associated with preterm birth (now costs an estimated 52 billion/year) and other reproductive complications. Little is known about the causes or underlying processes of BV and recurrences of the condition occur in a majority of women within months of antibiotic treatment. Successful completion of this project will 1) result in a better understandin of the molecular and biochemical etiology of BV and 2) provide proof of concept that sialidase enzyme activity may be a promising drug target for preventing BV-associated adverse outcomes.
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|Robinson, Lloyd S; Lewis, Warren G; Lewis, Amanda L (2017) The sialate O-acetylesterase EstA from gut Bacteroidetes species enables sialidase-mediated cross-species foraging of 9-O-acetylated sialoglycans. J Biol Chem 292:11861-11872|
|Gilbert, Nicole M; O'Brien, Valerie P; Lewis, Amanda L (2017) Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog 13:e1006238|
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