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Principal Investigator: Amanda L. Lewis
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $570,002
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT:
One-third of women in the U.S. have bacterial vaginosis (BV), a condition associated with greater risks of
reproductive tract infections and preterm birth. BV is characterized by loss of lactobacilli and polymicrobial
overgrowth of diverse potential pathogens, including Gardnerella vaginalis. Vaginal sialidase activity is found in
nearly all women with BV and is independently associated with adverse outcomes. However, little is known
regarding how sialidase supports dysbiosis and disease. This proposal examines how the sialidase produced by
certain subtypes of G. vaginalis participates in the molecular pathogenesis of vaginal and intrauterine infection
and encourages overgrowth of diverse BV bacteria.
We have identified the genetic basis of G.v. sialidase activity and found that 80% of BV cases have G.v. encoding
the sialidase genes nanH2 or nanH3, and 80% of women with nanH2-positive or H3-positive vaginal microbiota
have BV. Our data suggests that G.v. sialidase fundamentally transforms the cellular glycan landscape in BV
and shows that glycan degradation encourages pathogen colonization. In three specific aims, this proposal will
use human vaginal samples, diverse G.v. isolates, a mouse model that replicates relevant features of BV, new
wild-type and paired nanH3 mutant G.v. strains, and novel ex vivo models employing native human vaginal
communities 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 relationship between G.v. clades and biochemical and
cellular phenotypes in human clinical samples and compare sialidase positive and negative G.v. clades and a
G.v. sialidase mutant in our mouse vaginal colonization model. In Aim 2, we will use our repository of live native
vaginal communities in vitro to test how the availability of free sialic acid and exposed glycans, both
consequences of sialidase activity, influence BV community composition and also examine the relationship
between nanH2/H3-positive G.v. and bacterial burden and diversity in clinical specimens. Finally, Aim 3 we will
evaluate samples from a longitudinal cohort of pregnant women to determine whether women who went on to
experience preterm birth have higher levels of vaginal nanH2/H3-positive G.v., larger numbers of exfoliated
epithelial cells, degraded mucus and epithelial glycans, and more diverse microbiomes with higher vaginal
bacterial burden compared to term controls. The successful completion of these aims will have an important
positive impact on this field by identifying G.v. subtypes that drive pathophysiology, defining mechanisms by
which G.v. sialidase supports the development of dysbiosis and disease, and identifying biomarkers that might
be used in clinical surveillance efforts to prevent preterm birth.
Terms: <Abscission><Acylneuraminyl hydrolase><Bacteria><Bacterial Vaginitis><Bacterial Vaginosis><Binding><Biochemical><Categories><Cellular Transformation><Clinical><Clinical Data><Collection><Communities><Consumption><Corynebacterium vaginale><DNA Sequence><Data><Development><Disease><Disorder><Dysfunction><Enzyme Gene><Enzymes><Epithelial Cells><Epithelium><Excision><Extirpation><Feeds><Functional disorder><Funding><G vaginalis><G. vaginalis><Gardnerella><Gardnerella vaginalis><General Taxonomy><Generalized Growth><Genes><Genetic><Glycans><Growth><H vaginalis><H. vaginalis><Haemophilus vaginalis><Human><In Vitro><Lactobacillus><Long-term cohort><Longitudinal cohort><Longterm cohort><Measures><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Mucous body substance><Mucus><Murine><Mus><Mutate><N-Acetylneuraminic Acids><N-Acylneuraminate Glycohydrolases><Neuraminidase><Nonspecific Vaginitis><Oligosaccharide Sialidase><Paper><Pathogenesis><Phenotype><Physiopathology><Play><Polysaccharides><Pregnancy Complications><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Publishing><Removal><Reproductive Tract Infections><Research Specimen><Ribosomal RNA><Risk><Role><Sampling><Sialic Acids><Sialidase><Specimen><Stretching><Surgical Removal><Swab><Taxonomy><Testing><Tissue Growth><Vagina><Woman><adverse consequence><adverse outcome><biomarker identification><biomarker validation><complications during pregnancy><depository><developmental><dysbacteriosis><dysbiosis><dysbiotic><exo alpha sialidase><expectant mother><expecting mother><experience><experiment><experimental research><experimental study><experiments><human model><identification of biomarkers><identification of new biomarkers><intra-uterine infection><intrauterine infection><marker identification><marker validation><metaplastic cell transformation><microbial><microbial imbalance><microbiome><model of human><mouse model><mucous><murine model><mutant><non-specific vaginitis><novel><ontogeny><pathogen><pathophysiology><pregnancy-related complications><pregnant mothers><premature childbirth><premature delivery><preterm delivery><prevent><preventing><rRNA><repository><reproductive><resection><social role><tool><vagina infection><vagina microbiota><vaginal flora><vaginal infection><vaginal microbial community><vaginal microbiota><vaginal microflora>