NIH grant: Contribution of Group B Streptococcal adhesin BspC to neonatal intestinal colonization and interactions with Candida albicans (1F31AI200351-01)

retained text

NIH grant 1F31AI200351-01: Contribution of Group B Streptococcal adhesin BspC to neonatal intestinal colonization and interactions with Candida albicans
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Arianne Julia Crossen. Award: $38597.
Start: 2026-08-01T00:00:00.
Project Summary
 Streptococcus agalactiae, or Group B Streptococcus (GBS) is the leading cause of neonatal meningitis
worldwide. Though GBS benignly colonizes the intestinal and female reproductive tract in 30% of healthy adults,
exposure to GBS can lead to invasive disease in neonates. Prophylactic intrapartum antibiotics have significantly
reduced the incidence of early-onset disease, but late-onset disease, occurring 7 to 90 days post birth, currently
has no preventative measures. In these cases, colonization of the neonatal gastrointestinal tract can lead to
serious invasive disease with ongoing neurological sequalae in 50% of survivors. The mechanisms by which
GBS colonizes the intestinal tract are not well defined, and we aim to better characterize this step in disease
progression. Surface-anchored antigen I/II family adhesins are a widespread virulence factor among
streptococcal species, serving to promote bacterial adhesion to host cells. In GBS, Group B streptococcal
surface protein C (BspC) is particularly associated with hypervirulent meningitis-associated sequence type 17
(ST-17) strains and has been shown to promote GBS adherence to vaginal epithelial cells. We hypothesize that
BspC contributes to GBS' ability to colonize the intestinal tract. Preliminary data reveals that an isogenic bspC
mutant in the ST-17 strain COH1 displays significantly impaired adherence to both Caco-2 and primary human
infant colonic epithelial cells compared to its wildtype counterpart. Recombinant BspC has been shown to interact
with intermediate filament protein cytokeratin 19 (K19), and treatment of Caco-2 cells with a K19-specific
antibody significantly reduced GBS adherence, indicating the importance of this interaction in BspC-mediated
adherence. In a neonatal murine meningitis model, mice infected with bspC GBS survived significantly better
than wildtype infected mice, along with displaying significantly reduced intestinal bacterial burden, supporting a
role for BspC in colonization in vivo. Interestingly, BspC has been shown to contribute to GBS interactions with
the fungus Candida albicans. C. albicans is an opportunistic fungal pathogen that colonizes the neonatal
intestinal tract and is also responsible for significant invasive disease in premature neonates. Our experiments
have shown that the presence of C. albicans enhances GBS adherence to intestinal epithelial cells. From these
preliminary data, I hypothesize that BspC contributes to GBS persistence in the neonatal GI tract through both
direct interaction with intestinal epithelial cells and indirectly through interaction with C. albicans, leading to the
opportunity for progression to invasive disease. I will address these hypotheses with the following aims: Aim 1:
Characterize the mechanisms by which BspC promotes GBS neonatal intestinal colonization; Aim 2:
Assess the effect of Candida albicans on GBS intestinal colonization. The studies outlined in this proposal
will increase our understanding of how bacterial virulence factors could serve as therapeutic targets to inhibit
GBS intestinal colonization, and consequentially limit neonatal invasive GBS disease.

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