PROJECT
Adverse
morbidity
when
tissue
associated
maternal
(FGT)
likely
SUMMARY
pregnancy outcomes, including premature birth and stillbirth, are the leading causes of neonatal
and mortality. A frequent cause of preterm birth and stillbirth is intrauterine infection, which occurs
bacteria ascend from the vagina into the uterus and invade the amniotic cavity, leading to inflammation,
damage, and adverse pregnancy outcomes. Group B Streptococcus (GBS) is one such bacterium
with ascending infection and adverse pregnancy outcomes. The principal risk factor for this is
vaginal colonization; however the mechanisms by which GBS persist i n the
and ascend to the uterus remain unknown. GBS colonization status is intermittent and can be transient,
reflecting a combination of GBS determinants, antagonism by commensal flora, and host immune
, female genital tract
responses. The current proposal seeks to address these dynamic aspects of GBS vaginal carriage, specifically
1) bacterial adherence to host cells/tissue of the FGT, 2) competition with vaginal microbiota, and 3) evasion of
host defense. Recent studies have demonstrated that GBS stimulates vaginal epithelial exfoliation by
activating epithelial-to-mesenchymal transition (EMT), leading to loss of barrier function and GBS
dissemination to the upper FGT and fetus. We have recently discovered a GBS surface adhesin, BspC, that
directly interacts with host intermediate filaments, including keratin 19 and vimentin, a canonical marker of
EMT. We hypothesize that when EMT is induced the BspC-vimentin interaction plays an important role in GBS
vaginal persistence and ascending infection. We have further discovered that GBS has a type VII secretion
system (T7SS) that contributes to colonization. We hypothesize that T7SS is important for competition with
vaginal microbiota for niche establishment and secreting anti-eukaryotic toxins that may invoke a host immune
response. We have also demonstrated that IL-17A is produced during GBS colonization and that IL-17+ cells,
such as MAITs and T cells, actually contributed to GBS ascending spread. We hypothesize that
IL-17
induced
BspC-vimentin These hypotheses will be addressed in the following
specific aims: AIM 1: Elucidate the contribution of BspC and intermediate filaments to GBS vaginal
persistence, AIM 2: Examine the function of newly discovered GBS T7SS in mediating vaginal niche
establishment and inter-bacterial competition, AIM 3: Determine the contribution of IL-17 and MAITs to the
pathogenesis of GBS colonization. These studies should increase our understanding of the bacterial and host
factors involved in the colonization and persistence within the FGT that impact GBS ascending infection and
neonatal disease.
IL-17 and
producing T cells in the FGT induce EMT and barrier breakdown. This comes full circle; Once EMT is
as a defensive response to initiate cellular exfoliation, GBS hijacks this process, possibly through a
interaction, to persistent in the FGT.
