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Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract

Award Number: R01AI153332
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $533,737 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	4/11/2025	NON-COMPETING CONTINUATION	$533,737
														Subtotal = $533,737

Issue Date FY: 2024 ( Subtotal = $618,561 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	002	4	5/24/2024	NON-COMPETING CONTINUATION	$53,374
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	4	2/15/2024	NON-COMPETING CONTINUATION	$480,363
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	4	2/16/2024	SUPPLEMENT FOR EXPANSION	$84,824
														Subtotal = $618,561

Issue Date FY: 2023 ( Subtotal = $678,220 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	3	1/27/2023	NON-COMPETING CONTINUATION	$533,737
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	12/23/2022	SUPPLEMENT FOR EXPANSION	$29,830
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	002	3	2/23/2023	SUPPLEMENT FOR EXPANSION	$114,653
														Subtotal = $678,220

Issue Date FY: 2022 ( Subtotal = $533,737 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	2/8/2022	NON-COMPETING CONTINUATION	$533,737
														Subtotal = $533,737

Issue Date FY: 2021 ( Subtotal = $533,737 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	3/3/2021	NEW	$533,737
														Subtotal = $533,737

Grand Total All Awards = $2,897,992

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Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract

Award Number: R01AI153332

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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