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Microbial Interactions between Gardnerella, Prevotella, and Atopobium Prior to Incident Bacterial Vaginosis

Award Number: R01AI146065
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT: Bacterial vaginosis (BV), the most common cause of vaginal discharge, is associated with multiple adverse outcomes. The rate of recurrence after therapy is >60% yet BV etiology remains unknown. BV is characterized by loss of vaginal lactobacilli and increases in facultative (Gardnerella vaginalis) and strict anaerobes. G. vaginalis, present in 95-100% of BV cases, is more virulent than other BV-associated bacteria in vitro. However, it is also found in women with normal flora and colonization is not sufficient for BV development. A notable feature of BV is the appearance of a multi-species bio¿lm on vaginal epithelial cells containing abundant G. vaginalis, fewer Atopobium vaginae, and other undefined bacterial species. We hypothesize that G. vaginalis initiates BV biofilm formation, but incident BV (iBV) requires incorporation of other key bacteria into the biofilm that alter the transcriptome of the polymicrobial consortium. This is consistent with our finding that, among women who have sex with women, the mean relative abundance of Prevotella bivia, G. vaginalis, and A. vaginae became sequentially higher prior to iBV. We propose that a similar distribution of these bacterial species will increase prior to iBV in women who have sex with men (WSM). Our specific aims are: Aim 1. Investigate changes in the vaginal microbiota preceding iBV in a longitudinal study of WSM. We will obtain twice daily vaginal specimens from 150 women with normal vaginal flora (Nugent score 0-3) and follow them for iBV (Nugent score 7-10 on =4 consecutive vaginal specimens) for 60 days. 16S rRNA gene sequencing targeting V4 [and broad range 16S rRNA gene qPCR] will be done in women for the 14 days prior to iBV as well as age-comparable women maintaining normal vaginal microbiota. Aim 2: Determine the contribution of P. bivia to the multi-species BV biofilm in vivo. We will use peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) probes previously optimized for G. vaginalis and A. vaginae to analyze BV biofilm formation over time in clue cells from vaginal specimens from women with iBV in Aim 1, focusing on the 14 days prior to iBV. We will design, validate, and optimize a new P. bivia PNA-FISH probe for multiplex use (Aim 2A). Light microscopy PNA-FISH will be performed on specimens from women with iBV and negative controls (Aim 2B). Confocal laser scanning microscopy FISH will be used to determine the interspatial localization of the 3 bacteria of interest in the BV biofilm on clue cells from women with iBV (Aim 2C). Aim 3. Identify molecular markers associated with iBV by using RNA sequencing to analyze the transcriptome of G. vaginalis, P. bivia, and A. vaginae. We will probe specific bacterial interactions during the 14 days prior to iBV, first by RNA sequencing using in vitro models in a chemically defined medium simulating vaginal secretions (mGTS) (Aim 3A). Venn-diagram analysis will select the most commonly up-regulated genes shared in the in vitro assays. The in vivo relevance of potential molecular markers for development of iBV will be assessed by qPCR, using vaginal samples from women with iBV and negative controls in Aim 1 (Aim 3B).


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: 2024 ( Subtotal = $541,402 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	1/24/2024	NON-COMPETING CONTINUATION	$541,402
														Subtotal = $541,402

Issue Date FY: 2023 ( Subtotal = $617,292 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	1/24/2023	NON-COMPETING CONTINUATION	$617,292
														Subtotal = $617,292

Issue Date FY: 2022 ( Subtotal = $627,727 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	2/1/2022	NON-COMPETING CONTINUATION	$627,727
														Subtotal = $627,727

Issue Date FY: 2021 ( Subtotal = $641,615 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	1/11/2021	NON-COMPETING CONTINUATION	$641,615
														Subtotal = $641,615

Issue Date FY: 2020 ( Subtotal = $676,657 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	1/31/2020	NEW	$676,657
														Subtotal = $676,657

Grand Total All Awards = $3,104,693

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Microbial Interactions between Gardnerella, Prevotella, and Atopobium Prior to Incident Bacterial Vaginosis

Award Number: R01AI146065

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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