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Host-Pathogen Interactions in a Cystic Fibrosis Polymicrobial Infection Model

Award Number: F31HL172440
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Host-Pathogen Interactions in a Cystic Fibrosis Polymicrobial Infection Model - ABSTRACT Cystic fibrosis (CF) is characterized by the formation of thick mucus in the lung leading to chronic infection of various pathogens that are prone to developing antibiotic tolerance. Despite effective modulator therapy (HEMT) that improves lung function and many clinical outcomes, HEMT does not eliminate chronic, antibiotic-tolerant lung infections, the major cause of morbidity and mortality in CF. Although most people with CF (pwCF) have multispecies lung infections, almost all published studies focus on single-species infection models. Thus, polymicrobial-host interactions in CF are not completely understood, especially under physiologically relevant conditions such as anoxia typical of mucus plugs. The overarching goal of our work is to use in vitro models to gain insight into how polymicrobial infections develop in pwCF. Bacterial pathogens have been shown to secrete membrane vesicles (bEVs) that diffuse through the CF mucus to deliver virulence factors such as DNA, RNA, and proteins to their targets. As recent studies have shown that the first exposure to bacterial products alters DNA methylation and gene silencing that affect subsequent exposures, our hypothesis is that pwCF develop chronic infections in part due to epigenetic changes caused by preexposure to CF pathogens that reduce the HBEC immune response to infection over time. This application aims to characterize the effects of an in vitro model of CF polymicrobial infection on human bronchial epithelial cells (HBEC) with preexposure to bEVs secreted by the common CF pathogen Staphylococcus aureus. The polymicrobial culture contains four prevalent and abundant CF pathogens: Pseudomonas aeruginosa, S. aureus, Streptococcus sanguinis, and Prevotella melanogenica. Using transcriptomic and proteomic analysis, cytokine analysis, ATAC-Seq, and DNA methylation analysis, this study aims to elucidate the host HBEC response to treatment with bEVs. This study will contribute to our understanding of host-pathogen interactions in the CF lung and potentially identify novel therapeutic targets during infection. This project will provide the applicant with a broad range of both bioinformatic and lab techniques that will provide a strong foundation for her long-term goal of becoming an academic researcher.


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: 2026 ( Subtotal = $49,538 )
2026	2026	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	000	3	3/3/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	000	2	11/28/2024	NON-COMPETING CONTINUATION	$48,974
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	001	2	9/6/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	002	1	9/6/2024	NEW	$1,280
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	001	1	12/26/2023	NEW	$0
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Lung Diseases Research	000	1	12/26/2023	NEW	$47,694
														Subtotal = $48,974

Grand Total All Awards = $148,050

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Host-Pathogen Interactions in a Cystic Fibrosis Polymicrobial Infection Model

Award Number: F31HL172440

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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