Author ORCID Identifier
Date of Award
2025
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Dr. Bruce A. Stanton
Abstract
Cystic Fibrosis (CF) is a multisystemic genetic disorder caused by mutations in the CFTR gene, resulting in chronic pulmonary infections, hyperinflammation, and progressive lung damage. Among the pathogens that colonize CF lungs, Pseudomonas aeruginosa (P. aeruginosa) is predominant, infecting over 50% of adults with CF and developing antibiotic resistance over time. Current modulator therapies fail to address persistent bacterial infections, chronic inflammation, or irreversible lung damage, underscoring the need for novel therapeutic strategies. In our previous in vitro studies, we demonstrated that extracellular vesicles (EVs) secreted by primary Human Bronchial Epithelial Cells (HBECs) inhibit P. aeruginosa growth by reducing the abundance of biofilm-associated proteins and disrupting antibiotic resistance pathways through the delivery of microRNA let-7b-5p. We expanded on these findings in our current work to show that these HBEC-derived EVs also reduce P. aeruginosa lung burden, attenuate inflammation, and lower neutrophil infiltration in a CF mouse model. To further address potential immunogenicity associated with HBEC-derived EVs, we engineered EVs from Mesenchymal Stromal Cells (MSCs), to contain the microRNA let-7b-5p. In vivo, these engineered EVs significantly reduced bacterial burden and inflammation in CF mice. Using in vitro systems, we further discovered that one of the mechanisms by which let-7b-5p loaded MSC EVs act in vivo involves reducing the inflammatory response of primary CF bronchial epithelial cells to Pseudomonas aeruginosa and inhibiting its ability to form biofilms on these cells. Our work highlights a novel dual anti-infective and anti-inflammatory therapeutic strategy for CF. This platform holds significant promise for optimizing delivery strategies and expanding its clinical applicability to target additional respiratory pathogens.
Original Citation
1. Sarkar S, Barnaby R, Nymon AB, Taatjes DJ, Kelley TJ, Stanton BA. Extracellular vesicles secreted by primary human bronchial epithelial cells reduce Pseudomonas aeruginosa burden and inflammation in cystic fibrosis mouse lung. Am J Physiol Lung Cell Mol Physiol. 2024 Feb 1;326(2):L164-L174. doi: 10.1152/ajplung.00253.2023. Epub 2023 Dec 12. PMID: 38084406; PMCID: PMC11279747.
2. Sarkar, S. et al. Extracellular Vesicles Derived from Mesenchymal Stromal Cells Reduce Pseudomonas aeruginosa Lung Infection and Inflammation in Mice. 2025.03.30.646208 Preprint at https://doi.org/10.1101/2025.03.30.646208 (2025).
Recommended Citation
Sarkar, Sharanya, "ENGINEERING EXTRACELLULAR VESICLES (EVs) TO COMBAT INFECTION AND INFLAMMATION IN CYSTIC FIBROSIS" (2025). Dartmouth College Ph.D Dissertations. 416.
https://digitalcommons.dartmouth.edu/dissertations/416
