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Screening for small-molecule inhibitors of respiratory syncytial viral infection in infant bronchial epithelial barrier

Award Number: R21AI196505
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Screening for small-molecule inhibitors of respiratory syncytial viral infection in infant bronchial epithelial barrier - PROJECT SUMMARY Respiratory syncytial virus (RSV) primarily infects ciliated cells in the human bronchial epithelium. RSV infection can cause severe disease in infants and children younger than 2 years of age. So far, RSV vaccine development has been unsuccessful and treatment of severe RSV disease in young children remains supportive care. In contrast, RSV-infected adults have only mild symptoms. In a recent study, we found that the human bronchial epithelial barrier plays a critical role in determining severity of RSV infection with age. Preliminary single-nuclear RNA sequencing of RSV-infected, neonatal and adult ciliated cells has identified multiple signaling pathways in response to RSV that differ between the two age groups. These preliminary findings lead to the central hypothesis that small-molecule inhibitors of the signaling pathways regulated by age in infant ciliated cells in response to RSV infection can be identified by high-throughput screening as potential therapeutics. To this end, we have established a high-throughput screening platform using RSVGFP pre-infected neonatal bronchial epithelial cells generated from basal stem cells (BSCs) in a 96-transwell format. The proposal leverages this platform to screen a L2100 stem cell signaling pathway compound library that features 1243 compounds with bioactivities overlapping age-related signaling responses to RSV in neonatal ciliated cells. Our screening is facilitated by a robust method of BSC derivation from tracheal aspirate, which circumvents technical difficulties in accessing infant lung tissues required for conventional BSC isolation. To complement human bronchial epithelial cells as an in vitro model, precision-cut lung slices (PCLSs) prepared from infant donor lungs will be employed as an ex vivo model. We have designed a stage-screening strategy including primary, counter, and secondary screenings followed by mechanistic investigation of top-ranked compounds. This project is led by Dr. Ai (PI, lung development and airway hyperactive disease in children (asthma and RSV infection)) in consultation with Dr. Krishnan (airway physiology and high-throughput drug screening). Dr. Ai and Dr. Krishnan are long-term collaborators and together have established several methods and established the imaging platform employed for the proposed library screening. The project is expected to identify candidate compounds for future therapeutic testing using pre-clinical animal models of infant RSV disease. The findings of epithelium-derived mechanisms of RSV infection may be translatable to other respiratory viruses that elicit similar age-related infection and thus inform the fundamental biology of age in susceptibility and severity of human respiratory diseases.


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 = $233,250 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	9/10/2026	NEW	$233,250
														Subtotal = $233,250

Grand Total All Awards = $233,250

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Screening for small-molecule inhibitors of respiratory syncytial viral infection in infant bronchial epithelial barrier

Award Number: R21AI196505

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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