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Mechanisms of cetylpyridinium chloride inhibition of immune cell function

Award Number: R15ES034567
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/11/2022
PERIOD OF PERFORMANCE END DATE: 08/19/2025
AWARD TERMINATION DATE: 08/20/2025

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Mechanisms of cetylpyridinium chloride inhibition of immune cell function - People are widely exposed to high (mM) doses of the positively-charged antibacterial agent cetylpyridinium chloride (CPC) via janitorial and personal care products and foods treated with CPC, yet little is known about its toxicology in humans, especially below the critical micelle concentration (~900 µM). While applied CPC is retained in the oral mucosa and is released into saliva such that low-µM CPC continuously bathes oral cells, there is a dearth of publications on the effects of CPC on eukaryotes. The Gosse lab has discovered that exposure to non- cytotoxic, low-µM CPC concentrations potently inhibits signaling of mast cells, key players in the immune and nervous systems that share core signaling elements with T cells and other cell types. In mast cells, upon antigen crosslinking of cell surface receptors, a tyrosine phosphorylation cascade ensues, leading to activation of PLCγ1 enzymatic cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) and subsequent Ca2+ mobilization and degranulation: microtubule transport of granules to the cell surface, leading to exocytosis of bioactive substances such as histamine and serotonin. Analogous aggregation of T cell receptors leads also to tyrosine phosphorylation, Ca2+ mobilization, and downstream T cell function. CPC effects on both mast and T cell function will be determined. Preliminary data have led to the hypothesis that CPC inhibits immune cell function by electrostatically interfering with phosphorylation and PIP2, leading to displacement of PIP2-binding proteins, disrupted nanoscale clustering of PIP2, muted release of Ca2+ from endoplasmic reticulum (ER) stores, and, thereby, inhibited inflow of Ca2+ to the cytosol and extinguished microtubule polymerization. CPC effects on phosphorylation will be assessed by multiple means. Confocal microscopy and plate reader experiments will define CPC effects on sub-cellular localization and function of PLCγ1; of PLCγ1 product inositol 1,4,5-trisphosphate which initiates release of ER Ca2+; of Ca2+ dynamics in ER, mitochondria, Golgi, and cytosol; and of key elements downstream of Ca2+ including protein kinase C, phospholipase D, and microtubules. Whether CPC directly displaces PIP2 from its partner proteins will be measured. Super-resolution fluorescence photoactivation localization microscopy will interrogate nanoscale CPC effects on PIP2 clusters and other protein interactions crucial to immune function, including co-localization of Git1 regulator with tubulin as well as PIP2 with machinery required for granule exocytosis. This research will uncover the mechanisms underlying CPC disruption of immune cell function in order to fulfill an urgent need by providing insights into CPC effects on environmental human health.


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 = -$27,460 )
2026	2022	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Environmental Health	000	1	1/28/2026	TERMINATION	-$27,460
														Subtotal = -$27,460

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Environmental Health	000	1	6/5/2025	NEW	$0
2025	2022	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Environmental Health	001	1	8/20/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $426,405 )
2022	2022	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL RM 422	ORONO	ME	04469	PENOBSCOT	USA	Environmental Health	000	1	8/11/2022	NEW	$426,405
														Subtotal = $426,405

Grand Total All Awards = $398,945

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Mechanisms of cetylpyridinium chloride inhibition of immune cell function

Award Number: R15ES034567

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/11/2022

PERIOD OF PERFORMANCE END DATE: 08/19/2025

AWARD TERMINATION DATE: 08/20/2025

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