Cetylpyridinium chloride (CPC) reduces zebrafish mortality from influenza infection: Super-resolution microscopy reveals CPC interference with multiple protein interactions with phosphatidylinositol 4,5-bisphosphate in immune function.
In: Toxicology and applied pharmacology, Jg. 440 (2022-04-01), S. 115913
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Zugriff:
The COVID-19 pandemic raises significance for a potential influenza therapeutic compound, cetylpyridinium chloride (CPC), which has been extensively used in personal care products as a positively-charged quaternary ammonium antibacterial agent. CPC is currently in clinical trials to assess its effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity. Two published studies have provided mouse and human data indicating that CPC may alleviate influenza infection, and here we show that CPC (0.1 μM, 1 h) reduces zebrafish mortality and viral load following influenza infection. However, CPC mechanisms of action upon viral-host cell interaction are currently unknown. We have utilized super-resolution fluorescence photoactivation localization microscopy to probe the mode of CPC action. Reduction in density of influenza viral protein hemagglutinin (HA) clusters is known to reduce influenza infectivity: here, we show that CPC (at non-cytotoxic doses, 5-10 μM) reduces HA density and number of HA molecules per cluster within the plasma membrane of NIH-3T3 mouse fibroblasts. HA is known to colocalize with the negatively-charged mammalian lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ); here, we show that nanoscale co-localization of HA with the PIP 2 -binding Pleckstrin homology (PH) reporter in the plasma membrane is diminished by CPC. CPC also dramatically displaces the PIP 2 -binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) from the plasma membrane of rat RBL-2H3 mast cells; this disruption of PIP 2 is correlated with inhibition of mast cell degranulation. Together, these findings offer a PIP 2 -focused mechanism underlying CPC disruption of influenza and suggest potential pharmacological use of this drug as an influenza therapeutic to reduce global deaths from viral disease.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
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Cetylpyridinium chloride (CPC) reduces zebrafish mortality from influenza infection: Super-resolution microscopy reveals CPC interference with multiple protein interactions with phosphatidylinositol 4,5-bisphosphate in immune function.
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Autor/in / Beteiligte Person: | Raut, P ; Weller, SR ; Obeng, B ; Soos, BL ; West, BE ; Potts, CM ; Sangroula, S ; Kinney, MS ; Burnell, JE ; King, BL ; Gosse, JA ; Hess, ST |
Zeitschrift: | Toxicology and applied pharmacology, Jg. 440 (2022-04-01), S. 115913 |
Veröffentlichung: | New York, NY : Academic Press ; <i>Original Publication</i>: New York., 2022 |
Medientyp: | academicJournal |
ISSN: | 1096-0333 (electronic) |
DOI: | 10.1016/j.taap.2022.115913 |
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