tetano
Editor, Senior Moderator
Toxicol Appl Pharmacol
. 2022 Feb 8;115913.
doi: 10.1016/j.taap.2022.115913. Online ahead of print.
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
Prakash Raut[SUP] 1 [/SUP], Sasha R Weller[SUP] 2 [/SUP], Bright Obeng[SUP] 2 [/SUP], Brandy L Soos[SUP] 2 [/SUP], Bailey E West[SUP] 2 [/SUP], Christian M Potts[SUP] 2 [/SUP], Suraj Sangroula[SUP] 2 [/SUP], Marissa S Kinney[SUP] 2 [/SUP], John E Burnell[SUP] 2 [/SUP], Benjamin L King[SUP] 2 [/SUP], Julie A Gosse[SUP] 3 [/SUP], Samuel T Hess[SUP] 4 [/SUP]
Affiliations
Abstract
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-3 T3 mouse fibroblasts. HA is known to colocalize with the negatively-charged mammalian lipid phosphatidylinositol 4,5-bisphosphate (PIP[SUB]2[/SUB]); here, we show that nanoscale co-localization of HA with the PIP[SUB]2[/SUB]-binding Pleckstrin homology (PH) reporter in the plasma membrane is diminished by CPC. CPC also dramatically displaces the PIP[SUB]2[/SUB]-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) from the plasma membrane of rat RBL-2H3 mast cells; this disruption of PIP[SUB]2[/SUB] is correlated with inhibition of mast cell degranulation. Together, these findings offer a PIP[SUB]2[/SUB]-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.
Keywords: Cetylpyridinium chloride; Influenza; Phosphatidylinositol 4,5-bisphosphate; Quaternary ammonium compound; Super-resolution microscopy; Zebrafish.
. 2022 Feb 8;115913.
doi: 10.1016/j.taap.2022.115913. Online ahead of print.
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
Prakash Raut[SUP] 1 [/SUP], Sasha R Weller[SUP] 2 [/SUP], Bright Obeng[SUP] 2 [/SUP], Brandy L Soos[SUP] 2 [/SUP], Bailey E West[SUP] 2 [/SUP], Christian M Potts[SUP] 2 [/SUP], Suraj Sangroula[SUP] 2 [/SUP], Marissa S Kinney[SUP] 2 [/SUP], John E Burnell[SUP] 2 [/SUP], Benjamin L King[SUP] 2 [/SUP], Julie A Gosse[SUP] 3 [/SUP], Samuel T Hess[SUP] 4 [/SUP]
Affiliations
- PMID: 35149080
- PMCID: PMC8824711
- DOI: 10.1016/j.taap.2022.115913
Abstract
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-3 T3 mouse fibroblasts. HA is known to colocalize with the negatively-charged mammalian lipid phosphatidylinositol 4,5-bisphosphate (PIP[SUB]2[/SUB]); here, we show that nanoscale co-localization of HA with the PIP[SUB]2[/SUB]-binding Pleckstrin homology (PH) reporter in the plasma membrane is diminished by CPC. CPC also dramatically displaces the PIP[SUB]2[/SUB]-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) from the plasma membrane of rat RBL-2H3 mast cells; this disruption of PIP[SUB]2[/SUB] is correlated with inhibition of mast cell degranulation. Together, these findings offer a PIP[SUB]2[/SUB]-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.
Keywords: Cetylpyridinium chloride; Influenza; Phosphatidylinositol 4,5-bisphosphate; Quaternary ammonium compound; Super-resolution microscopy; Zebrafish.