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

被引：17

作者：

Raut, Prakash ^{[1
]}

Weller, Sasha R. R. ^{[2
]}

Obeng, Bright ^{[2
]}

Soos, Brandy L. L. ^{[1
,2
]}

West, Bailey E. E. ^{[1
,2
]}

Potts, Christian M. M. ^{[1
,2
]}

Sangroula, Suraj ^{[2
]}

Kinney, Marissa S. S. ^{[1
,2
]}

Burnell, John E. E. ^{[1
,2
]}

King, Benjamin L. L. ^{[2
]}

Gosse, Julie A. A. ^{[1
,2
]}

Hess, Samuel T. T. ^{[1
]}

机构：

[1] Univ Maine, Dept Phys & Astron, Orono, ME USA

[2] Univ Maine, Dept Mol & Biomed Sci, Orono, ME USA

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2022年 / 440卷

基金：

美国国家卫生研究院;

关键词：

Influenza; Cetylpyridinium chloride; Quaternary ammonium compound; Phosphatidylinositol; 4; 5-bisphosphate; Zebrafish; Super-resolution microscopy; CRITICAL MICELLE CONCENTRATION; MAST-CELLS; MEMBRANE ASSOCIATION; EFFECTOR DOMAIN; PIP2; PHOSPHOINOSITIDES; ACTIN; ORGANIZATION; SURFACTANTS; INHIBITION;

D O I：

10.1016/j.taap.2022.115913

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 mu M, 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 mu M) 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 (PIP2); here, we show that nanoscale co-localization of HA with the PIP2-binding Pleckstrin homology (PH) reporter in the plasma membrane is diminished by CPC. CPC also dramatically displaces the PIP2- binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) from the plasma membrane of rat RBL-2H3 mast cells; this disruption of PIP2 is correlated with inhibition of mast cell degranulation. Together, these findings offer a PIP2-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.

引用

页数：16

共 115 条

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