Abstract
Background: Berberine (BBR) is an isoquinoline alkaloid which exhibits a variety of biological and therapeutic properties, and has been reported by some to block replication of the influenza virus. However, contradictory results have also been presented, and the mechanistic explanation is lacking. Methods: A panel of cell lines (Madin–Darby canine kidney (MDCK), adenocarcinoma human alveolar basal epithelial cells (A549), lung epithelial type I (LET1)) and primary human airway epithelial cells (HAE) susceptible to influenza virus infection were infected with a seasonal influenza A virus in the presence or absence of BBR. Cytotoxicity towards cell lines was measured using XTT assay. The yield of the virus was analyzed using RT-qPCR. To study the molecular mechanism of BBR, confocal microscopy and Western blot analyses of cellular fractions were applied. Results and conclusions: Our results show cell-type-dependent anti-influenza properties of BBR in vitro which suggests that the compound acts on the cell and not the virus. Importantly, BBR hampers influenza replication in primary human airway epithelium 3D cultures that mimic the natural replication site of the virus. Studies show that the influenza A virus upregulates the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway and hijacks this pathway for nucleolar export of the viral ribonucleoprotein. Our results suggest that BBR interferes with this process and hampers influenza A replication.
Highlights
The influenza viruses are among the most important human pathogens, with types A and B being the most clinically relevant for humans [1,2], and type A being the sole cause of pandemics
The most common in vitro model was used, i.e., the cell line derived from Madin–Darby canine kidney cells (MDCK)
We performed a standard virus replication assay by infecting the MDCK cells in the presence or absence of BBR
Summary
The influenza viruses are among the most important human pathogens, with types A and B being the most clinically relevant for humans [1,2], and type A being the sole cause of pandemics. Co-infection of a single cell results in shuffling of these genomic RNA puzzles, and new, hybrid progeny emerges. Reassortants are usually less fit and are eliminated, but in sporadic cases, a new strain appears that is able to effectively infect human cells but is not recognized by our defense systems. Methods: A panel of cell lines (Madin–Darby canine kidney (MDCK), adenocarcinoma human alveolar basal epithelial cells (A549), lung epithelial type I (LET1)) and primary human airway epithelial cells (HAE) susceptible to influenza virus infection were infected with a seasonal influenza A virus in the presence or absence of BBR. BBR hampers influenza replication in primary human airway epithelium 3D cultures that mimic the natural replication site of the virus. Our results suggest that BBR interferes with this process and hampers influenza A replication
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