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Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

By Marion C. Bichet, Wai Hoe Chin, William Richards, Yu-Wei Lin, Laura Avellaneda-Franco, Catherine A Hernandez, Arianna Oddo, Oleksandr Chernyavskiy, Volker Hilsenstein, Adrian Neild, Jian Li, Nicolas Hans Voelcker, Ruzeen Patwa, Jeremy Barr

Posted 08 Sep 2020
bioRxiv DOI: 10.1101/2020.09.07.286716

For over 100 years, bacteriophages have been known as viruses that infect bacteria. Yet it is becoming increasingly apparent that bacteriophages, or phages for short, have tropisms outside their bacterial hosts. During phage therapy, high doses of phages are directly administered and disseminated throughout the body, facilitating broad interactions with eukaryotic cells. Using live cell imaging across a range of cell lines we demonstrate that cell type plays a major role in phage internalisation and that smaller phages (< 100 nm) are internalised at higher rates. Uptake rates were validated under physiological shear stress conditions using a microfluidic device that mimics the shear stress to which endothelial cells are exposed to in the human body. Phages were found to rapidly adhere to eukaryotic cell layers, with adherent phages being subsequently internalised by macropinocytosis and functional phages accumulating and stably persisting intracellularly. Finally, we incorporate these results into an established pharmacokinetic model demonstrating the potential impact of phage accumulation by these cell layers, which represents a major sink for circulating phages in the body. Understanding these interactions will have important implications on innate immune responses, phage pharmacokinetics, and the efficacy of phage therapy. ### Competing Interest Statement The authors have declared no competing interest.

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