Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy
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 J. Barr
Affiliations
Marion C. Bichet
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia
Wai Hoe Chin
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia
William Richards
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia
Yu-Wei Lin
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia
Laura Avellaneda-Franco
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia
Catherine A. Hernandez
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA
Arianna Oddo
Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC, 3800, Australia; Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia
Department of Mechanical and Aerospace Engineering, Monash University, Clayton Campus, Clayton, VIC 3800, Australia
Jian Li
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia
Nicolas Hans Voelcker
Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC, 3800, Australia; Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC 3168, Australia
Ruzeen Patwa
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia
Jeremy J. Barr
School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia; Corresponding author
Summary: It is increasingly apparent that bacteriophages, viruses that infect bacteria and more commonly referred to as simply phages, have tropisms outside their bacterial hosts. Using live tissue culture cell imaging, we demonstrate that cell type, phage size, and morphology play a major role in phage internalization. Uptake was validated under physiological conditions using a microfluidic device. Phages adhered to mammalian tissues, with adherent phages being subsequently internalized by macropinocytosis, with functional phages accumulating intracellularly. We incorporated these results into a pharmacokinetic model demonstrating the potential impact of phage accumulation by cell layers, which represents a potential sink for circulating phages in the body. During phage therapy, high doses of phages are directly administered to a patient in order to treat a bacterial infection, thereby facilitating broad interactions between phages and mammalian cells. Understanding these interactions will have important implications on innate immune responses, phage pharmacokinetics, and the efficacy of phage therapy.
