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

doi:10.1016/j.isci.2021.102287

Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy

iScience. 2021 Mar 9;24(4):102287. doi: 10.1016/j.isci.2021.102287. eCollection 2021 Apr 23.

Authors

Marion C Bichet¹, Wai Hoe Chin¹, William Richards¹, Yu-Wei Lin², Laura Avellaneda-Franco¹, Catherine A Hernandez³, Arianna Oddo^{4

5}, Oleksandr Chernyavskiy⁶, Volker Hilsenstein⁶, Adrian Neild⁷, Jian Li², Nicolas Hans Voelcker^{4

5

8}, Ruzeen Patwa¹, Jeremy J Barr¹

Affiliations

¹ School of Biological Sciences, Monash University, Clayton Campus, 25 Rainforest Walk, Clayton, VIC, 3800, Australia.
² Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia.
³ Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC, 3800, Australia.
⁵ Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia.
⁶ Monash Micro Imaging, Monash University, Clayton Campus, Clayton, VIC, 3800, Australia.
⁷ Department of Mechanical and Aerospace Engineering, Monash University, Clayton Campus, Clayton, VIC 3800, Australia.
⁸ Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC 3168, Australia.

Abstract

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.

Keywords: Immunology; Microbiology; Virology.