Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters

Author:

Barr Jeremy J.,Auro Rita,Sam-Soon Nicholas,Kassegne Sam,Peters Gregory,Bonilla Natasha,Hatay Mark,Mourtada Sarah,Bailey Barbara,Youle Merry,Felts Ben,Baljon Arlette,Nulton Jim,Salamon Peter,Rohwer Forest

Abstract

Bacteriophages (phages) defend mucosal surfaces against bacterial infections. However, their complex interactions with their bacterial hosts and with the mucus-covered epithelium remain mostly unexplored. Our previous work demonstrated that T4 phage with Hoc proteins exposed on their capsid adhered to mucin glycoproteins and protected mucus-producing tissue culture cells in vitro. On this basis, we proposed our bacteriophage adherence to mucus (BAM) model of immunity. Here, to test this model, we developed a microfluidic device (chip) that emulates a mucosal surface experiencing constant fluid flow and mucin secretion dynamics. Using mucus-producing human cells andEscherichia coliin the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4∆hocphage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4∆hocphage. This suggests that phage adherence to mucus increases encounters with bacterial hosts by some other mechanism. Phages are traditionally thought to be completely dependent on normal diffusion, driven by random Brownian motion, for host contact. We demonstrated that T4 phage particles displayed subdiffusive motion in mucus, whereas T4∆hocparticles displayed normal diffusion. Experiments and modeling indicate that subdiffusive motion increases phage–host encounters when bacterial concentration is low. By concentrating phages in an optimal mucus zone, subdiffusion increases their host encounters and antimicrobial action. Our revised BAM model proposes that the fundamental mechanism of mucosal immunity is subdiffusion resulting from adherence to mucus. These findings suggest intriguing possibilities for engineering phages to manipulate and personalize the mucosal microbiome.

Funder

HHS | National Institutes of Health

HHS | NIH | National Institute of General Medical Sciences

Gordon and Betty Moore Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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