Bacteriophages Can Treat and Prevent<i>Pseudomonas aeruginosa</i>Lung Infections

Debarbieux, Laurent; Leduc, Dominique; Maura, Damien; Morello, Eric; Criscuolo, Alexis; Grossi, Olivier; Balloy, Viviane; Touqui, Lhousseine

doi:10.1086/651135

Cited by 274 publications

(293 citation statements)

References 34 publications

(37 reference statements)

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“…Alterations of these physical parameters are known to occur in diseased mucosal surfaces [e.g., the high mucin concentrations (>4% wt/vol) and acidified mucosa characteristic of cystic fibrosis] (40,44). Although numerous studies have documented the effective use of phages to treat cystic fibrosis-associated bacterial infections (45,46), how physical and physiological changes in the lung might affect phage diffusion, the frequency of productive phage-host encounters, and bacterial infection dynamics remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

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

Barr

Auro

Sam-Soon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

176

186

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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 and Escherichia coli in the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4Δhoc phage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4Δhoc phage. 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 T4Δhoc particles 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.BAM | virus | mucus | subdiffusion | search strategy I n all animals, mucosal surfaces provide critical immunological services by both protecting against invading bacterial pathogens and supporting large communities of commensal microorganisms (1, 2). Being exposed to the environment, mucosal surfaces are also the infection sites for many important bacterial diseases, including acute diarrhea and cystic fibrosis in humans. This, combined with their accessibility, make mucosal surfaces attractive venues for phage therapy; that is, the use of bacteriophages (phages) to treat and clear bacterial infections (3,4). Clinical success so far has been erratic (5). The complexities and dynamics of the mucus layer are rarely considered, and the activity of phages therein is mostly unknown. Not surprisingly, phages effective in vitro do not consistently reduce mucosal bacterial host levels in vivo (6, 7). An understanding of the interactions between phages and their bacterial hosts within the relevant physiological environment is critical for consistent success of phage therapy applications.The multilayered mucus is composed primarily of gel-forming mucin glycoproteins that are continually secreted by the underlying epithelium (8). The mucin...

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Section: Discussionmentioning

confidence: 99%

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

Barr

Auro

Sam-Soon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

176

186

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“…Besides rapid coevolution, further complications could arise from interspecific bacterial competition due to polymicrobial nature of bacterial infections: many human infections contain multiple different pathogenic bacterial and other microbial species (Peters, Jabra‐Rizk, O'May, Costerton, & Shirtliff, 2012). Considerable genotypic variation also exists between different strains of a pathogen, and this variation is known to differ between different patients and to affect the pathogen susceptibility to phages (Debarbieux et al., 2010; Essoh et al., 2013; Friman, Ghoul, Molin, Johansen, & Buckling, 2013). Understanding the relative importance and interactive effects of these potentially complicating factors is thus crucial for developing reliable and consistent phage therapy treatments.…”

Section: Introductionmentioning

confidence: 99%

Bacterial competition and quorum‐sensing signalling shape the eco‐evolutionary outcomes of model in vitro phage therapy

Mumford

Friman

2016

Evolutionary Applications

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The rapid rise of antibiotic resistance has renewed interest in phage therapy – the use of bacteria‐specific viruses (phages) to treat bacterial infections. Even though phages are often pathogen‐specific, little is known about the efficiency and eco‐evolutionary outcomes of phage therapy in polymicrobial infections. We studied this experimentally by exposing both quorum‐sensing (QS) signalling PAO1 and QS‐deficient lasR Pseudomonas aeruginosa genotypes (differing in their ability to signal intraspecifically) to lytic PT7 phage in the presence and absence of two bacterial competitors: Staphylococcus aureus and Stenotrophomonas maltophilia–two bacteria commonly associated with P. aeruginosa in polymicrobial cystic fibrosis lung infections. Both the P. aeruginosa genotype and the presence of competitors had profound effects on bacteria and phage densities and bacterial resistance evolution. In general, competition reduced the P. aeruginosa frequencies leading to a lower rate of resistance evolution. This effect was clearer with QS signalling PAO1 strain due to lower bacteria and phage densities and relatively larger pleiotropic growth cost imposed by both phages and competitors. Unexpectedly, phage selection decreased the total bacterial densities in the QS‐deficient lasR pathogen communities, while an increase was observed in the QS signalling PAO1 pathogen communities. Together these results suggest that bacterial competition can shape the eco‐evolutionary outcomes of phage therapy.

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“…Several animal studies have demonstrated the efficacy and safety of phage therapy in the treatment of different infections [29][30][31]. In humans, potential applications of phages include the phage-mediated prevention and phage treatment expanding from conventional phage therapy, treatment with phage enzymes (e.g.…”

Section: B) Phage Therapy (Including Derivatives)mentioning

confidence: 99%