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Modelling the spatiotemporal complexity of interactions between pathogenic bacteria and a phage with a temperature-dependent life cycle switch.

ABSTRACT: We apply mathematical modelling to explore bacteria-phage interaction mediated by condition-dependent lysogeny, where the type of the phage infection cycle (lytic or lysogenic) is determined by the ambient temperature. In a natural environment, daily and seasonal variations of the temperature cause a frequent switch between the two infection scenarios, making the bacteria-phage interaction with condition-dependent lysogeny highly complex. As a case study, we explore the natural control of the pathogenic bacteria Burkholderia pseudomallei by its dominant phage. B. pseudomallei is the causative agent of melioidosis, which is among the most fatal diseases in Southeast Asia and across the world. We assess the spatial aspect of B. pseudomallei-phage interactions in soil, which has been so far overlooked in the literature, using the reaction-diffusion PDE-based framework with external forcing through daily and seasonal parameter variation. Through extensive computer simulations for realistic biological parameters, we obtain results suggesting that phages may regulate B. pseudomallei numbers across seasons in endemic areas, and that the abundance of highly pathogenic phage-free bacteria shows a clear annual cycle. The model predicts particularly dangerous soil layers characterised by high pathogen densities. Our findings can potentially help refine melioidosis prevention and monitoring practices.

SUBMITTER: Egilmez HI

PROVIDER: S-EPMC7902855 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Modelling the spatiotemporal complexity of interactions between pathogenic bacteria and a phage with a temperature-dependent life cycle switch.

Egilmez Halil I HI Morozov Andrew Yu AY Galyov Edouard E EE

Scientific reports 20210223 1

We apply mathematical modelling to explore bacteria-phage interaction mediated by condition-dependent lysogeny, where the type of the phage infection cycle (lytic or lysogenic) is determined by the ambient temperature. In a natural environment, daily and seasonal variations of the temperature cause a frequent switch between the two infection scenarios, making the bacteria-phage interaction with condition-dependent lysogeny highly complex. As a case study, we explore the natural control of the pa ...[more]

PMID: 33623124

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Project description:Phage therapy is one alternative to cure infections caused by antibiotic resistant bacteria. Due to the narrow host range of phages, hundreds to thousands of phages are required to cover the diversity of bacterial pathogens. In personalized phage therapy, fast selection of the phages for individual patients is essential for successful therapy. The aims of this study were to set up a rapid hydrogel-based liquid phage susceptibility assay (PST) for the selection of phages for therapeutic use and to establish a "ready-to-screen" plate concept, where phages are readily stored in hydrogel as small droplets in microtiter plate wells. We first tested four commercially available hydrogels (GrowDex, Askina, Purilon, and Intrasite) for their suitability as phage matrices in PSTs with four phages, two of which infecting Escherichia coli and two Staphylococcus aureus. Of these four hydrogels, GrowDex was the best matrix for PST, as it did not inhibit bacterial growth, released phages quickly when mixed with bacterial culture, and maintained phage viability well. We then optimized the assay for both optical density and microscopy readers using GrowDex as matrix with 23 bacterial strains representing 10 different species and 23 phages possessing different morphologies and genome sizes. When the bacterial growth was monitored by microscopy reader, the PST was executed in just 3 hours, and there was no need for overnight culturing bacterial cells prior to the assay, whereas using optical density reader, bacteria had to be pre-cultured overnight, and the assay time was five hours. Finally, we evaluated the effect of three different chemical stabilizers (trehalose, hyaluronic acid, and gelatin) in a six-month stability assay with six model phages. These phages assay behaved very differently in respect to the chemical stabilizers, and there was not a single stabilizer suitable for all phages. However, when gelatin (0.01%) or hyaluronic acid (0.2 mg/ml) was used as stabilizer, all tested phages were still considered as positives in PST after a six-month storage in 1 ml volume. In "ready-to-screen" plates, the differences in phage stabilities were even more profound, varying from two to six months for the most and least stable phages, respectively.

Project description:Phages shape the structure of natural bacterial communities and can be effective therapeutic agents. Bacterial resistance to phage infection, however, limits the usefulness of phage therapies and could destabilise community structures, especially if individual resistance mutations provide cross-resistance against multiple phages. We currently understand very little about the evolution of cross-resistance in bacteria-phage interactions. Here we show that the network structure of cross-resistance among spontaneous resistance mutants of Pseudomonas aeruginosa evolved against each of 27 phages is highly modular. The cross-resistance network contained both symmetric (reciprocal) and asymmetric (nonreciprocal) cross-resistance, forming two cross-resistance modules defined by high within- but low between-module cross-resistance. Mutations conferring cross-resistance within modules targeted either lipopolysaccharide or type IV pilus biosynthesis, suggesting that the modularity of cross-resistance was structured by distinct phage receptors. In contrast, between-module cross-resistance was provided by mutations affecting the alternative sigma factor, RpoN, which controls many lifestyle-associated functions, including motility, biofilm formation, and quorum sensing. Broader cross-resistance range was not associated with higher fitness costs or weaker resistance against the focal phage used to select resistance. However, mutations in rpoN, providing between-module cross-resistance, were associated with higher fitness costs than mutations associated with within-module cross-resistance, i.e., in genes encoding either lipopolysaccharide or type IV pilus biosynthesis. The observed structure of cross-resistance predicted both the frequency of resistance mutations and the ability of phage combinations to suppress bacterial growth. These findings suggest that the evolution of cross-resistance is common, is likely to play an important role in the dynamic structure of bacteria-phage communities, and could inform the design principles for phage therapy treatments.

Dataset Information

Modelling the spatiotemporal complexity of interactions between pathogenic bacteria and a phage with a temperature-dependent life cycle switch.

Publications

Modelling the spatiotemporal complexity of interactions between pathogenic bacteria and a phage with a temperature-dependent life cycle switch.

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