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Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University.

ABSTRACT: Bacteriophage therapy is one potential strategy to treat antimicrobial resistant or persistent bacterial infections, and the year 2021 marked the centennial of Felix d'Hérelle's first publication on the clinical applications of phages. At the Center for Phage Biology & Therapy at Yale University, a preparatory modular approach has been established to offer safe and potent phages for single-patient investigational new drug applications while recognizing the time constraints imposed by infection(s). This study provides a practical walkthrough of the pipeline with an Autographiviridae phage targeting Pseudomonas aeruginosa (phage vB_PaeA_SB, abbreviated to ΦSB). Notably, a thorough phage characterization and the evolutionary selection pressure exerted on bacteria by phages, analogous to antibiotics, are incorporated into the pipeline.

SUBMITTER: Wurstle S

PROVIDER: S-EPMC10834462 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University.

Würstle Silvia S Lee Alina A Kortright Kaitlyn E KE Winzig Franziska F An William W Stanley Gail L GL Rajagopalan Govindarajan G Harris Zach Z Sun Ying Y Hu Buqu B Blazanin Michael M Hajfathalian Maryam M Bollyky Paul L PL Turner Paul E PE Koff Jonathan L JL Chan Benjamin K BK

Scientific reports 20240201 1

Bacteriophage therapy is one potential strategy to treat antimicrobial resistant or persistent bacterial infections, and the year 2021 marked the centennial of Felix d'Hérelle's first publication on the clinical applications of phages. At the Center for Phage Biology & Therapy at Yale University, a preparatory modular approach has been established to offer safe and potent phages for single-patient investigational new drug applications while recognizing the time constraints imposed by infection(s ...[more]

PMID: 38302552

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Project description:There is a continuously expanding gap between predicted phage gene sequences and their corresponding functions, which has largely hampered the development of phage therapy. Previous studies reported several phage proteins that could interfere with the intracellular processes of the host to obtain efficient infection. But few phage proteins that protect host against phage infection have been identified and characterized in detail. Here, we isolate a phage, vB_Pae_QDWS, capable of infecting Pseudomonas aeruginosa PAO1 and report that its encoded Gp21 protein protects PAO1 against phage infection. Expression of Gp21 regulates bacterial quorum sensing with an inhibitory effect in low cell density and an activation effect in high cell density. By testing the type IV pilus (TFP)-mediated twitching motility and transmission electron microscopy analysis, Gp21 was found to decrease the pilus synthesis. Further, by constructing the TFP synthesis gene pilB mutant and performing adsorption and phage resistance assay, we demonstrated that the Gp21 protein could block phage infection via decreasing the TFP-mediated phage adsorption. Gp21 is a novel protein that inhibits phage efficacy against bacteria. The study deepens our understanding of phage-host interactions. IMPORTANCE The majority of the annotated phage genes are currently deposited as "hypothetical protein" with unknown function. Research has revealed that some phage proteins serve to inhibit or redirect the host intracellular processes for phage infection. Conversely, we report a phage encoded protein Gp21 that protects the host against phage infection. The pathways that Gp21 involved in antiphage defense in Pseudomonas aeruginosa PAO1 interfere with quorum sensing and decrease type IV pilus-mediated phage adsorption. Gp21 is a novel protein with a low sequence homology with other reported twitching inhibitory proteins. As a lytic phage-derived protein, Gp21 expression protects P. aeruginosa PAO1 from reinfection by phage vB_Pae_QDWS, which may explain the well-known pseudolysogeny caused by virulent phages. Our discoveries provide valuable new insight into phage-host evolutionary dynamics.

Dataset Information

Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University.

Publications

Optimized preparation pipeline for emergency phage therapy against Pseudomonas aeruginosa at Yale University.

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