Bacteriophages engineered to display foreign peptides may become short‐circulating phages. Issue 4 (29th April 2019)

• Record Type: Journal Article
• Authors: Hodyra‐Stefaniak, Katarzyna; Lahutta, Karolina; Majewska, Joanna; Kaźmierczak, Zuzanna; Lecion, Dorota; Harhala, Marek; Kęska, Weronika; Owczarek, Barbara; Jończyk‐Matysiak, Ewa; Kłopot, Anna; Miernikiewicz, Paulina; Kula, Dominika; Górski, Andrzej; Dąbrowska, Krystyna
• Other Names: Dusfresne Alain guestEditor.; Ellis Tom guestEditor.; Landini Paolo guestEditor.; Marqués Silvia guestEditor.; Prieto Auxi guestEditor.
• Is Part Of: Microbial biotechnology. Volume 12:Issue 4(2019:Jul.)
• Page Start: 730
• Page End: 741
• Publication Date: 2019-04-29
• Subjects: Microbial biotechnology -- Periodicals; Biotechnology; Microbiology; 660.62
• DOI: 10.1111/1751-7915.13414
• Languages: English
• ISSNs: 1751-7915

Abstract

Summary: Bacteriophages draw scientific attention in medicine and biotechnology, including phage engineering, widely used to shape biological properties of bacteriophages. We developed engineered T4‐derived bacteriophages presenting seven types of tissue‐homing peptides. We evaluated phage accumulation in targeted tissues, spleen, liver and phage circulation in blood (in mice). Contrary to expectations, accumulation of engineered bacteriophages in targeted organs was not observed, but instead, three engineered phages achieved tissue titres up to 2 orders of magnitude lower than unmodified T4. This correlated with impaired survival of these phages in the circulation. Thus, engineering of T4 phage resulted in the short‐circulating phage phenotype. We found that the complement system inactivated engineered phages significantly more strongly than unmodified T4, while no significant differences in phages' susceptibility to phagocytosis or immunogenicity were found. The short‐circulating phage phenotype of the engineered phages suggests that natural phages, at least those propagating on commensal bacteria of animals and humans, are naturally optimized to escape rapid neutralization by the immune system. In this way, phages remain active for longer when inside mammalian bodies, thus increasing their chance of propagating on commensal bacteria. The effect of phage engineering on phage pharmacokinetics should be considered in phage design for medical purposes. Abstract : We developed seven engineered T4‐derived bacteriophages presenting tissue homing peptides on capsids; these peptides targeted the lung and prostate, facilitated translocation from the gut to blood, and the brain. We evaluated phage accumulation in targeted tissues, spleen, liver and phage circulation in blood (in mice). Contrary to expectations, accumulation of engineered bacteriophages in targeted organs was not observed. Moreover, three engineered phages achieved tissue titers up to 2 orders of magnitude lower than unmodified T4. Thus, engineering of T4 phage resulted in the short‐circulating phage phenotype. Seeking immune reactions determining the short‐circulating phenotype, we found that the complement system inactivated engineered phages significantly more strongly than unmodified T4. The short‐circulating phage phenotype of the engineered phages suggests that natural phages, at least those propagating on symbiotic bacteria of animals and humans, are naturally optimized to escape rapid neutralization by the immune system, specifically by the complement cascade.