Stable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Gut

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dc.contributor.authorHsu, Bryan B.en
dc.contributor.authorWay, Jeffrey C.en
dc.contributor.authorSilver, Pamela A.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2020-05-29T14:24:59Zen
dc.date.available2020-05-29T14:24:59Zen
dc.date.issued2020-01-28en
dc.description.abstractElimination or alteration of select members of the gut microbiota is key to therapeutic efficacy. However, the complexity of these microbial inhabitants makes it challenging to precisely target bacteria. Here, we deliver exogenous genes to specific bacteria by genomic integration of temperate phage for long-lasting modification. As a real-world therapeutic test, we engineered lambda phage to transcriptionally repress Shiga toxin by using genetic hybrids between lambda and other lambdoid phages to overcome resistance encoded by the virulence-expressing prophage. We show that a single dose of engineered phage propagates throughout the bacterial community and reduces Shiga toxin production in an enteric mouse model of infection without markedly affecting bacterial concentrations. Our work reveals a new framework for transferring functions to bacteria within their native environment. IMPORTANCE With the increasing frequency of antibiotic resistance, it is critical to explore new therapeutic strategies for treating bacterial infections. Here, we use a temperate phage, i.e., one that integrates itself into the bacterial genome, to neutralize the expression of a virulence factor by modifying bacterial function at the genetic level. We show that Shiga toxin production can be significantly reduced in vitro and in the mammalian gut. Alternative to traditional applications of phage therapy that rely on killing bacteria, our genetics-based antivirulence approach introduces a new framework for treating bacterial infections.en
dc.description.notesThis project was funded by the Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative (OPP1150555), the Defense Advanced Research Program Agency (DARPA BRICS HR0011-15-C-0094), and funds from Harvard Medical School. B.B.H. received support from the Rosenbloom postdoctoral fellowship.en
dc.description.sponsorshipBill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative [OPP1150555]; Defense Advanced Research Program Agency (DARPA BRICS)United States Department of DefenseDefense Advanced Research Projects Agency (DARPA) [HR0011-15-C-0094]; Harvard Medical School; Rosenbloom postdoctoral fellowshipen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1128/mSystems.00013-20en
dc.identifier.issn2379-5077en
dc.identifier.issue1en
dc.identifier.othere00013-20en
dc.identifier.pmid31992629en
dc.identifier.urihttp://hdl.handle.net/10919/98612en
dc.identifier.volume5en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectShiga toxinen
dc.subjectbacteriophageen
dc.subjectmicrobiomeen
dc.subjectantivirulenceen
dc.titleStable Neutralization of a Virulence Factor in Bacteria Using Temperate Phage in the Mammalian Guten
dc.title.serialmSystemsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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