Restriction endonuclease cleavage of phage DNA enables resuscitation from Cas13-induced bacterial dormancy

Type VI CRISPR systems protect against phage infection using the RNA-guided nuclease Cas13 to recognize viral messenger RNA. Upon target recognition, Cas13 cleaves phage and host transcripts non-specifically, leading to cell dormancy that is incompatible with phage propagation. However, whether and...

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Bibliographic Details
Published in:	Nature microbiology Vol. 8; no. 3; pp. 400 - 409
Main Authors:	Williams, Madison C., Reker, Alexandra E., Margolis, Shally R., Liao, Jingqiu, Wiedmann, Martin, Rojas, Enrique R., Meeske, Alexander J.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-03-2023 Nature Publishing Group
Subjects:	631/326/1320 631/326/1321 Bacteria - genetics Bacteriophages - genetics Bacteriophages - metabolism Biomedical and Life Sciences CRISPR CRISPR-Cas Systems Deoxyribonucleic acid DNA DNA Restriction Enzymes - genetics DNA Restriction Enzymes - metabolism DNA Restriction-Modification Enzymes - genetics Dormancy Endonuclease Genomes Infectious Diseases Life Sciences Listeria Medical Microbiology Microbiology mRNA Nuclease Parasitology Phages Restriction-modification RNA phages RNA, Viral - genetics Synergism Virology
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Summary:	Type VI CRISPR systems protect against phage infection using the RNA-guided nuclease Cas13 to recognize viral messenger RNA. Upon target recognition, Cas13 cleaves phage and host transcripts non-specifically, leading to cell dormancy that is incompatible with phage propagation. However, whether and how infected cells recover from dormancy is unclear. Here we show that type VI CRISPR and DNA-cleaving restriction-modification (RM) systems frequently co-occur and synergize to clear phage infections and resuscitate cells. In the natural type VI CRISPR host Listeria seeligeri , we show that RM cleaves the phage genome, thus removing the source of phage transcripts and enabling cells to recover from Cas13-induced cellular dormancy. We find that phage infections are neutralized more effectively when Cas13 and RM systems operate together. Our work reveals that type VI CRISPR immunity is cell-autonomous and non-abortive when paired with RM, and hints at other synergistic roles for the diverse host-directed immune systems in bacteria. Deployment of some CRISPR-Cas systems stunts host growth by degrading all transcripts, but Listeria seeligeri reverses dormancy using restriction-modification-based phage DNA targeting.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The project was conceived by M.C.W., A.E.R. and A.J.M. Experiments were performed by M.C.W., A.E.R. and A.J.M. Bioinformatic analysis was conducted by M.C.W., S.R.M. and A.J.M. J.L. and M.W. isolated L. seeligeri strains. Pilot microscopy experiments were performed with assistance from E.R.R. The paper was written and edited by M.C.W., A.E.R., S.R.M. and A.J.M. Author contributions
ISSN:	2058-5276 2058-5276
DOI:	10.1038/s41564-022-01318-2