The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus
Abstract CRISPR-Cas9 immune systems protect bacteria from foreign DNA. However, immune efficiency is constrained by Cas9 off-target cleavages and toxicity. How bacteria regulate Cas9 to maximize protection while preventing autoimmunity is not understood. Here, we show that the master regulator of vi...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60871-6 |
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| author | Adeline Pastuszka Maria-Vittoria Mazzuoli Chiara Crestani Léonie Deborde Odile Sismeiro Coralie Lemaire Vanessa Rong Myriam Gominet Elise Jacquemet Rachel Legendre Philippe Lanotte Arnaud Firon |
| author_facet | Adeline Pastuszka Maria-Vittoria Mazzuoli Chiara Crestani Léonie Deborde Odile Sismeiro Coralie Lemaire Vanessa Rong Myriam Gominet Elise Jacquemet Rachel Legendre Philippe Lanotte Arnaud Firon |
| author_sort | Adeline Pastuszka |
| collection | DOAJ |
| description | Abstract CRISPR-Cas9 immune systems protect bacteria from foreign DNA. However, immune efficiency is constrained by Cas9 off-target cleavages and toxicity. How bacteria regulate Cas9 to maximize protection while preventing autoimmunity is not understood. Here, we show that the master regulator of virulence, CovR, regulates CRISPR-Cas9 immunity against mobile genetic elements in Streptococcus agalactiae, a pathobiont responsible for invasive neonatal infections. We show that CovR binds to and represses a distal promoter of the cas operon, integrating immunity within the virulence regulatory network. The CovR-regulated promoter provides a controlled increase in off-target cleavages to counteract mutations in the target DNA, restores the potency of old immune memory, and stimulates the acquisition of new memory in response to recent infections. Regulation of Cas9 by CovR is conserved at the species level, with lineage specificities suggesting different adaptive trajectories. Altogether, we describe the coordinated regulation of immunity and virulence that enhances the bacterial immune repertoire during host-pathogen interaction. |
| format | Article |
| id | doaj-art-bb19aa7a56144bd09fbd6018c34b0e3e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bb19aa7a56144bd09fbd6018c34b0e3e2025-08-20T03:37:37ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-60871-6The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B StreptococcusAdeline Pastuszka0Maria-Vittoria Mazzuoli1Chiara Crestani2Léonie Deborde3Odile Sismeiro4Coralie Lemaire5Vanessa Rong6Myriam Gominet7Elise Jacquemet8Rachel Legendre9Philippe Lanotte10Arnaud Firon11Université de Tours, INRAE, UMRInstitut Pasteur, Université Paris Cité, Department of MicrobiologyInstitut Pasteur, Université Paris Cité, Biodiversity and Epidemiology of Bacterial Pathogens, Department of Global HealthInstitut Pasteur, Université Paris Cité, Department of MicrobiologyInstitut Pasteur, Université Paris Cité, Department of MicrobiologyUniversité de Tours, INRAE, UMRUniversité de Tours, INRAE, UMRInstitut Pasteur, Université Paris Cité, Department of MicrobiologyInstitut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics HubInstitut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics HubUniversité de Tours, INRAE, UMRInstitut Pasteur, Université Paris Cité, Department of MicrobiologyAbstract CRISPR-Cas9 immune systems protect bacteria from foreign DNA. However, immune efficiency is constrained by Cas9 off-target cleavages and toxicity. How bacteria regulate Cas9 to maximize protection while preventing autoimmunity is not understood. Here, we show that the master regulator of virulence, CovR, regulates CRISPR-Cas9 immunity against mobile genetic elements in Streptococcus agalactiae, a pathobiont responsible for invasive neonatal infections. We show that CovR binds to and represses a distal promoter of the cas operon, integrating immunity within the virulence regulatory network. The CovR-regulated promoter provides a controlled increase in off-target cleavages to counteract mutations in the target DNA, restores the potency of old immune memory, and stimulates the acquisition of new memory in response to recent infections. Regulation of Cas9 by CovR is conserved at the species level, with lineage specificities suggesting different adaptive trajectories. Altogether, we describe the coordinated regulation of immunity and virulence that enhances the bacterial immune repertoire during host-pathogen interaction.https://doi.org/10.1038/s41467-025-60871-6 |
| spellingShingle | Adeline Pastuszka Maria-Vittoria Mazzuoli Chiara Crestani Léonie Deborde Odile Sismeiro Coralie Lemaire Vanessa Rong Myriam Gominet Elise Jacquemet Rachel Legendre Philippe Lanotte Arnaud Firon The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus Nature Communications |
| title | The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus |
| title_full | The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus |
| title_fullStr | The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus |
| title_full_unstemmed | The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus |
| title_short | The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus |
| title_sort | virulence regulator covr boosts crispr cas9 immunity in group b streptococcus |
| url | https://doi.org/10.1038/s41467-025-60871-6 |
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