The virulence regulator CovR boosts CRISPR-Cas9 immunity in Group B Streptococcus

Adeline Pastuszka, Maria-Vittoria Mazzuoli, Chiara Crestani, Léonie Deborde, Odile Sismeiro, Coralie Lemaire, Vanessa Rong, Myriam Gominet, Elise Jacquemet, Rachel Legendre, Philippe Lanotte () and Arnaud Firon ()
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Adeline Pastuszka: UMR
Maria-Vittoria Mazzuoli: Department of Microbiology
Chiara Crestani: Department of Global Health
Léonie Deborde: Department of Microbiology
Odile Sismeiro: Department of Microbiology
Coralie Lemaire: UMR
Vanessa Rong: UMR
Myriam Gominet: Department of Microbiology
Elise Jacquemet: Bioinformatics and Biostatistics Hub
Rachel Legendre: Bioinformatics and Biostatistics Hub
Philippe Lanotte: UMR
Arnaud Firon: Department of Microbiology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60871-6

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