Pastuszka Adeline, Mazzuoli Maria-Vittoria, Crestani Chiara, Deborde Léonie, Sismeiro Odile, Lemaire Coralie, Rong Vanessa, Gominet Myriam, Jacquemet Elise, Legendre Rachel, Lanotte Philippe, Firon Arnaud
Université de Tours, INRAE, UMR, 1282 ISP, Tours, France.
CHRU de Tours, Service de Bactériologie-Virologie, Tours, France.
Nat Commun. 2025 Jul 1;16(1):5678. doi: 10.1038/s41467-025-60871-6.
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.
CRISPR-Cas9免疫系统保护细菌免受外源DNA的侵害。然而，免疫效率受到Cas9脱靶切割和毒性的限制。细菌如何调节Cas9以在预防自身免疫的同时最大化保护作用尚不清楚。在这里，我们表明，毒力主调节因子CovR调节无乳链球菌（一种导致侵袭性新生儿感染的致病共生菌）针对移动遗传元件的CRISPR-Cas9免疫。我们表明，CovR结合并抑制cas操纵子的一个远端启动子，将免疫整合到毒力调节网络中。CovR调节的启动子可控制脱靶切割的增加，以抵消靶DNA中的突变，恢复旧免疫记忆的效力，并刺激针对近期感染获得新的记忆。CovR对Cas9的调节在物种水平上是保守的，谱系特异性表明不同的适应轨迹。总之，我们描述了免疫和毒力的协调调节，这种调节在宿主-病原体相互作用期间增强了细菌的免疫库。
