Researchers from the University of Michigan Medical School and the Institute of Microbiology, Chinese Academy of Sciences, have uncovered a new feature of the type I CRISPR-Cas system in Neisseria bacteria, according to a July 24 paper published in Nature. The study found that this system contains additional embedded innate immunity genes and that type I CRISPR acts as a manager to regulate these built-in defense mechanisms.
Yan Zhang, Associate Professor of Biological Chemistry and Microbiology and Immunology at University of Michigan Medical School, said, "Our core finding here is bacteria anti-phage defense systems can be organized into a layered regulatory hierarchy." Zhang added, "In our case CRISPR-Cas acts as a commander-in-chief that regulates the repression and de-repression of other innate defense system genes that are tucked within the CRISPR-Cas locus."
The research team explained that under normal circumstances, production of these defense genes must be controlled because their activation can stifle bacterial growth. This regulation occurs when the CRISPR-Cas complex binds to promoter sequences on the defense genes, blocking their transcription. However, if CRISPR is defective or disarmed during phage infection, it lifts this repression and activates backup defenses against bacteriophages.
"CRISPR is the front line of defense during phage infections, but when CRISPR is defective or disarmed in some way, it lifts the repression, leading to a burst of production of the innate defense systems as backup weapons to wipe out the phages," Zhang said. She also noted that while phages may use peptide inhibitors to disable Cas machinery, this only triggers further backup defenses within this layered hierarchy.
Zhang said this understanding could benefit industries relying on bacteria by helping engineer more robust strains resistant to phages or by aiding development in phage therapy for antibiotic-resistant pathogens. "To make better phage therapies that kill antibiotics-resistant bacterial pathogens, we need to understand what hidden defense systems might be there so we might engineer the phages to outsmart them," she said.
The work builds on previous genetic platforms developed by Xufei Zhou and Xin Li in Zhang's lab. Zhang described it as "a truly pleasant collaboration," crediting Ming Li’s team for initiating and driving key aspects of the project.
