CRISPR Capture, Destroy, and Counter-Attack Mechanisms

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Project Summary CRISPR-Cas adaptive immune systems are deployed by prokaryotic organisms to protect them from potential lethal infection by viruses. As a counter-defense strategy, certain viruses produce anti-CRISPR (ACR) proteins capable of inactivating CRISPR-mediated, anti-viral immunity. Diverse CRISPR-Cas systems function by capturing short viral sequences within the CRISPR locus of the host genome and using expressed crRNAs and associated Cas nucleases for viral recognition and destruction. The identities and functions of viral ACRs in subverting distinct CRISPR-Cas systems are only just now being revealed. The primary objectives of our research program are: 1) to understand the molecular basis of mechanisms underlying both host CRISPR-Cas immune pathways and anti-CRISPR activities of viruses and 2) to exploit knowledge gained to contribute and improve CRISPR-based applications. Using an established and powerful combination of molecular, genetic, structural and biochemical approaches, with invaluable contributions from a team of superb collaborators, we will continue to work to dissect pathways and delineate molecular mechanisms governing diverse CRISPR-Cas systems. Furthermore, we will gain key insight on ACR-mediated mechanisms used by viruses to thwart CRISPR immunity. Innovative CRISPR-based tools and technologies are providing transformative advances in basic and medical research. The knowledge gained by our research will contribute directly to ongoing efforts aimed at exploiting diverse CRISPR-Cas systems as powerful research tools (e.g. for genome editing and controlled gene expression, to selectively detect and target human viral and bacterial pathogens, and for limiting the spread of antibiotic resistance). Moreover, understanding the detailed modes of action of diverse ACRs is necessary for establishing ACRs as important new research tools for selective and safe utilization of different CRISPR-based technologies.