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CBASS: Life, Death and cyclic nucleotides

Objective

All living things are subject to attack by viruses. Cells have evolved many different immune systems to protect themselves, including the adaptive and innate immune systems of vertebrates and the CRISPR and restriction:modification systems of bacteria. Viruses have developed potent countermeasures to subvert these systems, and this perpetual arms race has been a strong driving force in evolution throughout the history of life on Earth. CBASS (cyclic-oligonucleotide-based antiphage signalling systems) is a newly discovered bacterial immune system with evolutionary links to the eukaryotic cGAS-STING innate immune pathway. CBASS generates an astonishing array of cyclic di- and tri-nucleotide signalling molecules that in turn activate a diverse range of effector proteins to combat phage infection. These cyclic nucleotide second messengers thus lead to life or death decisions for infected cells. CBASS are abundant in pathogens and the microbes that dominate the human digestive system: this microbiome and the viruses that infect it are now implicated in diverse aspects of human health. This is a powerful and complex defence system, but fundamental aspects are not understood. How is viral infection detected by bacteria, triggering cyclic nucleotide production? What are the consequences for the cell: does activation inevitably lead to cell death, or is there a mechanism to switch it off? What role does protein modification play? Furthermore, how do viruses overcome CBASS defence? These questions will be addressed using a cutting-edge combination of structural and molecular biology, bioinformatics, biochemistry and microbiology. We propose a ground-breaking study of CBASS defence, with a focus on discovery of new enzymes, pathways and mechanisms. This work will open up new paradigms in bacterial cell signalling with broad implications for our understanding of microbial physiology, infection and the evolution of immune systems.

Call for proposal

ERC-2020-ADG
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Host institution

THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Address
North Street 66 College Gate
KY16 9AJ St Andrews
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 785 866

Beneficiaries (1)

THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
United Kingdom
EU contribution
€ 1 785 866
Address
North Street 66 College Gate
KY16 9AJ St Andrews
Activity type
Higher or Secondary Education Establishments