CBASS: Life, Death and cyclic nucleotides

Descripción del proyecto

Estudio del nuevo sistema inmunitario bacteriano descubierto basado en oligonucleótidos cíclicos

Todos los seres vivos son propensos a los ataques de los virus, y las células han desarrollado diferentes sistemas inmunitarios para protegerse, como los sistemas inmunitarios innatos y adaptativos de los vertebrados y los sistemas de modificación/restricción y CRISPR de las bacterias. Los sistemas de señalización antifago basados en oligonucleótidos cíclicos (CBASS, por sus siglas en inglés) son una familia de sistemas inmunitarios bacterianos recién descubiertos, la cual genera un conjunto de moléculas de señalización trinucleótidas y dinucleótidas cíclicas que activa proteínas efectoras para luchar contra la infección por bacteriófagos. En el proyecto CBASS, financiado con fondos europeos, se propone un estudio fundamental sobre la defensa del CBASS a fin de identificar nuevas enzimas, vías y mecanismos. El objetivo es revelar la manera en que las bacterias detectan las infecciones víricas, las consecuencias para las células, el papel que desempeñan las modificaciones proteicas y el modo en que los virus superan la defensa del CBASS.

Objetivo

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.