Cyclic oligoadenylate signalling - a new type of antiviral response

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All living things have evolved the ability to respond to changes in their environment in a way that maximises their fitness. For example, bacteria swim towards a food source, and away from a harmful chemical. To achieve this, they need a way to convert an environmental signal into a signal inside the cell, and they do this with a class of molecules called "second messengers". In 2017 an entirely new class of second messengers was discovered in bacteria and archaea: cyclic oligoadenylates (cOA). cOA molecules are made by joining together molecules of Adenosine triphosphate (ATP) to form rings of 3, 4, 5 and 6 building blocks. The enzyme that makes cOA is a cyclase that is part of a large complex important in the CRISPR system. This effector complex, which goes by several names (Csm, Cmr, Type III) can sense the presence of a virus in the cell by binding specifically to its genetic material. When the viral RNA is bound, the cyclase is switched on and cOA second messengers are synthesised to signal to the cell that it is infected. This sets in chain an antiviral response that includes changes in gene expression and activation of ribonucleases (RNA cutting enzymes) that degrade RNA in the cell. This might help buy some time for the cell to kill the virus, or alternatively might push the cell into dormancy or even death. Any of these outcomes, while not necessarily good for the cell, can be good for the cell's neighbours. And as these neighbours tend to be related, this process is favoured by evolution as it stops infection spreading.In this grant, we propose to study this new cOA signalling system in a model organism known as Sulfolobus solfataricus - which is found in volcanic pools, thriving at high temperatures and acidic conditions. Sulfolobus is an ideal model system for the biochemical, genetic and structural studies we want to carry out. It has a well understood CRISPR system and a good number of proteins activated by the cOA signalling molecule. We will examine how cOA is synthesised and degraded, and how it binds to and activates the downstream proteins that elicit the antiviral response. The work will help us to understand the fundamental properties of this exciting new antiviral signalling system. Since many crop and human pathogens have CRISPR type III systems, this work could ultimately find application in new methods to combat these diseases. The proposal fits well with the BBSRC strategic priority area: Integrative Microbiome Research.