Viruses inhibit TIR gcADPR signalling to overcome bacterial defence

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals(1-3). In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function(1). We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are 'sponges' that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ''-2' glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1 ''-3' gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1 ''-2' gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity.

Automated summary

The Toll/interleukin-1 receptor (TIR) domain is a crucial component of immune receptors that detect pathogen invasion in various organisms. This study reveals a new mode of action by which phages inhibit host immunity by binding and sequestering immune signaling molecules produced by TIR-domain proteins. The chemical structure of the central immune signaling molecule has been defined, providing insights into the mechanisms of pathogen-host interactions.