Bacterial infections play a pivotal role in infectious disease, such as cystic fibrosis (CF). Immunity is the first line of defence to fight microbial pathogens and the STING signalling is the main host pathway that triggers the immune response upon infections. STING is activated upon bacterial infection and has a major role on the induction of type I interferons (IFN1), necessary for bacterial clearance. 

We have recently shown that inhibition of Transglutaminase 2 (TG2) protein results in an enhanced anti-microbial response in CF. We also found that TG2 could regulate the STING pathway, highlighting its implication in the host response to bacteria. 

The goal of this project was to dissect out the role of STING signalling in CF to find new possible targets to develop host-directed therapies. We aimed to elucidate the TG2-dependent regulation of STING in CF models infected with Pseudomonas Aeruginosa (Pa). Mouse models, with mutation F508, have been employed to perform infections and STING and TG2 regulators have been also administered to modulate the STING signalling.

We found that the STING signalling is inadequately activated in CF condition and the use of molecules able to directly activate STING (agonists), such as 2’,3-cGAMP, is able to restore the immune response against bacterial colonization. Indeed, upon the treatment with the STING agonist, we found a reduction of bacterial colonization correlated to the IFN‐β enhanced production. We also confirmed these results in primary cells obtained from CF patients with F508 mutation. Our work indicates that the STING pathway integrity is crucial in the CF response against pathogens and that can be restored by the treatment with 2’,3’-cGAMP.

The correct functioning of STING pathway is fundamental in counteracting bacterial infections, especially of Pa. Therefore, the restoration of the pathway in CF could be exploited as a possible target for the treatment of the disease.