DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response

Induction of type I interferons by the bacterial secondary messengers cyclic-di-GMP (c-di-GMP) or cyclic-di-AMP (c-di-AMP) is dependent on a signaling axis involving the STING adaptor, TBK1 kinase and IRF3 transcription factor. Here we identified the helicase DEAD box polypeptide 41 (DDX41) as a pattern recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via shRNA in murine or human cells inhibited the induction of innate immune genes and resulted in defective STING, TBK1 and IRF3 activation in response to c-di-GMP or c-di-AMP. These results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by the DDX41 PRR, which complexes with STING to signal to TBK1-IRF3 and activate the interferon response.