Interplay between human STING genotype and bacterial NADase activity in S. pyogenes infection – unraveling the molecular underpinnings of invasive infection and interindividual disease variability.

Invasive Streptococcus pyogenes infections are characterized by excessive inflammation associated with high fatality rates. However, the outcome of these infections varies considerably among patients, largely for unknown reasons.

Our preliminary results reveal that the enzymatic activity of the NADase allele-variants expressed by invasive strains suppresses bacteria-derived cyclic-di-AMP-induced STING-signaling in macrophages and that a NADase-STING genotype interplay contributes to invasiveness and interindividual disease variability in humans.

Using genetic, biochemical and bioinformatic approaches this 4-year project aims to determine (WP1) the mechanism by which NADase suppresses STING-signaling and (WP2) how the genotypic interplay regulates inflammation in vivo, as well as to explore it for immunotherapeutic treatment strategies.

We also propose to (WP3) trace the functionally distinct allele-variants of human STING over time and space, promising knowledge regarding the origin and evolution of our ability to respond to cytosolic cyclic-dinucleotides, a key innate immune function in both bacterial and viral infection.

Thus, the proposed work addresses basic scientific problems that are of major clinical significance – as emphasized by the recent surge of invasive S. pyogenes infections among children in Europe – and promises knowledge that may improve diagnosis and patient management, as well as informing new treatment strategies.