The immune system has the intricate task to detect and eliminate pathogens that are of danger to our organism. In this regard, the ability to distinguish “self” from ”non-self” is of the most fascinating and important tasks of our immune system. Central to this task is a repertoire of pattern recognition receptors (PRRs) that have evolved to detect to the presence of microorganism through the sensing of so-called microbe-associated molecular patterns (MAMPs). Moreover, it has become evident that also endogenous, normally compartmentalized molecules – referred to as danger-associated molecular patterns (DAMPs) – can engage the same receptor systems to trigger inflammatory and antimicrobial responses. In our research we are trying to understand the molecular mechanisms of one major pathway of MAMP/DAMP recognition, which is the recognition of pathogen-derived DNA within the cytosol.
Intracellular DNA sensing strategies
Over the past years several distinct classes of DNA sensors have been identified, which survey the cytosol for the presence of microbial-derived DNA and which trigger potent inflammatory and antiviral immune response when such substances are encountered (Figure 1). The PYHIN protein AIM2 was identified as an intracellular DNA sensor that activates a proteolytic cascade, which unfolds an inflammatory response through the secretion of IL-1β and also leads to a certain form of cell death (pyroptosis). However AIM2 is not required for the DNA-induced activation of de novo gene expression. The pathways that coordinate these responses turned out to involve distinct sensing mechanisms, yet the major sensing function is carried out by the cytosolic nucleotidyltransferase cyclic GAMP synthase (cGAS). Upon sensing DNA products cGAS synthesizes the cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), which acts as a 2nd messenger molecule and is recognized by the ER-resident protein stimulator of interferon genes (STING). Notably, next to sensing cGAMP STING is also crucial for the innate recognition of bacterial derived CDNs, such as cyclic di-GMP or cyclic di-AMP. After sensing CDNs STING triggers downstream signaling pathways to induce the up-regulation of antiviral and proinflammatory genes. There is one exception where cGAS and STING are dispensable for type I IFN responses upon DNA recognition, which is selectively activated by AT-rich DNA. This additional DNA recognition pathway bases on an indirect sensing mechanism, wherein AT-rich DNA is transcribed by RNA polymerase III to generate a stimulatory RNA intermediate, which subsequently activates antiviral gene expression via the RNA sensor RIG-I. By implementing a variety of distinct approaches our current research efforts aim at providing a better understanding of the molecular details of these pathways as well as their regulation during pathogen infection.
In trans antiviral signaling mechanisms