Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1.

Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1ß (IL-1ß) production. Whereas the inflammasome regulates IL-1ß secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways.

Nucleic acid driven sterile inflammation.

The etiology of sterile inflammatory conditions is complex and affected by a variety of genetic, environmental and stochastic factors. But despite this overt complexity, progress has been made in elucidating mechanisms underlying disease pathogenesis. An intriguing new finding that has emerged over the past years was the realization that innate immune receptors participate in driving or aggravating disease manifestation. Originally identified as sensors of pathogens and as initiators of antimicrobial immune responses, receptors of the innate immune system recognize a variety of highly conserved microbe associated molecular patterns (MAMPs), including nucleic acids (NAs). While the sensing of DNA and RNA enables detection of a broad range of pathogens this strategy comes at a cost. Indeed, the capacity of NAs to accidentally activate innate sensors significantly contributes to inappropriate responses to self. In this review we will discuss recent findings based on established disease models.