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

Abstract

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-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β 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.

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

“…IFN activation is associated with disease progression in tuberculosis (TB) and other infectious diseases. ESX-1 activity also leads to inflammasome activation and secretion of the proinflammatory cytokine IL-1␤ (40). Finally, Mt-EsxA secretion has been shown to be required for formation of TB granulomas and the persistence of mycobacteria in these lesions (42).…”

“…Finally, Mt-EsxA secretion has been shown to be required for formation of TB granulomas and the persistence of mycobacteria in these lesions (42). A recent model for cGAS and STING signaling postulates that Mt-EsxA may stimulate IFN signaling via pore formation and DNA transfer into the host cell cytosol (40,41).…”

“…In M. tuberculosis, secretion of Mt-EsxA by the ESX-1 pathway into host cells activates cyclic GMP-AMP synthase (cGAS) and cyclic GMP-AMP (cGAMP) signaling via STING, the mammalian sensor for cytoplasmic DNA and bacterial cyclic dinucleotides (38), thereby stimulating type I interferon (IFN) responses (39)(40)(41). IFN activation is associated with disease progression in tuberculosis (TB) and other infectious diseases.…”

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

“…Cyclic GMP-AMP synthase (cGAS) senses cytosolic Mtb DNA in an ESAT6-dependent, not fully unraveled manner, and cGASinduction leads to production of type I interferons (IFN) and autophagy [169][170][171]. As shown in mice, IL-1β balances type I IFN for Mtb growth control by avoidance of excessive inflammation [167].…”

“…Furthermore, ESAT6 is essential for the induction of apoptotic cell death in macrophages [219] and apoptosis has been reported to be both beneficial for the host and for bacterial spread [220]. The intracellular growth of Mtb was also controlled by ESAT6-dependent sensing of Mtb DNA by the cytosolic receptor cGAS, which leads to the induction of type I interferon and autophagy [169,170]. The origin of cytosolic Mtb DNA is not clear, bud could stem from membrane vesicle buds released from Mtb [183].…”