Deficiency of the AIM2–ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-γ Immunity in Mycobacterial Infection

Abstract

The nucleic acids of can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1β. However, whether cross-talk occurs between AIM2-IL-1β and cyclic GMP-AMP synthase-type I IFN signaling upon infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2 mice reciprocally induces overreactive IFN-β and depressive IFN-γ responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow-derived macrophages and bone marrow-derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-β levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2-IL-1β signaling pathway negatively regulates the STING-type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from infection. This finding has potential clinical significance.

Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

“…In addition, other studies have suggested that the bacterial burden does not differ between STING-deficient and WT mice, indicating that the cGAS/STING pathway is dispensable for controlling M. tuberculosis infections ( 17 , 57 ). Here, we found that M. tuberculosis MmsA can target STING for type I IFN production downregulation, which might contribute to the pathogenesis of mycobacterial infection, in accordance with previous studies ( 59 , 60 ).…”

“…A mycobacterial phosphodiesterase called CdnP suppresses STING activation and the type I IFN response via the hydrolysis of bacterially derived c-di-AMP and host-derived cGAMP ( 24 ). It was shown that another regulator, ASC, a key component of the inflammasome, inhibits type I IFN production by interacting with STING and disrupting its association with TBK1 via the C terminus ( 60 ). It is interesting that STING and autophagy are closely associated during M. tuberculosis infection.…”

Type I interferons in tuberculosis: Foe and occasionally friend

“…Mycobacterial DNA in the host cytosol can also be sensed by absent in melanoma 2 (AIM-2) protein, which partially contributes to the activation of the NLRP3-inflammasome, promoting the maturation of the protective cytokine IL-1β ( Shah et al, 2013 ; Wassermann et al, 2015 ). This AIM-2–IL-1β signaling pathway has been recently reported to negatively regulate the STING-dependent type I IFN production in macrophages and dendritic cells (DCs) by inhibiting the association between STING and TBK1 ( Yan et al, 2018 ).…”

Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies

“…70 In addition, during Mycobacterial infection, activated AIM2 mediated inflammasomes can interact with STING and block the activation of TBK1 and IRF3, thus inhibiting the induction of IFN-β. 71 The NLR containing protein 3 (NLRP3) has been well characterized to play important roles in viral infection and viral nucleic acid sensing. 64 However, it is unclear whether NLRP3 directly senses viral DNA or RNA.…”