The Crosstalk Between DNA-Sensing Pathways Upon M.tuberculosis Infection

Tuberculosis is a major infectious disease caused by Mycobacterium tuberculosis in the lungs.It is one of the top ten diseases leading to death in the world,and the mortality rate ranks first among the diseases caused by a single factor,which poses a serious threat to the human public health.Currently,the global control of tuberculosis faces three major challenges:the lack of effective vaccines,rapid and sensitive diagnostics and effective treatment strategies for drug-resistant forms of M.tuberculosis.According to research reports,the immune system plays a key role in the host defense against M.tuberculosis.The improvement of the overall cognitive system of the immune system contributes to the development and application of new vaccines,diagnostics and novel treatment strategies.The lungs of the host were infected by M.tuberculosis through the respiratory tract.The diverse pathogen-associated molecular patterns(PAMPs)of the bacteria are recognized by the pattern recognition receptors(PRRs)on the innate immune cells,which activates a series of immune-related responses.Among all the PAMPs,the genome DNA of the bacteria play a very important role.Studies reported that the genome DNA of M tuberculosis is mainly recognized by two DNA receptors.One is the DNA receptor—cGAS,which activates the downstream important adaptor protein STING.Next,STING activates the phosphorylase TBK1 and the transcription factor IRF3,finally inducing the production of Type I IFN.The other is the DNA sensor—AIM2,which binds to DNA and activates the downstream inflammasome signaling pathway,including ASC and caspase-1,ultimately inducing the production of the inflammatory IL-1β and IL-18.Data from clinical samples and mouse models suggest that the GAS-STING-Type I IFN signaling pathway may be detrimental to the host defense against M tuberculosis,while the AIM2-ASC-IL-β signaling pathway enhances the body’s antibacterial ability.Because the balance between AIM2-IL-1βand cGAS-Type I IFN signaling governs the outcome of M.tuberculosis infection,it is important to address whether there is a cross-talk between these two signaling pathways which recognize the same immunogen but mediate the opposite functional result during M.tuberculosis infection in vivo.In order to address this scientific question,AIM2 knockout mice were infected with bacteria to investigate the regulation of AIM2 pathway on the production of IFN-β induced by the cGAS signaling pathway.Results showed that the deletion of AIM2 promoted the production of more IFN-β,leading to higher infection burdens and more severe pathology,suggesting that the AIM2-ASC-IL-1β signaling pathway may negatively regulate the cGAS-STING-Type I IFN signaling pathway upon M.tuberculosis infection.Our in-depth mechanistic study indicated that the ASC in the AIM2 signaling pathway competes with the TBK1 in the cGAS signaling pathway for binding to the upstream molecule STING in BMDC and BMDM,which blocks the transmission of the activation signal and ultimately inhibits the induction of Type I IFN.More importantly,ASC expression is inversely correlated with IFN-β levels in PBMCs from tuberculosis patients.These data reveal a novel mechanism that involved in the host defense against M.tuberculosis infection.The hosts protect themselves from M.tuberculosis infection may not only through the activation of the AIM2-ASC-IL-1βsignaling pathway,but also through negatively regulating the induction of Type I IFN.The bidirectional regulation of AIM2 plays an important role in regulating the outcome of diseases caused by tuberculosis infection.Moreover,results from the PBMC samples of tuberculosis patients suggest that our study may have potential clinical significance.