Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1

• Published in: Advanced biology 2024-10, Vol.8 (10), p.e2400174-n/a
• Main Authors: Malik, Asrar Ahmad, Shariq, Mohd, Sheikh, Javaid Ahmad, Fayaz, Haleema, Srivastava, Gauri, Thakuri, Deeksha, Ahuja, Yashika, Ali, Saquib, Alam, Anwar, Ehtesham, Nasreen Z., Hasnain, Seyed E.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - immunology; dsDNA; Humans; Interferon Type I - immunology; Interferon Type I - metabolism; IRF3; M. tb; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; mtDNA; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - pathogenicity; Nucleotidyltransferases - genetics; Nucleotidyltransferases - immunology; Nucleotidyltransferases - metabolism; phosphodiesterase; Signal Transduction - immunology; TBK1; Tuberculosis - immunology; Tuberculosis - metabolism; Tuberculosis - microbiology; Type‐I IFNs
• ISSN: 2701-0198; 2701-0198
• DOI: 10.1002/adbi.202400174

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease‐related deaths worldwide. It uses ESX‐1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS‐STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas‐sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non‐human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS‐STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS‐STING1 pathway can help develop new ways to fight tuberculosis. Mycobacterium tuberculosis, a lethal intracellular pathogen, exploits ESX‐1 T7SS to infiltrate host cells, initiating CGAS‐STING1 activation. This pathway induces type I interferon and cytokine release, driving autophagy. Recent cgas‐sting1 knockout studies contest the assumed protective function of type I IFNs. Furthermore, M. tb interference in the CGAS‐STING1 pathway exacerbates its pathogenicity, emphasizing the need for further investigation into tuberculosis mitigation.