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

Wassermann, R., et al. Cell Host Microbe, 2015. 17(6):799-810.

Speaker: Wei-Ren Cheng (鄭惟仁)                                      Time: 15:00~16:00, Dec 23, 2015

Commentator: Dr. Lein-I Ho (何漣漪 教授)                       Place: Room 601

Abstract

Tuberculosis is a high mortality disease that mainly caused by Mycobacterium tuberculosis (Mtb). Pathogenic mycobacteria manipulate innate immunity by ESX-1 secretion system, which transfers bacterial effector molecules into host cytosol (1). Macrophages detect Mtb-associated molecule patterns to initiate innate immunity via two cytosolic sensing systems: cyclic dinucleotide sensor STING and NLRP3 or AIM2 inflammasome (2, 3). For now, how intracellular host receptor is activated in an ESX-1-dependent manner remains unclear. The authors investigated the role of cytosolic sensor during Mtb infection by STING or STING upstream cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) knockout cells. Results indicated that both STING and cGAS are responsible for type I interferon (IFN) responses upon Mtb infection. After the co-localization of Mtb DNA and cGAS wasdemonstrated by immunofluorescence microscope, they further characterized the molecular events mediated by ESX-1. Results showed that the production of type I IFN and Mtb infection-related cytokines, was affected by the presence of ESX-1. However, ESX-1 didn’t alter IL-1β production in cGASor STING knockout cells. To clarify the mechanism, the authors targeted the components of inflammasome complex, and found that both DNA sensor AIM2 and NLRP3 are essential for inflammasome-mediated IL-1β production during Mtb infection. To further explore the role of ESX-1 in these pathways, the author employed distinct Mtb strains and established the importance of ESX-1-secreted substrates in certain signaling pathway activation. Moreover, the therapeutic potential of these substrates has also been proved. Taken together, ESX-1 activates different cytosolic DNA sensing system and leads to type I IFN and IL-1β production. Base on this discovery, manipulating ESX-1 or ESX-1-secreted substrates may become a potential treatment for Mtb infection.

Reference:

1.  1.     Stoop, E.J., W. Bitter, and A.M. van der Sar, Tubercle bacilli rely on a type VII army for pathogenicity. Trends Microbiol, 2012. 20(10): p. 477-84.

2. 2.      Dorhoi, A., et al., Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. Eur J Immunol, 2012. 42(2): p. 374-84.

3.  3.     Saiga, H., et al., Critical role of AIM2 in Mycobacterium tuberculosis infection. Int Immunol, 2012. 24(10): p. 637-44.