TB Study Reveals How Pathogens Inhibit Pyroptosis

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), has remained a leading public health threat worldwide and resulted in an average of 1.5 million deaths yearly. To learn more about this pathogen’s molecular mechanisms, Chinese researchers outlined a previously undefined pathway by which Mtb counteracts host immunity. Their work, recently published in Science, reveals that tyrosine phosphatase PtpB inhibits the host’s inflammasome-pyroptosis pathway by hijacking the host ubiquitin.

Mtb has evolved several intracellular strategies for survival, one of which includes a set of eukaryotic-like effectors, though much remains unknown about their role in pathogen-host interactions. The team, led by Prof. LIU Cuihua at the Institute of Microbiology at the Chinese Academy of Sciences (IMCAS), has previously investigated potential targets for the development of anti-TB treatments based on these interactions.

In this study, the scientists examined Mtb’s whole genome to predict secreted eukaryotic-like proteins with eukaryotic-like domains that might target host factors directly. Once identified, these Mtb proteins were further analyzed with an inflammasome reconstitution system for screening inhibitors of the inflammasome-pyroptosis pathways.

Out of the 201 predicted Mtb-secreted eukaryotic proteins examined, the researchers discovered PtpB as a key bacterial effector extensively secreted by Mtb to inhibit NOD-like receptor protein 3 (NLRP3) and missing in melanoma 2 (AIM2) inflammasome pathways. 

Further testing revealed that PtpB reduced pyroptosis and GSDMD-dependent cytokine production to support Mtb intracellular survival in macrophages. PtpB secreted by Mtb targets and dephosphorylated host plasma membrane phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and phosphatidylinositol-4-monophosphate (PI4P) to prevent N-terminal cleavage fragment of GSDMD (GSDMD-N) from triggering immune responses.

Additionally, PtpB’s specific ubiquitin-interacting motif (UIM)-like region appears necessary for this phosphatase activity to bind to ubiquitin. The host GSDMD-dependent immune responses were strengthened when phospholipid phosphatase activity or the UIM-like area of PtpB was disrupted, which decreased intracellular pathogen survival.

The findings show a previously unknown pathogen defense mechanism that involves modifying the structure of the host membrane to prevent pyroptosis and undermine host immunity. By targeting the PtpB-Ub-phospholipid-pyroptosis axis, these results may assist researchers in designing a new TB treatment.