Mycobacterium tuberculosis PE25/PPE41 protein complex induces necrosis in macrophages: Role in virulence and disease reactivation?

• The Mycobacterium secreted protein PE25/PPE41 drives TNF-α secretion.
• PE25/PPE41 protein induces necrotic cell death, but not apoptosis, in macrophages.
• Necotic cell death induced by PE25/PPE41 is independent of TNF-α/NFκB/AP-1 pathways.
• PE25/PPE41 possibly acts as virulence factor, by an ‘immune quorum sensing’ mechanism.
• Necrotic cell death may help in mycobacterial dissemination and re-activation.

Necrotic cell death during TB infection is an important prerequisite for bacterial dissemination and virulence. The underlying mechanisms and the bacterial factors involved therein are not well understood. The Mycobacterium tuberculosis (M. tuberculosis) co-operonic PE25/PPE41 protein complex, similar to ESAT-6/CFP-10, belonging to the PE/PPE and ESAT-6 families of genes has co-expanded and co-evolved in the genomes of pathogenic mycobacteria. We report a novel role of this highly immunogenic PE25/PPE41 protein complex in inducing necrosis, but not apoptosis, in macrophages. We propose that these protein complexes of M. tuberculosis, secreted by similar/unique transport system (Type VII), have an important role in M. tuberculosis virulence and disease reactivation.