Mycobacterium tuberculosis PE5 stimulates anti-inflammatory cytokine production via innate immune toll-like receptor 4 signaling.

Abstract

Mycobacterium tuberculosis possesses an intricate system of virulence factors that aid in providing resilience to the pathogen within the milieu of the host. M.tb expresses unique proteins, PE/PPE, that are conserved and play a crucial role in pathogenesis. A conserved member of the PE family Rv0285 (PE5) of Mycobacterium tuberculosis (M.tb) has been earlier characterized as an essential and secretory protein that is a critical regulator of host immune response. We have shown that the PE5 protein consists of lysosomal targeting sequences and is stable at low pH, thereby allowing the protein to be localized to the lysosome. In-silico studies suggest that PE5 interacts with TLR4. This was validated using the TLRs knockout macrophage cell lines. PE5 increases the anti-inflammatory cytokine via the TLR4 receptor. Recombinant M. smegmatis expressing M.tb-PE5 protein survives within the macrophage as compared to control M. smegmatis, suggesting its role in providing resilience to survive within the macrophage. FDA drugs were screened for that interaction with the PE5 protein. Interaction of Nystatin and Conivaptan hydrochloride with PE5 results in stable binding and provides proof of concept about the possibility of repurposing these molecules as an anti-tubercular drug.