Our understanding of the PE/PPE family of proteins in M. tuberculosis (Mtb) pathogenesis is still evolving and their critical roles in the host immunomodulation are still in the discovery process. Earlier studies from our group have shown that TLR2-LRR domain plays an important role in regulating cytokine signalling by PPE proteins. The importance of TLR2-LRR domain 16-20 in the regulation of PPE17-induced pro-inflammatory signalling has been established recently. However, it is yet to find whether other PPE protein also targets the TLR2-LRR 16-20 domain for induction of pro-inflammatory responses. In the current study, we have explored the structural parameters and possible role of PPE65 in generating pro-inflammatory signalling molecules mediated through IRAK3 downstream of TLR2-LRR domain 16-20. This study conceptualizes the functional characteristics of PPE65 in infection condition and might possibly provide valuable information in exploring this protein as an immunomodulator in Mtb infection. (C) 2018 Elsevier Inc. All rights reserved.