Identification of internalin-A-like virulent proteins in Leishmania donovani.

Background: An active immune surveillance and a range of barriers to infection allow the host to effectively eliminate microbial pathogens. However, pathogens may use diverse strategies to subdue such host defences. For instance, one such mechanism is the use of leucine-rich repeat (LRR) proteins by pathogens (microbial) to cause infection. In this study, we aimed at identifying novel virulence factor(s) in Leishmania donovani, based on the possibility of lateral gene transfers of bacterial virulence factor(s) to L. donovani.

Methods: Rigorous homology searching protocols including Hidden Markov Model (HMM) and BLASTp based searches were employed to detect remote but significant similarities between L. donovani proteins and bacterial virulence factors.

Results: We found that some L. donovani proteins are similar to internalin-A (Inl-A) protein of Listeria monocytogenes, a surface LRR protein that helps mediate host cell invasion by interacting with E-cadherin on the cell membrane. However, to date, no such invasion mechanism has been reported in Leishmania donovani, the causative agent of visceral leishmaniasis. Moreover, a comparative LRR motif analysis of L. donovani Inl-A-like proteins against the Inl-A protein of L. monocytogenes revealed existence of characteristic consensus LRR regions, suggesting a reliable evolutionary relationship between them. Further, through rigorous three dimensional (3D) modeling of L. donovani Inl-A-like proteins and subsequent molecular docking studies we suggest the probability of human E-cadherin binding with the L. donovani Inl-A-like proteins.

Conclusions: We have identified three potential candidates (UniProt ID: E9B7L9, E9BMT7 and E9BUL5) of Inl-A-like LRR containing proteins in L. donovani with the help of systematic whole genome sequence analysis. Thus, herein we propose the existence of a novel class of Inl-A-like virulence factor proteins in L. donovani and other Leishmania species based on sequence similarity, phylogenetic analysis and molecular modelling studies in L. donovani.