Delineating infection strategies of Leishmania donovani secretory proteins in Human through host-pathogen protein Interactome prediction

Abstract

Interactions of Leishmania donovani secretory virulence factors with the host proteins and their interplay during the infection process in humans is poorly studied in Visceral Leishmaniasis. Lack of a holistic study of pathway level de-regulations caused due to these virulence factors leads to a poor understanding of the parasite strategies to subvert the host immune responses, secure its survival inside the host and further the spread of infection to the visceral organs. In this study, we propose a computational workflow to predict host-pathogen protein interactome of L.donovani secretory virulence factors with human proteins combining sequence-based Interolog mapping and structure-based Domain Interaction mapping techniques. We further employ graph theoretical approaches and shortest path methods to analyze the interactome. Our study deciphers the infection paths involving some unique and understudied disease-associated signaling pathways influencing the cellular phenotypic responses in the host. Our statistical analysis based in silico knockout study unveils for the first time UBC, 1433Z and HS90A mediator proteins as potential immunomodulatory candidates through which the virulence factors employ the infection paths. These identified pathways and novel mediator proteins can be effectively used as possible targets to control and modulate the infection process further aiding in the treatment of Visceral Leishmaniasis.

Keywords: Leishmania donovani; Protein-Protein Interaction (PPI); host–pathogen interaction; interolog mapping; network analysis; visceral leishmaniasis.