Therapeutic potential of rWnt5A in curbing Leishmania donovani infection.

Abstract

In view of the antagonism of Wnt5A signaling toward microbial pathogens, we were interested in evaluating the therapeutic potential of recombinant Wnt5A (rWnt5A) in curbing Leishmania donovani infection. Initially, using L. donovani-infected RAW 264.7 and peritoneal macrophages, we demonstrated that application of rWnt5A as opposed to the vehicle control to the infected cells significantly dampens L. donovani infection. Inhibition of infection was associated with increase in cell-associated reactive oxygen species (ROS), and blocked by the ROS production inhibitor diphenylene iodonium chloride (DPI). rWnt5A, but not the vehicle control (PBS: phosphate-buffered saline) administration to L. donovani-infected mice appreciably reduced the infection load, and inhibited disease progression as evident from the preservation of splenic white pulp architecture. rWnt5A administration, moreover, led to elevation of both cell-associated ROS and the activation of splenic T cells. Substantial increase in T cell-associated Interleukin-2 (IL-2) and Granzyme B (GRB) upon exposure of splenic lymphocytes harvested from rWnt5A-treated mice to L. donovani-infected RAW 264.7 macrophages in vitro validated the occurrence of L. donovani-responsive T cell activation in vivo. In summary, this study unveils the therapeutic potential of rWnt5A in curbing L. donovani infection and the progression of experimental visceral leishmaniasis possibly through increase in cellular ROS and T cell activation. Accordingly, it opens up a new avenue of investigation into the use of rWnt5A as a therapeutic agent for restraining the progression of drug-resistant L. donovani infection.