Wnt5A Signaling Restrains Leishmania donovani infection in a mouse model

Abstract

Abstract Objective In view of the emergence of drug resistant strains of L. donovani and persistence of Kala-azar, it is important to understand how host derived factors promote immune resistance to L. donovani infection. Accordingly, considering the role of Wnt5A in maintenance of immune homeostasis, our objective is to evaluate the potential of host Wnt5A signaling in restraining L. donovani infection independent of drug sensitivity or resistance, utilizing a mouse model. Methods Effect of Wnt5A depletion on L. donovani infection was deciphered using Wnt5A heterozygous mice with reference to wild type cohorts, where mice were infected with L. donovani promastigotes through iv route. Effect of augmented Wnt5A signaling on L. donovani infection was investigated by iv injection of recombinant Wnt5A protein (rWnt5A) prior to infection. Infection load in liver and spleen was enumerated by Leishman Donovan Unit (LDU) and evaluated by histology. Plasma cytokine levels were checked by ELISA. Results Wnt5A heterozygous mice display substantially more disorganized splenic germinal centers and liver granulomas and about 50–60% more LDU upon L. donovani infection as compared to their wild type partners. rWnt5A treatment causes 40–80% reduction in infection load, which correlates with decrease or abolition of splenic germinal center disorganization and liver granulomas, and increase in pro-inflammatory cytokine to anti-inflammatory cytokine ratio. Conclusion Our results indicate that (i) Wnt5A signaling protects the host from L. donovani infection independent of drug sensitivity or resistance and (ii) rWnt5A has potential as a prophylactic agent for prevention of L. donovani infection and incidence of Kala-azar.