Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis.

Shreyasi Maity,Arijit Chakraborty,Anjan Kumar Das,Malini Sen,Syamal Roy,Sushil Kumar Mahata

doi:10.3389/fimmu.2022.818266

Abstract

Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.

Highlights

Visceral leishmaniasis (VL) or Kala-azar is a vector borne disease transmitted by the sand fly and caused by infection with the parasite Leishmania donovani (L. donovani)
In view of the fact that Wnt5A signaling antagonizes L. donovani infection in macrophages [19] we wanted to examine if Wnt5A signaling regulates the progression of experimental visceral leishmaniasis
In association with our observation of the Wnt5A dependent prevalence of splenic CD4 and CD8 T cells in the backdrop of L. donovani infection, we demonstrated that Wnt5A pretreatment of L. donovani infected mice led to a moderately increased presence of CD169+ marginal metallophillic macrophages (MMM), which are known to engulf pathogens, and collaborate with white pulp dendritic cells for antigen presentation to T cells (Figure 7A) [34, 35]

Summary

Introduction

Visceral leishmaniasis (VL) or Kala-azar is a vector borne disease transmitted by the sand fly and caused by infection with the parasite Leishmania donovani (L. donovani). Different modes of therapy for VL are available, the increasing emergence of drug resistant strains makes treatment complicated [3,4,5]. In this scenario it is important to understand the intricacies of the host – parasite interactions and how host immunity can be boosted to counter the parasite infection. Keeping in mind the documented role of Wnt5A signaling in the regulation of bacterial infections and immune homeostasis [6,7,8,9,10], we became interested in evaluating the influence of Wnt5A on L. donovani infection and progression of VL

Methods

Results

Conclusion