Abstract
The parasites of the genus Leishmania survive and proliferate in the host phagocytic cells by taking control over their microbicidal functions. The parasite also promotes differentiation of antigen-specific anti-inflammatory cytokines producing effector T cells, which eventually results in disease pathogenesis. The mechanisms that parasites employ to dominate host adaptive immunity are largely unknown. For the first time, we report that L. donovani, which causes visceral leishmaniasis in the Indian subcontinent, upregulates the expression of an immune inhibitory receptor i.e., CD300a on antigen presenting and phagocytic cells to dampen their effector functions. The blocking of CD300a signals in leishmania antigens activated macrophages and dendritic cells enhanced the production of nitric oxide, pro-inflammatory cytokines along with MHCI/II genes expression, and reduced parasitic uptake. Further, the abrogation of CD300a signals in Leishmania infected mice benefited antigen-experienced, i.e., CD4+CD44+ and CD8+CD44+ T cells to acquire more pro-inflammatory cytokines producing phenotypes and helped in the early clearance of parasites from their visceral organs. The CD300a receptor blocking also enhanced the conversion of CD4+ T effectors cells to their memory phenotypes i.e., CCR7high CD62Lhigh up to 1.6 and 1.9 fold after 14 and 21 days post-infection, respectively. These findings implicate that CD300a is an important determinant of host phagocytic cells functions and T cells differentiation against Leishmania antigens.
Highlights
Leishmania donovani belongs to the family of intracellular protozoan parasites of the genus Leishmania that causes visceral leishmaniasis (VL), which is fatal if left untreated [1]
We have explored the role of CD300a in the regulation of effector functions of macrophages, dendritic cells, and antigen experienced T cells in L. donovani infection
The expression of CD300a both, at mRNA (Figures 1A, C) and protein (Figures 1B, D) levels were found significantly increased in macrophages (Mj) and bone marrow-derived dendritic cells (BMDCs) infected with L. donovani at all the time points, i.e., 12h, 24h, 36h being maximum at 24h post-infection
Summary
Leishmania donovani belongs to the family of intracellular protozoan parasites of the genus Leishmania that causes visceral leishmaniasis (VL), which is fatal if left untreated [1]. Since the identification of the causative agent, the pentavalent antimonial compounds had remained a mainstay treatment for all forms of leishmaniasis but the emergence of drug-resistant parasites has restricted their use in many endemic regions [2]. The efficacy of these two drugs is being questioned for their inability to produce a sterile cure, which is evident by an unusual presentation of VL in the form of post kala azar dermal leishmaniasis (PKDL) even years after successful treatment [5]. Recent studies suggest that individuals with PKDL are potential parasite reservoirs and may be a reason for disease surges in endemic and non-endemic regions [6, 7]. For the identification of potential protective immune correlates more studies are needed to explore the host-parasite relationship
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