Leishmania donovani Utilize Sialic Acids for Binding and Phagocytosis in the Macrophages through Selective Utilization of Siglecs and Impair the Innate Immune Arm

Background: leishmania donovani,belonging to a unicellular protozoan parasite,display the differential level of linkage-specific sialic acids on their surface. sialic acids binding immunoglobulin-like lectins (siglecs) are a class of membrane-bound receptors present in the haematopoetic cell lineages interact with the linkage-specific sialic acids. here we aimed to explore the utilization of sialic acids by leishmania donovani for siglec-mediated binding,phagocytosis,modulation of innate immune response and signaling pathways for establishment of successful infection in the host. methodology/principle findings: we have found enhanced binding of high sialic acids containing virulent strains (ag83+sias) with siglec-1 and siglec-5 present on macrophages compared to sialidase treated ag83+sias (ag83-sias) and low sialic acids-containing avirulent strain (ur6) by flow cytometry. this specific receptor-ligand interaction between sialic acids and siglecs were further confirmed by confocal microscopy. sialic acids-siglec-1-mediated interaction of ag83+sias with macrophages induced enhanced phagocytosis. additionally,sialic acids-siglec-5 interaction demonstrated reduced ros,no generation and th2 dominant cytokine response upon infection with ag83+sias in contrast to ag83-sias and ur6. sialic acids-siglecs binding also facilitated multiplication of intracellular amastigotes. moreover,ag83+sias induced sialic acids-siglec-5-mediated upregulation of host phosphatase shp-1. such sialic acids-siglec interaction was responsible for further downregulation of mapks (p38,erk and jnk) and pi3k/akt pathways followed by the reduced translocation of p65 subunit of nf-κβ to the nucleus from cytosol in the downstream signaling pathways. this sequence of events was reversed in ag83-sias and ur6-infected macrophages. besides,siglec-knockdown macrophages also showed the reversal of ag83+sias infection-induced effector functions and downstream signaling events. conclusions/significances: taken together,this study demonstrated that virulent parasite (ag83+sias) establish a unique sialic acids-mediated binding and subsequent phagocytosis in the host cell through the selective exploitation of siglec-1. additionally,sialic acids-siglec-5 interaction altered the downstream signaling pathways which contributed impairment of immune effector functions of macrophages. to the best of our knowledge,this is a comprehensive report describing sialic acids-siglec interactions and their role in facilitating uptake of the virulent parasite within the host. © 2016 roy,mandal.