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

Citation: Roy S, Mandal C (2016) Leishmania donovani Utilize Sialic Acids for Binding and Phagocytosis in the Macrophages through Selective Utilization of Siglecs and Impair the Innate Immune Arm. PLoS Negl Trop Dis 10(8): e0004904. doi:10.1371/journal.pntd.0004904
Published: August 5, 2016

Abstract
Leishmania_donovaniBackground: 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.

Author Summary: Sialic acids are nine carbon sugars present on terminal cell surface glycoproteins and glycolipids. Siglec is a membrane receptor that belongs to an immunoglobulin super family present in almost all the haematopoetic cell lineages. There are 14 different types of siglecs present on human immune cells that take an active part in balancing the magnitude of immunological reactions. In general, these siglecs bind with sialic acids and negatively regulate the immune response. Leishmania contains sialic acids on its surface. Virulent parasites utilize this sugar to bind with macrophages through siglec-1 and siglec-5 compared to low sialic acids containing avirulent parasites. Such sialic acids-siglec-mediated interactions exhibited a suppressed host immune response which helped them to establish successful infection compared to desialylated virulent and avirulent parasites, as well as, siglec-depleted macrophages. Interestingly, interaction between sialic acids and siglec-1 induced enhanced phagocytosis, while sialic acids-siglec-5 interaction upregulated the phosphatase SHP-1. This interaction with the virulent strain exhibited deactivation of various downstream signaling pathways and ultimately controlled translocation of a functional component of transcription factor NF-κβ for regulation of cytokines and other effector molecules in infected macrophages. Thus, the interaction between the parasite and the host cells through sialic acids-siglec binding is clearly a newly identified mechanism by which parasites can establish successful infection by subverting the host’s innate immune response.

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