title: Leishmania donovani Utilize Sialic Acids for Binding and Phagocytosis in the Macrophages through Selective Utilization of Siglecs and Impair the Innate Immune Arm.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors: Saptarshi
authors: S
authors: Roy
authors: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors: Chitra
authors: C
authors: Mandal
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007893:Leishmania donovani / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D008264:Macrophages / Q000737:chemistry* / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D012794:Sialic Acids; D009569:Nitric Oxide; D020929:Mitogen-Activated Protein Kinase Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6