Infections with parasitic worms (helminths) suppress inflammation in a variety of human inflammatory disorders. It is thought that worms or their products induce regulatory T (Treg) cells and alternatively activated macrophages that dampen the effector functions of inflammatory T cells. However, the helminth immunoregulatory mechanisms are still incompletely understood. The regulation of inflammatory responses is mainly mediated via the innate immune system through antigen presenting cells (APC), including dendritic cells (DC) and macrophages (M?). DC and M? have unique plasticity in adopting various functional phenotypes through specific signaling via surface receptors, such as Toll- like receptors (TLRs) and glycan-binding proteins including C-type lectin receptors (CLRs). Molecular cross-talk of CLR- and TLR-mediated signals in DC is the main determinant that shapes the balance between immunity and tolerance. Our central hypothesis is that specific glycans of helminths and their spatial presentation induce CLR-mediated signaling pathways in APC, which contribute to the generation of anti-inflammatory and regulatory adaptive immune responses that confer protection against inflammation. To test this hypothesis we propose 3 specific aims.
(Aim 1 a) We will identify the glycan ligands of T. suis and S. mansoni that bind to specific CLRs on DC and M? by glycan microarray analysis; (1b) We will define the relationship between the avidity of glycan-binding by CLRs and the capacity of the APC to internalize the glycans via these receptors.
(Aim 2 a) We will define the signaling pathways induced by glycans of T. suis and S. mansoni glycoproteins, and their influence on TLR-induced signaling pathways; (2b) We will define how the structural composition and spatial presentation of the helminth glycans relate to their capacity to generate anti-inflammatory-type APC.
(Aim 3 a) We will define how DC pulsed with selected helminth glycans suppress the generation of inflammatory T cells; (3b) We will explore the relationship between the capacity of selected glycans to induce anti-inflammatory properties in APC in vitro, and their capacity to induce host protection in vivo, using the murine model for experimental autoimmune encephalomyelitis (EAE).
The molecular mechanisms by which parasitic helminths protect against chronic inflammatory diseases are poorly understood, but studies suggest that unique glycan structures expressed on the parasite glycoproteins can suppress both disease pathogenesis and inflammatory responses. Our studies proposed here are highly mechanistic and innovative because they directly explore glycans and their recognition by antigen-presenting cells and probe the biological consequences of these interactions. Elucidation of these molecular mechanisms offers exciting possibilities to develop immune therapies for inflammatory disorders.
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