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.
|Laan, Lisa C; Williams, Andrew R; Stavenhagen, Kathrin et al. (2017) The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 31:719-731|
|Hoeksema, Marten A; Laan, Lisa C; Postma, Juliette J et al. (2016) Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling. FASEB J 30:2826-36|
|Mickum, Megan L; Rojsajjakul, Teerapat; Yu, Ying et al. (2016) Schistosoma mansoni ?1,3-fucosyltransferase-F generates the Lewis X antigen. Glycobiology 26:270-85|
|Mickum, Megan L; Prasanphanich, Nina Salinger; Song, Xuezheng et al. (2016) Identification of Antigenic Glycans from Schistosoma mansoni by Using a Shotgun Egg Glycan Microarray. Infect Immun 84:1371-1386|
|Prasanphanich, Nina S; Song, Xuezheng; Heimburg-Molinaro, Jamie et al. (2015) Intact reducing glycan promotes the specific immune response to lacto-N-neotetraose-BSA neoglycoconjugates. Bioconjug Chem 26:559-71|
|Klaver, Elsenoor J; Kuijk, Loes M; Lindhorst, Thisbe K et al. (2015) Schistosoma mansoni Soluble Egg Antigens Induce Expression of the Negative Regulators SOCS1 and SHP1 in Human Dendritic Cells via Interaction with the Mannose Receptor. PLoS One 10:e0124089|
|Kooij, Gijs; Braster, Rens; Koning, Jasper J et al. (2015) Trichuris suis induces human non-classical patrolling monocytes via the mannose receptor and PKC: implications for multiple sclerosis. Acta Neuropathol Commun 3:45|
|Klaver, E J; van der Pouw Kraan, T C T M; Laan, L C et al. (2015) Trichuris suis soluble products induce Rab7b expression and limit TLR4 responses in human dendritic cells. Genes Immun 16:378-87|
|Mickum, Megan L; Prasanphanich, Nina S; Heimburg-Molinaro, Jamie et al. (2014) Deciphering the glycogenome of schistosomes. Front Genet 5:262|
|Mimche, Sylvie M; Nyagode, Beatrice A; Merrell, Matthew D et al. (2014) Hepatic cytochrome P450s, phase II enzymes and nuclear receptors are downregulated in a Th2 environment during Schistosoma mansoni infection. Drug Metab Dispos 42:134-40|
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