Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles

Abstract

Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.

Keywords: extracellular vesicle; helminths; immunosuppression; intracellular pathways; pattern recognition receptors.

Figure 1

Involvement of TLRs and CLRs during interaction with HDPs. TLRs and CLRs are widely targeted by HDPs during induction of immunomodulation and hyporesponsiveness in APCs. HDPs not only alter the expression of TLRs and CLRs in APCs but also masterfully manipulate their intracellular signaling. Some HDPs are able to redirect TLR4 signaling toward MAPK pathway and ERK1/2 activation supporting Treg/Th2 induction. In addition, co-engagement of DC-SIGN along with TLR4 enables HDPs to trigger unknown intracellular pathways which cross-inhibit MyD88 and NFκB activation. HDPs can further restrain NFκB activity via DC-SIGN-mediated RAF signaling along with upregulation of negative regulators of TLRs signaling, such as SOCSs and PI3K. Obviously, strict inhibition of NFκB as the main transcription factor supporting inflammation results in prevention of priming Th1 cells. Other CLRs have been reported to participate in priming Treg/Th2 cells upon stimulation by HDPs. For example, some HDPs suppress phosphorylation of Dectin1/2-induced Syk molecule and through which inhibit deviation of immune response toward Th1. On the other hand, MR and MGL upon activation by HDPs through an unknown mechanism support Treg/Th2 differentiation. Degrading host key intracellular molecules is another strategy that HDPs exploit to reprogram host immunity. Omega-1, ES-62, and FheCL1 by degrading host mRNA, endosomal TLR4, and TLR3, respectively, not only strengthen Treg/Th2 responses but also forestall anti-parasite immunity. NLRP3 also has been revealed to be targeted by some HDPs to modulate inflammatory responses. However, there has been reported that some HDPs are able to fight anti-worm immunity by stimulation of NLRP3 leading to release of IL-1B and Th1 amplification.

Figure 2

Some HDPs has been shown to target non-PRRs sensors including Kv1.3 and TCRs on T cells. Blocking Kv1.3 can significantly decrease Th1 cell activity and proliferation. Also, presenting HDPs on the MHCII leads to induction a weak TCR signaling in naïve CD4 T cells which corroborates Th2 differentiation. Of note, the main phenotype of Th2 response elicited by helminths and their products is “modified Th2” immunity in which IL-5, IL-13, eosinophlilia, and IgE are all downregulated, while IL-4, TGFβ, and IL-10 are increased. BCR signaling has also been shown to be impaired by some HDPs which prevent B cell activation. HDPs have recently been more considered as magic components which are able to mimic or block several host key mediators which play an important role in immunosuppression and Th2 amplification, respectively.

Figure 3

Schematic illustration of known effects imposed by helminth-derived EVs during interaction with host immunity. As illustrated here, EVs can affect different host cells including immune cells and intestinal epithelial cells (IECs). Also, they can potentially be used to develop new vaccines against helminths. EVs deliver cargo containing various biomolecules to host cells which can interfere with host cell gene transcription. EVs are internalized by macrophages and IECs via unknown mechanism and target IL-33R and DUSP1 expression reducing signal transmission and leads to inhibition of helminth expulsion. EVs have also shown great potential in priming host immunity along with Alum as a vaccine complex against helminth infections. Effective suppression of both classical Mϕ and AAMϕ have also been reported, implying EVs are well-equipped with a wide range of active components. In addition to in vitro studies, immunomodulatory functions of EVs have also been monitored in in vivo model in which allergic responses, associated cytokines, ILC2, and eosinophilia are down-regulated in Alternaria-exposed mice.