Hidden in plain sight: How helminths manage to thrive in host blood

Abstract

Parasitic helminths have evolved a plethora of elegant stratagems to regulate and evade the host immune system, contributing to their considerable persistence and longevity in their vertebrate hosts. Various mechanisms to achieve this state have been described, ranging from interfering with or actively modulating host immune responses to hiding from immune recognition. Because they damage surrounding vessels and disturb blood flow, blood-borne and blood-feeding parasites in particular must deal with much more than immune effector cells. Management of the host complement system and coagulation cascade, as well as the development of processes of hiding and masking, represent hallmarks of life in blood. Here we review recent findings on putative evasion strategies employed by blood-borne parasitic helminths, focusing on the interaction with and utilisation of host serum components by nematodes and trematodes.

Keywords: blood-borne; coagulation; complement system; helminth; host factors; immune evasion; innate immunity.

Figure 1

Schematic representation of the main outstanding questions related to the utilisation of host serum sialoglycoproteins by adult schistosomes. Are EVs coated passively or as an active and specific process? At which point do host glycoconjugates become associated with parasite EVs? In the trematodes Schistosoma mansoni and Fasciola hepatica, evidence points to the tegument, digestive and excretory systems as sources of EVs (1) (de la Torre-Escudero et al., 2016; Bennett et al., 2020; Dagenais et al., 2021; Bennett et al., 2022). In addition, lectin histochemistry of whole adult worms with SNA-I, a lectin which recognises structures with α2-6-linked terminal SA, strongly labelled sub-tegumental cell bodies of the parasite (Dagenais et al., 2021), suggesting uptake of SA into those cells. Consequently, it is plausible that schistosomes might acquire serum glycoproteins via the tegument. Could schistosomes have receptors on sub-tegumental cell surfaces that recognize sialic acid as a signal for endocytosis (2)? Alternatively, the coating of EVs might occur upon their release in host blood (3). Do EVs emanate from sub-tegumental cells (4)? Does SA mediate interaction with target cells and/or EV uptake (5)? Future research should address these outstanding questions and investigate the involvement of SA in cellular interaction and EV uptake. miRNA, microRNA; mRNA, messenger RNA; RISC, RNA-induced silencing complex.

Figure 2

Interference between parasitic helminths with the secondary hemostasis and complement cascade. The image depicts some (non-exhaustive) points of interactions between helminth E/S products and the interconnected coagulation cascade and complement system, an integral part of innate immunity. While parasite molecules have inhibitory effects on host processes, Schistosoma mansoni stimulates plasmin activation to promote fibrinolysis (Mebius et al., 2013). The trematode also indirectly inhibits fibrin clot formation and stabilisation, interacts with FXII, thrombin, and complement C3 and C4 (Mebius et al., 2013; Da’dara et al., 2017; Wang et al., 2017; Wang et al., 2018). Hookworms interact with FVII and FX (reviewed in Abuzeid et al., 2020). Haemonchus contortus impairs C1q and C3 functions (Vedamurthy et al., 2015). Dirofilaria immitis was shown to decrease FX activity (Diosdado et al., 2020). Angiostrongylus vasorum interferes with fibrin clot stabilization, with tissue factor, and mannose-binding lectin associated protease 2 (MASP2) (Gillis-Germitsch et al., 2021; Tritten et al., 2021b). Interference with platelet activation or aggregation (bright red cell; primary hemostasis) was described for hookworm and S. mansoni products (Del Valle et al., 2003; Elzoheiry et al., 2018a). The coagulation and complement cascades are depicted according to Danckwardt et al. (2013). TF, tissue factor; PK, prekallikrein; TAFI, thrombin activatable fibrinolysis inhibito; MASP2, Mannose-binding lectin-associated serine protease 2.