Immune Evasion Strategies of Schistosomes

Abstract

Human schistosomes combat the unique immune systems of two vastly different hosts during their indirect life cycles. In gastropod molluscs, they face a potent innate immune response composed of variable immune recognition molecules and highly phagocytic hemocytes. In humans, a wide variety of innate and adaptive immune processes exist in proximity to these parasites throughout their lifespan. To survive and thrive as the second most common parasitic disease in humans, schistosomes have evolved many techniques to avoid and combat these targeted host responses. Among these techniques are molecular mimicry of host antigens, the utilization of an immune resistant outer tegument, the secretion of several potent proteases, and targeted release of specific immunomodulatory factors affecting immune cell functions. This review seeks to describe these key immune evasion mechanisms, among others, which schistosomes use to survive in both of their hosts. After diving into foundational observational studies of the processes mediating the establishment of schistosome infections, more recent transcriptomic and proteomic studies revealing crucial components of the host/parasite molecular interface are discussed. In order to combat this debilitating and lethal disease, a comprehensive understanding of schistosome immune evasion strategies is necessary for the development of novel therapeutics and treatment plans, necessitating the discussion of the numerous ways in which these parasitic flatworms overcome the immune responses of both hosts.

Keywords: Biomphalaria glabrata; immune evasion; immunomodulation; schistosome; schistosomiasis.

Figure 1

Immunosuppression tactics in the intermediate host. (A) Snails employ a wide variety of both humoral and cellular factors in combatting schistosome infections, many of which incorporate with each other to facilitate parasite killing. The humoral factors are largely composed of PRRs but also feature cytotoxic components such as biomphalysin. The cellular arm of the immune response features BgTLR displaying granulocytes, which envelope invading schistosomes, and hyalinocytes, which seemingly focus on the production of humoral factors and cell signaling molecules. (B) Parasites employ molecular mimicry by utilizing surface molecules and E/S products which share glycosylation patterns seen in snail plasma and on the surface of circulating hemocytes. Sharing such glycosylation patterns has been shown to correlate with survival during infection, suggesting these shared epitopes help schistosomes avoid recognition within the snail. (C) Molecular mimicry is also employed by the production of immune cell inactivating hormones like those produced by the snail which renders normally lethal hemocytes inactive and unable to kill invading sporocysts. (D) In order to avoid recognition by host pattern recognition receptors, schistosomes employ a highly variable series of polymorphic mucins. These mucins are recognized by host BgFREPs, and the variable nature of both the mucins and FREPs has led to the understanding that successful recognition of SmPoMucs by FREPs is a key determinant of infection success. If the host FREP can recognize the SmPoMucs and the surface of a sporocyst, that sporocyst will likely be killed, while having an unrecognizable SmPoMuc leads to immune evasion by avoiding BgFREP recognition. Such killing is thought to be at least partially dependent on a humoral BgFREP/BgTEP/Biomphalysin complex. (E) In order to generate a highly variable surface mucin, numerous processes occur to give rise to the considerable amount of variability seen between different sporocyst SmPoMucs. (F) Miracidia employ a venom allergen like protein which has been shown to upregulate the production of a B. glabrata matrix metalloproteinase (BgMMP1). This metalloproteinase is hypothesized to facilitate degradation of host connective tissues. Such degradation would allow for easier movement further into the host during initial infection. (G) E/S products from developing sporocysts facilitate the downregulation of key anti-parasitic functions in hemocytes. While some of these proteins have been identified, others remain of an unknown composition and are merely referred to by their size. (H) SmLeish-2 released by the parasite reduces hemocyte motility and therefore downregulates parasite encapsulation. This allows for continued movement and development of the sporocyst within the host.

Figure 2

Immunosuppression tactics in the human host. Schistosomes travelling through employ different immune evasion methodologies depending upon their location and life cycle stage. (A) As cercariae penetrate the skin, numerous proteases of different families help facilitate the cleavage of host molecules. The degradation of key structural components such as numerous collagens and elastin by these proteases helps the parasite descend through the epidermis, penetrate through the basement membrane, and eventually navigate the dermis in the search for a nearby venule. The invading larvae also release numerous immunosuppressants such as Sm16 and prostaglandins which alter leukocyte function in an attempt to avoid cell mediated death by creating a favorable immune environment. (B) Adults can also release molecules to reduce blood clotting in the area immediately surrounding a mated pair. This wide variety of molecules may be involved in the degradation of host plasma components to facilitate feeding, but their capacity to act as anti coagulants also implies the creating of a milieu in which the worms are able to move freely without fear of being killed by the coagulation of the blood in which they are emersed. (C) Adult worms in the mesenteric blood vessels incorporate host molecules into their tegument. Many of these molecules are important immune factors, which are bound in such a way as to prevent proper opsonization. IgG is found via its Fc portion, making in unrecognizable to cell found Fc receptors. Complement component C3 is also bound, although the effects of this association are not completely understood. Finally host MHCI can also be found bound to adult worms via its β2-microglobulin domain. The worm also targets mammalian factors not only for capture, but also for inactivation, as evidenced by schistosome paramyosin inhibiting membrane attack complex formation. (D) Schistosomes release a wide variety of parasite derived factors into their environment to create tolerable conditions for their survival. These molecules perform many different tasks, including the inhibition of cysteine proteases (Sj cysteine protease inhibitor), the blocking of neutrophil elastase (SmKI), and the alteration of antigen processing in macrophages (SjTpx). (E) Schistosome eggs release several factors which is key in skewing the T cell response towards the Th2 phenotype necessary for migration through the intestinal wall. These include α-1, which causes TH2 type granuloma formation through basophil mediated IL-4 production, and Ω-1, which brings about M2 polarization by altering dendritic cell antigen presentation. The chemokine binding protein SmCKBP is also present and reduces recruitment of varying leukocytes.