Abstract
Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma, typically found in tropical and subtropical freshwater environments. Recognized by the World Health Organization as a major emerging disease, schistosomiasis is characterized by the parasite’s ability to modulate and evade the host immune system, enabling long-term persistence within the human body. This immunomodulation not only supports chronic infection but also drives disease pathology, particularly through granulomatous inflammation surrounding parasite eggs trapped in host tissues. A deeper understanding of the immunological interactions between Schistosoma spp. and the human host is crucial for guiding the development of novel therapies. This review aims to delineate the immunological dynamics of Schistosoma infection across different stages of disease progression, with a particular focus on site-specific host–parasite interactions that shape both the acute and chronic phases of schistosomiasis.
Introduction
Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma, typically found in tropical and subtropical freshwater environments (1, 2). Recognized by the World Health Organization as one of the major emerging diseases (3), schistosomiasis poses a significant public health challenge, particularly in low- and middle-income countries (4). Its prevalence is closely linked to poor sanitation, limited access to clean water, and overcrowded living conditions (5–9)—factors that facilitate transmission and hinder effective disease control. The infection is endemic in regions with insufficient healthcare infrastructure (10–13), making coordinated prevention and treatment efforts difficult. Currently, the only available treatment is praziquantel, which is effective at the individual level but insufficient for achieving environmental eradication. Moreover, concerns over the potential emergence of drug-resistant strains of Schistosoma (14–16) have intensified the search for alternative strategies, including vaccines and immunomodulatory therapies (17, 18).
Several Schistosoma species can infect humans, but the most clinically relevant are S. japonicum, S. mansoni, and S. haematobium, responsible for intestinal and urinary schistosomiasis (2, 19). The parasite has a complex life cycle involving multiple morphologically distinct stages—miracidia, sporocysts, cercariae, schistosomula, and adult worms—across both intermediate (snail) and definitive (human) hosts (20). Adult worms live and reproduce in the host’s circulatory system, while their eggs migrate through tissues and are excreted to continue the cycle (Figure 1) (1, 19).
Figure 1
Schistosoma life cycle. Schematic representation of the Schistosoma life cycle. Eggs released by adult worms in the mesenteric veins are excreted into the external environment and hatch in freshwater, releasing miracidia that infect freshwater snails, the intermediate host. Within the snail, miracidia undergo asexual replication and produce cercariae, which are released into freshwater. Cercariae penetrate human skin, transform into schistosomula, migrate via the lungs, and mature into adult worms in the mesenteric veins. Egg deposition in host tissues induces granuloma formation and fibrosis, particularly in the liver.
A defining feature of Schistosoma infection is the parasite’s ability to evade and modulate the host immune response, allowing it to persist in the body for years. Although the host mounts strong immune reactions—especially against migrating larvae and egg antigens—Schistosoma has evolved sophisticated mechanisms to suppress or redirect these responses. This immunomodulation not only facilitates chronic infection but also drives disease pathology, particularly through granulomatous inflammation around eggs trapped in tissues. Understanding the immunological interplay between Schistosoma spp. and the human host is crucial for identifying individuals at risk of severe disease and for guiding the development of novel therapies. Key immune actors involved include macrophages, eosinophils, dendritic cells, regulatory T cells, and T-helper lymphocytes, particularly Th2-skewed responses. These elements shape both innate and adaptive immunity during infection and are targets of parasite-driven immune modulation.
Notably, the immunoregulatory environment induced by schistosomiasis can affect the course of other conditions, including autoimmune and allergic diseases, whose severity and progression may be altered in infected individuals (21). The objective of this review is to delineate the immunological dynamics between Schistosoma spp. and the human host across different stages of infection, with particular focus on the host–parasite interactions in different sites that define both the acute and chronic phases of schistosomiasis.
Overview of schistosoma infection and migration
Following their release from the snail intermediate host, Schistosoma cercariae penetrate the mammalian host’s skin, initiating the transition from a free-living to a parasitic life stage. Upon entry, they rapidly shed their tails and glycocalyx and differentiate into schistosomula (22), releasing excretory/secretory (E/S) products that facilitate immune evasion by modulating local cutaneous responses. After a short period of residence in the skin, during which they evade both innate and adaptive immune mechanisms, schistosomula enter the dermal vasculature and migrate via the bloodstream to the lungs (23). Despite prolonged exposure to pulmonary immune surveillance, they largely avoid elimination, aided by dynamic changes in tegumental composition, altered glycosylation patterns, and the release of immunomodulatory vesicles. From the lungs, the parasites travel to the liver, where they mature into sexually dimorphic adult worms. These adults establish themselves in the portal or mesenteric venous systems, depending on the species, and begin producing eggs (24). While some eggs are successfully excreted to sustain the transmission cycle, a substantial proportion become trapped in host tissues (25, 26). There, they elicit granulomatous inflammation, which contributes to both the immunopathology and long-term persistence of chronic schistosomiasis (27).
Cercariae: skin invasion and early immune modulation
Upon contact with a mammalian host, Schistosoma penetrate the skin—a major immunological barrier. The systemic interplay between Schistosoma and host’s immune system begins at this stage. It takes about two hours for the cercariae to lose its tail and remodel its surface membrane and metabolism to adapt to the skin environment; following initial invasion, schistosomula reside in the skin for several days during which several E/S molecules rich in proteases and glycoconjugates are released by the parasite (28, 29). Cercarial proteases exhibit broad substrate specificity against host dermal components (30, 31), and their inhibition significantly compromises the ability of Schistosoma to penetrate and establish within host tissues (32).
The human complement system can recognize and bind to the glycocalyx of Schistosoma cercariae. However, this initial immune response fails to eliminate the parasite or prevent its development into schistosomula, as the cercariae rapidly shed their glycocalyx, thereby discarding bound complement components and evading immune attack (33). Indeed, Wang et al. found that, at least in vitro, the complement attack may actually facilitate the metamorphosis of S. japonicum cercariae (34).
Schistosomula secrete molecules that suppress pruritus by acting on MrgprA3+ sensory neurons. In the absence of MrgprA3 activation, cutaneous myeloid antigen-presenting cells (APCs) predominantly produce IL-33 rather than IL-17, thereby promoting pathways associated with epidermal hyperplasia and altered skin homeostasis instead of IL-17–driven γδ T-cell recruitment and proliferation (35, 36).
Several studies have highlighted that the immune modulation exerted by cercariae and schistosomula is multifactorial, involving various types of host immune cells and multiple pathways. Notably, these studies underscore the crucial role played by the immunomodulatory cytokine IL-10. IL-10 plays a central role in limiting excessive inflammation by suppressing the activity of pro-inflammatory cytokines such as IFN-γ, TNF-α, and IL-12, and by inhibiting antigen-presenting cell function (37).
Stimulation of human whole-blood cultures with cercarial E/S material caused the early (within 24 h) release of greater quantities of regulatory IL-10 (38). A direct immunomodulatory role of cercariae is supported by experimental evidence showing that radiation-attenuated cercariae fail to induce IL-10 production and, more broadly, a regulatory T cell profile, in contrast to non-attenuated cercariae (39).
Findings from various studies indicate that IL-10 production may occur through distinct immunomodulatory mechanisms activated by Schistosoma. Ramaswamy et al. demonstrated how the parasite secretory products contain a factor that can potentially induce prostaglandin E2 (PGE2) production, that in turn promotes IL-10 secretion from human keratinocytes, although the molecular mechanism of this PGE2 induction from host cells is not fully understood (40). PGE2 may play a dual role: not only by promoting IL-10 production, but also as a potent vasodilator, potentially facilitating Schistosoma penetration into blood vessels.
CD4+ T cells became anergic and hyporesponsive following repeated percutaneous injections of Schistosoma larvae in a murine schistosomiasis model, through an IL-10–dependent mechanism (41); Sanin et al. reported similar findings: in mice repeatedly exposed to Schistosoma, an early IL-10–producing CD4+ T-cell population suppressed further CD4+ T-cell proliferation and the overall immune response in the skin (42). Schistosomula can also directly induce lymphocyte apoptosis: schistosomula secrete antigens capable of upregulating Fas ligand (FasL) expression on lymphocytes, thereby promoting the apoptosis of cutaneous T cells (43).
During the cutaneous phase of Schistosoma infection, not only lymphocyte functions are adversely impaired. Hervé et al. demonstrated that prostaglandin D2 (PGD2), produced by Schistosoma mansoni, inhibits the migration of epidermal Langerhans cells (LCs) to the draining lymph nodes (DLNs) through DP1 receptor stimulation (44). Furthermore, experiments by Angeli et al. suggest that this impaired LC migration may serve as an additional strategy employed by schistosomes to delay and evade the host immune response, with PGD2 playing a pivotal role in modulating cutaneous immune activity (45).
One possible strategy employed by Schistosoma mansoni cercariae may be to leverage host APCs as vehicles for the internalization of their E/S products.
Several proteins contained within the E/S products of Schistosoma mansoni have been shown to bind to mannose receptors (MR) expressed on macrophages. Experimental evidence indicates that macrophages lacking these receptors exhibit a Th1-biased response to the parasite, confirming that MR-mediated uptake of E/S proteins plays a critical role in shaping host immunity (46).
Among the E/S products released by Schistosoma mansoni cercariae were identified proteins belonging to the helminth defence molecule (HDM) family. One of these, Sm16, is internalized by macrophages and shown to modulate their activity and metabolism, leading to a reduced inflammatory response (47).
Sanin et al. demonstrated that Sm16 constitutes a quantitatively relevant fraction of Schistosoma mansoni cercarial E/S products released into the skin during invasion. This protein was shown to impair antigen processing and presentation by macrophages, most likely through interference with endosomal trafficking. These findings highlight Sm16 as a contributor to the immunoregulatory properties of cercarial E/S products and suggest its role in dampening dermal inflammation following percutaneous infection (48).
Another immunomodulatory mechanism employed by Schistosoma cercariae may involve a subset of dendritic cells (DCs) engaged in homeostasis and self-recognition. These DCs interact with authentic cercarial glycosphingolipids containing LeX and pseudo-LeY motifs via the C-type lectin receptor DC-SIGN (49). Additionally, experiments by Jenkins and Mountford support a pivotal role for DCs in promoting a Th2-polarized immune response following interaction with Schistosoma cercariae (50).
Cook et al. demonstrated that eosinophils also contribute to the modulation of the immune response against Schistosoma. In a model of repeated cercarial challenge, they observed a marked eosinophilic infiltration at the site of infection, which created an environment enriched in IL-4 and IL-13 (51). This cytokine milieu promoted the expansion of additional cell populations that suppress the anti-schistosomal immune response, including activated macrophage-like cells expressing arginase-1 and Ym-1, as well as a subset of functionally impaired MHC-II cells. Furthermore, their findings underscore that the development of these suppressive dermal cells is dependent on IL-4Rα signalling. Eosinophils and IL-4 are typically associated with a Th2-type immune response. This provides additional evidence that Schistosoma infection tends to induce a Th2-biased immunological profile from the earliest stages of infection. Studies on cercarial dermatitis further support the emergence of an IL-4–rich environment after cercarial challenge. Cercarial dermatitis, which occurs following repeated Schistosoma infections (52), is characterized by marked eosinophilia and elevated circulating IL-4 levels, highlighting the strong Th2 polarization of the local immune response (53).
Schistosomula: morphological transformation and pulmonary migration
After shedding its tail and transforming to a schistosomula, the parasite penetrates dermal blood vessels end with the blood flow reaches the lungs. Although species and strains vary in their rate of migration, even the most rapidly migrating species, such as S. japonicum, requires at least five days to reach the bloodstream and subsequently the lungs. That time frame would be expected to allow for the development of a more robust immune response against cercariae or schistosomula compared to that observed in the skin. However, the immune reaction in the lungs appears to resemble the response to a novel antigen, suggesting limited immunological priming during the initial stages of infection (54). Thus despite the exposure of Schistosoma membrane antigens, the host’s immune response remains relatively moderate during the early stages of infection.
Both molecular, in vitro, and in vivo studies suggest that Schistosoma spp. employs several strategies to evade the immune response throughout its juvenile phase, enabling it to reach full adult form in its final destination within the host’s liver. Attempts to target the migratory phase of Schistosoma infection generally result in disruption of the parasite’s tegument rather than acting against specific protein targets (55, 56). Vaccine prototypes directed at abundant yet less variable tegumental proteins have largely failed, suggesting these proteins are either poorly accessible to the immune system or not critical for parasite survival. In contrast, the most immunogenic schistosomula-derived molecules are the excretory-secretory (ES) products, a complex mixture of proteins and enzymes released primarily from the acetabular glands into host tissues and bloodstream, as well as directly from the tegument (57, 58). These E/S antigens elicit a Th1-skewed immune response (59, 60), unlike the predominantly Th2 responses induced by adult worms or egg antigens (61–63). Nevertheless, also immunization with E/S components has shown limited efficacy in preventing infection or progression to granulomatous pathology (64).
The schistosomula tegument proteome is highly dynamic during development, with many immunogenic apical membrane proteins downregulated compared to cercariae (65). Likewise, the profile of lytic enzymes involved in tissue invasion and immune evasion differs markedly from that of cercariae (65). Glycans on the schistosomula tegument act as pathogen-associated molecular patterns (PAMPs) and are recognized by macrophages and other antigen-presenting cells via TLR. However, the glycosylation pattern of lung-stage schistosomula differs significantly from cercarial and adult stages, with subtle modifications in sugar residues altering antibody binding affinity (66, 67). This variation likely contributes to the ineffectiveness of humoral responses generated during skin invasion (68). Correspondingly, lung schistosomula elicit an innate inflammatory response characterized by innate immune cell recruitment, including γδ T cells (54, 69). Furthermore, the glycosylation state of lipids in schistosomula ES vesicles also differs from adults (70, 71).
Collectively, these data support the hypothesis that schistosomula evade robust immune recognition by continually modifying or masking their most antigenic molecules during this vulnerable developmental window. This antigenic plasticity may also underlie the limited efficacy of vaccines based on schistosomula tegumental antigens in controlling adult worm burden and egg deposition (72).
In addition to antigenic modulation, lung schistosomula actively modulate host cytokine production to attenuate inflammatory damage. Elevated IL-6 levels observed during pulmonary schistosomiasis correlate with a less intense Th1 response and reduced tissue injury, as demonstrated by the heightened inflammation and damage seen in IL-6–deficient mice (73). Moreover, schistosomula tegument preparations induce IL-10 production and recruit regulatory T cells (Tregs) in murine models of airway inflammation, attenuating pro-inflammatory cytokine production and immune activation (74, 75).
The lipid layers at the host-parasite interface also appear critical for schistosomula survival. While their precise immunomodulatory roles remain unclear, disruption of cholesterol in the lipid membrane increases antibody accessibility to membrane markers in S. mansoni but not S. haematobium (76). Alterations to the lipid bilayer can enhance antigen exposure, and schistosomula rely heavily on both active and passive transport through the tegument for nutrient uptake, as they are not yet hematophagous. Nutrient passage can occur even with intact lipid barriers (77), indicating that changes in lipid composition, turnover, or integrity can significantly affect parasite physiology and host interactions. Disruption of sphingomyelin homeostasis, one of the most abundant unsaturated fatty acids in schistosomula lipid bilayers, has been shown to impair parasite growth and development (55). Similarly, treatment of early liver-stage schistosomula with tegument-damaging compounds reduces viability (78).
Complement activation represents a major early immune challenge for schistosomula, which are rapidly targeted predominantly via the alternative pathway. However, after approximately 24 hours, schistosomula evade complement-mediated killing by recruiting host regulatory proteins such as factor H (79). This complement resistance likely contributes to the limited efficacy of many vaccine candidates against cercarial challenge, with some studies showing that complement does not significantly participate in vaccine-mediated parasite killing (80).
Adult worms: systemic dissemination and long-term immune modulation
Schistosomula migrate through the bloodstream to the portal venous system, where they mature into sexually differentiated adult worms. Depending on the species, worms subsequently relocate to their final niche within either the mesenteric venous system (S. mansoni, S. japonicum) or the venous plexus of the genitourinary tract (S. haematobium) (1, 2). In contrast to cercariae and schistosomula, that evade the host immune system by quickly migrating and constantly changing their surface antigens, adult worms reside stably within specific blood vessels for extended periods and employ distinct long-term immune evasion strategies to persist without eliciting an effective immune response.
As with schistosomula, a key factor is likely the protection conferred at the host–parasite interface by the layers of the tegument. While schistosomula possess a three-layered tegument, adult worms develop a more complex structure composed of seven layers. The outermost layer of adult worm is particularly rich in sphingomyelin, which, according to Migliardo et al., can form a network of hydrogen bonds surrounding the parasite (81). This molecular barrier may shield protein and other immunogenic components of the tegument from recognition by the host immune system. Further studies from the same research group confirmed how adult worms show weaker interaction between outmost layer and the surrounding medium, corroborating the hypothesis that host parasite interface of adult worms is highly masked (82).
Another strategy employed by Schistosoma during its various developmental stages involves the expression of phosphatases on the tegument surface. These enzymes are capable of cleaving host circulating proteins, thereby preventing the activation of the complement system, the coagulation cascade, and other immune responses. The presence of phosphatases and/or suitable protease inhibitors has indeed been demonstrated (83–85). Studies conducted on the serum of infected patients confirm the activation of the complement system and suggest that Schistosoma possesses the ability to degrade activated components, ultimately rendering this immune response ineffective (33). Inal and Schifferli have shown that certain tegumental proteins of Schistosoma can bind to complement components C2 and C4, thereby interfering with the complement cascade (86).
The outermost layers and, more broadly, the tegument of adult worms contain numerous components capable of eliciting a significant Th1 response. Nevertheless, none of the investigated candidates has yet demonstrated sufficient efficacy in preventing cercarial challenge or in inducing effective immunization against adult worms or eggs, largely due to Schistosoma’s sophisticated immunomodulatory strategies.
Several attempts have been made using SWAP (Soluble Worm Antigen Preparation), a mixture of soluble antigens derived from centrifuged adult worms. However, this preparation is largely composed of antigens that are not abundant in the tegument. Proteomic analyses have shown that approximately half of the total SWAP mass consists of cytosolic and cytoskeletal proteins, which are not accessible or exposed to the host immune system. In contrast, only a small fraction—around 3%—corresponds to proteins associated with host-parasite interfaces such as the tegument and gut, which are considered more promising targets for a protective immune response (87).
The sequestration of antigens in regions that are poorly accessible to the host immune system appears to be one of the strategies employed by adult Schistosoma worms. This is further supported by evidence suggesting that significant modifications at the host-parasite interface may explain why certain components of the outer tegument of adult worms fail to elicit the same immune response they are capable of triggering during the lung-stage schistosomula (88). Immunization with antigens derived from adult worms has consistently shown lower protective efficacy compared to those obtained from earlier developmental stages (89), indicating that antigens from adult worms are less accessible to immune recognition. Supporting this, studies in which the tegument is altered or damaged—either directly or through stress conditions—demonstrate that surface antigens become more exposed, resulting in a more robust host immune response (90). In general, compromising the integrity of the tegument is considered an effective strategy for killing adult worms and enhancing the serological response to both adult worm and tegumental antigens, as observed with praziquantel treatment (91).
Some of the most immunogenic proteins may also exhibit significant polymorphism, as exemplified by SjTSP-2. This tegumental protein is highly expressed in adult worms and strongly induces IgG1 and IgG3 responses, yet it is characterized by a high degree of antigenic variability (92). Moreover, SjTSP-2 is not expressed in the tegument during the cercarial stage, but rather in the gut (93), which may explain its limited effectiveness in protecting against cercarial challenge.
Several surface antigens also exhibit significant differences in expression between male and female adult worms (94). As a result, despite the induction of a robust humoral response, infection is not eradicated. More broadly, the proteomic profile of adult worms has been shown to differ between sexes (95, 96), as does the composition and ultrastructure of the tegument (97). These factors may contribute to the distinct immunogenic potential of a given antigen depending on the sex of the parasite.
Schistosoma may not even require broad-spectrum strategies to neutralize the host’s antibody response, as the humoral response is largely focused on a limited set of parasite antigen. Krautz-Peterson et al. have shown that the host’s antibody response to Schistosoma is predominantly directed against a small set of conformational epitopes found on five major tegumental surface membrane proteins. These epitopes appear to dominate the humoral response. Despite the robustness of this circulating anti-tegumental antibody response, neither schistosomula nor adult worms seem to be significantly affected, suggesting that the parasite is able to withstand or evade the immune pressure exerted by these antibodies (98).
All these findings may help explain why, in vitro, several components derived from the outermost layer of the adult worm’s tegument have been shown to elicit a canonical Th1 immune response (99), but passive immunization directed versus the same component fail to confer a good protection against the infection (100–103), both in human and animal models or in vitro (104).
Schistosoma appears to possess highly effective mechanisms to counteract the host’s IgG-mediated immune response. In contrast, evidence from studies on naturally acquired immunity in resistant individuals suggests that IgE-mediated responses may play a more protective role. This type of immunity seems to develop gradually through repeated exposure to antigens that are normally hidden and only become accessible upon the death of adult worms, which can persist in the human host for several years. Over time, this intermittent antigen exposure promotes the expansion of IgE responses targeting specific schistosome proteins, including members of the tegument-allergen-like (TAL) family. Some of these antigens are shared between adult worms and schistosomula, potentially enhancing cross-stage immune recognition.
The delayed onset of an effective IgE response—often requiring years of infection and multiple reinfection cycles—may be partly explained by the parasite’s ability to interfere with IgE function. For instance, proteases present in the schistosome tegument have been shown to cleave CD23, releasing a soluble fragment that can bind to IgE and inhibits its activity (105).
Further studies have demonstrated that increases in IgE specific to soluble worm antigens (SWA) and Schistosoma protein Sm22.6 correlate positively with pre-treatment Th2 cytokine levels, particularly IL-5, but not with IFN-γ. These associations remain significant even after adjusting for variables such as infection intensity, age, and baseline IgE levels, suggesting that Th2 responsiveness is a key factor in the development of protective IgE responses. Notably, younger children often fail to mount sufficient IgE responses following antigen stimulation, likely due to an underdeveloped Th2 cytokine profile (106).
Genetic studies have also linked resistance to reinfection with specific HLA polymorphisms associated with enhanced IgE production against SWA antigens (107). Moreover, a Th2-skewed immune profile has been shown to confer greater protection in reinfection scenarios (108, 109), while a robust eosinophilic response may further support and modulate Th2 activity (110).
Interestingly, chronic schistosomiasis is often accompanied by an improvement in allergic and atopic conditions, suggesting that the suppression of effective IgE responses may be actively regulated. IL-10 appears to be a central mediator in this process (41, 111, 112), with elevated levels observed during Th2 responses in chronic infection (113). However, the precise mechanisms underlying this immunomodulation remain unclear (114).
Evidence supporting a direct role of adult worm components in inducing IL-10 production remains limited. In human models of single-sex Schistosoma infection—where individuals are exposed exclusively to male or female cercariae—a mixed Th1/Th2 immune response has been observed (115), including in male-only infections (116), without notable IL-10 induction. Similarly, several vaccine trials have elicited a balanced Th1/Th2 response, rather than a regulatory IL-10–dominated profile (100).
In contrast, animal models suggest that female worms may contribute to immune anergy and increased expression of immunoregulatory molecules such as CTLA-4 and IL-10 (117–119), a finding also supported in human studies (115), although in the latter case it is suspected that females may produce unfertilized eggs, potentially influencing the immune profile. Proteomic analyses have revealed sex-specific differences in protein expression (96), including in tegumental proteins (94), suggesting that male and female worms may possess distinct immunomodulatory capacities.
Schistosoma also appears to exert modulatory effects on DCs, the circulating antigen-presenting cells that typically initiate immune responses. In chronic schistosomiasis, both dermal and plasmacytoid DCs have been reported to exhibit an anergic phenotype and reduced expression of Toll-like receptor 2 (TLR2), although the underlying mechanisms remain unclear (120). Similarly, van der Biggelaar et al. observed that DCs in chronically infected individuals display hyporesponsiveness to adult worm antigens (121).
Additional evidence suggests that specific schistosome-derived molecules may actively shape DC function. For instance, lysophosphatidylserine (lyso-PS) from Schistosoma has been shown to induce IL-10–producing regulatory T cells via TLR2-dependent activation of DCs (122). Moreover, the adult worm secretome includes a homolog of human cyclophilin A, which has been demonstrated to act directly on DCs, preferentially promoting the expansion of regulatory T cells (123).
A cysteine protease inhibitor from Schistosoma japonicum (rSj-C) has been shown to impair antigen presentation by DCs. It inhibits lysosomal proteases, reducing MHC class II expression and potentially limiting the ability of DCs to activate adaptive immune responses (124).
Lipids derived from adult Schistosoma mansoni worms have been shown to exert immunomodulatory activity on macrophages, promoting their polarization toward an M2 phenotype (125). The release of metabokines such as succinate and lactate by adult worms, as demonstrated in the study by Skelly and Da’dara, also drives macrophage polarization toward an M2 phenotype (126).
Eggs: granuloma formation and Th2−biased immune response
Mature parasite pair and migrate to specific vascular niches depending on the species. Schistosoma mansoni and Schistosoma japonicum typically inhabit the mesenteric veins draining the intestines, while Schistosoma haematobium is found primarily in the venous plexus of the bladder. It is within these blood vessels that paired adult worms produce eggs, which are then deposited in the surrounding tissues (2, 19). Egg production usually begins several weeks after infection, once sexual maturity and pairing have occurred. These eggs play a central role in the pathogenesis of schistosomiasis, as their traversal through host tissues triggers intense immune responses and granuloma formation, leading to much of the disease’s morbidity (25).
To ensure transmission, the eggs must actively traverse host tissues to reach the intestinal or vesical lumen (127). This process is mediated by egg-secreted enzymes such as metalloproteases, which degrade the extracellular matrix and facilitate tissue penetration. Inhibition of these proteases has been shown to impair tissue digestion and significantly reduce egg excretion (128), highlighting their essential role in parasite transmission. However, many eggs fail to reach the lumen and become lodged in host tissues (26), where they elicit potent immune responses.
Mature eggs adhere to the endothelium and rapidly recruit immune cells, particularly eosinophils, macrophages, CD4+ T helper cells and fibroblasts, culminating in granuloma formation, a protective yet pathological structure that forms around trapped eggs. These granulomas serve a dual purpose: they encapsulate toxic egg antigens to limit local tissue damage, and they facilitate egg extrusion into the lumen. A compromised host immune response also results in a reduced rate of egg excretion, supporting the hypothesis that the granulomatous reaction is not only a consequence of infection but also facilitates the translocation of eggs across host tissues (129).
Despite this protective intent, chronic granulomatous inflammation leads to progressive fibrosis and organ dysfunction. Interestingly, only mature eggs induce granulomas, whereas immature eggs fail to recruit macrophages, suggesting the eggshell is initially immunologically inert. This likely provides a temporal window for the miracidium to mature before triggering host immunity (130).
Several components of Schistosoma eggs possess immunomodulatory activity and contribute to the distinctive immunological milieu associated with infection. These include both molecules that are actively excreted or secreted by the eggs, and those identified through the analysis of egg homogenates, such as many components of the soluble egg antigens (SEA). There is a broad consensus that Schistosoma eggs orchestrate a complex cytokine network that promotes Th2 polarization, facilitates granuloma formation, and tempers excessive inflammation.
Eggs trapped in liver capillaries activate endothelial cells and hepatic stellate cells (HSC) to secrete chemokines, CCL2 in particular, to recruit circulating leukocytes. Macrophages are a major component of Schistosoma-induced granuloma. Cytokine microenvironment, dominated by the Th2 cytokines IL-4 and IL-13, promotes the macrophage polarization toward a M2-like phenotype expressing arginase 1 and Fizz-I. M2 polarization is also influenced by direct contact with the eggs themselves. Zhu et al. demonstrated that peritoneal macrophages isolated from healthy mice exhibited elevated expression of chemokines such as CCL2, CCL17, and CCL22, along with IL-10 and Arg-1, following stimulation with S. japonicum SEA (131). Similarly, Xu et al. reported an increased production of IL-10 in RAW264.7 macrophages upon exposure to S. japonicum SEA (132).
The Th1-Th2 shift following egg deposition, with a progressive reduction in proinflammatory cytokines such as IFN-γ and TNF-α, represents a crucial step in the immune response to the parasite. This is demonstrated by the high mortality rate in mice deficient in IL-4 and IL-4/IL-10 (133–135). Conversely, neutralization of IFN-g or IL-12 results in accentuated fibrosis (136).
Time course experiments in murine model indicate a peak of Th2 cytokines (IL-4, IL-5 and IL-13) soon after egg deposition in the liver and an increase of IL-10 at later time point (137), revealing the onset of regulatory mechanisms that dampen the immune response. Overall, SEA has a dual effect on the immune system. On one side it promotes the development of Th2 cells, on the other, it induces regulatory mechanisms mediated by direct, such as induction of T cell apoptosis via FAS-FASL mediated pathway and the upregulation of PD-1 of T cells (138) and indirect effects, via modulation of the dendritic cell activation. In particular, DC exposed to SEA show impaired maturation following TLR stimulation, characterized by reduced expression of MHC class II molecules and other maturation markers (139).
Egg-derived glycolipids selectively stimulate monocytes to produce IL-10, IL-6, and TNF-α, underscoring the unique immunoregulatory properties of egg components (140) Among these, IPSE/α-1—a major glycoprotein released from the subshell region—induces IL-4 production and strong antibody responses, initiating Th2 immunity (141). SEA-derived Omega-1 potently drives Th2 polarization by acting on human dendritic cells via mannose receptor–mediated uptake, while it promotes a Th2/tolerogenic environment in DC by upregulating OX40L, reducing TNF-α production (142, 143) and inducing PGE2 synthesis via ERK signaling through Dectin-1 and Dectin-2 (144). IL-33 contributes to the early phase of type 2 responses, particularly in the gut, though it appears dispensable for parasite maturation and egg deposition (145). SEA also promote IL-4–producing cells, including eosinophils and mononuclear cells, which support polyclonal B cell activation (146). SEA influences B cell function by inducing IL-10 and CD86 expression in marginal zone B cells, independently of macrophages, and promotes regulatory B cell (Breg) differentiation via components like IPSE/α-1, but not omega-1 or kappa-5 (147). Egg-derived extracellular vesicles enriched in Sja-miR-71a suppress neutrophil and macrophage extracellular trap formation through the Sema4D/PPAR-γ/IL-10 axis, further reinforcing SEA’s anti-inflammatory profile (148). Beyond Th2 responses, IL-17–producing cells contribute to hepatic granuloma formation and fibrosis, correlating with ICOS expression and implicating Th17 cells in pathological remodeling (149). Conversely, IL-22 appears protective: schistosome eggs upregulate IL-22 while suppressing its binding protein, and IL-22-producing T cells attenuate IL-13-driven M2 macrophage polarization and fibrogenesis, reducing collagen synthesis and hepatic stellate cell proliferation (150, 151).
Consequence of the release of Th2 cytokine in the granuloma is the activation of hepatic stellate cells to produce collagen thus inducing periportal fibrosis (152). Both IL-4 and IL-13 are involved in the HSC activation. Nevertheless, IL-4 blockade failed to prevent the fibrotic process whereas IL-13 is now considered the major driving cytokine driving collagen production by HSC (153, 154) since blockade of the IL-4Ra, common receptor for IL-4 and IL-13, or directly IL-13 is highly effective in reducing liver fibrosis due to schistosoma egg deposition and increase survival (155, 156). As infections progress into chronicity, Type 2 responses decline, and regulatory responses prevail (5, 2931). Down-modulation of Type 2 responses and suppression of severe disease is thought to be primarily mediated by IL-10 (32), with its secretion attributed to Regulatory B cells (Bregs) (33, 34) and T cells (Tregs) (30, 35–37). Additionally, SEA promote apoptosis of CD4+ T cells via FasL-mediated pathways (138). In parallel, the upregulation of PD-1 on CD4+ T cells serves as an immune checkpoint that restrains pathogenic Th2 responses; its blockade exacerbates hepatic immunopathology without affecting egg burden (138). Regulatory T cells (CD4+CD25+FoxP3+) further suppress inflammation and limit tissue fibrosis during chronic infection, particularly within the colonic granulomas (157).
Conclusions and future directions
Schistosomiasis represents a paradigmatic case of host–parasite interaction in which survival depends on the capacity of the parasite to modulate and exploit host immunity (Figure 2). Notably, schistosomes employ a wide repertoire of immunomodulatory and immune-evasive strategies that enable them to complete their life cycle and disseminate within the host. Moreover, these mechanisms are not restricted to local sites of infection; rather, they exert systemic effects that reshape immune homeostasis at the organismal level. In this context, the parasite not only attenuates inflammatory responses to facilitate its persistence, but also leverages host immunity to promote egg expulsion, thereby ensuring transmission to the external environment. Importantly, the finely tuned immunoregulatory activities of Schistosoma extend beyond parasite survival, influencing the trajectory of autoimmune and inflammatory diseases in infected individuals, which often diverge from their classical pathophysiological course. Recent research has increasingly focused on exploiting the immunomodulatory properties of schistosome-derived molecules, particularly their capacity to promote Th2 responses, as a therapeutic approach for human disease (158). This strategy is being investigated in a variety of pathological contexts where excessive inflammation or autoimmunity plays a central role. For instance, experimental models have shown that SEA or other schistosoma derivates can ameliorate conditions such as inflammatory bowel disease (159, 160), multiple sclerosis (161), rheumatoid arthritis (162–164), diabetes (165, 166) and asthma (167, 168) and many other conditions. Many reviews have comprehensively summarized these advances, highlighting how parasite-derived immunomodulation is being translated into potential interventions aimed at restoring immune balance and reducing tissue damage in chronic inflammatory and autoimmune disorders (21, 24, 169).
Figure 2
Stage-specific immune modulation during the Schistosoma life cycle. Overview of host immune modulation at distinct stages of Schistosoma infection (1). Skin penetration is associated with the release of excretory/secretory (E/S) products, glycocalyx shedding, IL-10–mediated T cell hyporesponsiveness, impaired Langerhans cell (LC) migration, and eosinophil infiltration (2). During transient lung residency, schistosomula reduce antigen exposure, evade antibody and complement responses, and promote regulatory T cells (Tregs) and IL-6 production (3). Parasite maturation involves the establishment of molecular barriers, inhibition of dendritic cells (DC), degradation of complement components, interference with IgG-mediated immunity, and promotion of regulatory IL-10 responses (4). Egg deposition induces Th2-driven granulomatous inflammation, M2 macrophage polarization, activation of hepatic stellate cells, and regulatory mechanisms involving PD-1/FasL expression in CD4+ T cells. DC, dendritic cell; E/S, excretory/secretory products; LC, Langerhans cell; Treg, regulatory T cell.
An unavoidable consequence of the immunomodulatory capacity of Schistosoma is the persistent difficulty in developing an effective vaccine. Despite decades of research aimed at identifying antigens capable of blocking cercarial penetration or limiting parasite dissemination, results have remained disappointing. The parasite’s ability to manipulate host immunity prevents the establishment of durable protective responses, thereby undermining conventional vaccine strategies. Research efforts have concentrated on numerous vaccine candidates that remain under investigation at the preclinical stage (170). Among these, only four candidates—based on Schistosoma proteins or recombinant proteins such as Sm14 (171–173), Sm−p80 (174) (173), rSh28GST (175) (174) and Sm−TSP−2 (176, 177) have advanced to clinical evaluation (Table 1), although only one clinical trial has published its results to date (178). Despite research efforts, current efficacy outcomes remain insufficient. Although some candidates have shown encouraging pre−clinical performance, most still fail to reach the protective levels required for an effective schistosomiasis vaccine (179–183).
Table 1
| ClinicalTrials.gov ID | Antigen/target protein | Trial phase | Participant age group | Status |
|---|---|---|---|---|
| NCT05999825 | Sm-p80 | 2 | Adult | Unknown status |
| NCT01512277 | rSh28GST | 1 | Adult | Completed |
| NCT01154049 | Sm14 | 1 | Adult | Completed |
| NCT03110757 | Sm-TSP-2 | 1 | Adult | Completed |
| NCT05292391 | Sm-p80 | 1 | Adult | Completed |
| NCT05762393 | Sm-p80 | 1 | Adult | Active |
| NCT03041766 | Sm14 | 2 | Adult | Completed |
| NCT05658614 | Sm14 | 2 | Adult | Unknown status |
| NCT02337855 | Sm-TSP-2 | 1 | Adult | Completed |
| NCT03910972 | Sm-TSP-2 | 1, 2 | Adult | Completed |
| NCT00870649 | rSh28GST | 3 | Child | Completed |
| NCT03799510 | Sm14 | 3 | Child | Completed |
Overview of clinical trials (completed, active, or of unknown status) of schistosomiasis vaccine candidates.
This reality highlights the need for innovative strategies that integrate immunology and host–parasite interaction studies to advance therapy development against schistosomiasis. For these reasons, it becomes increasingly important to deepen our understanding of how Schistosoma manipulates host immune responses. Clarifying the mechanisms underlying parasite-driven immunoregulation is a necessary step toward the development of therapies capable of overcoming the barriers that have thus far limited progress in schistosomiasis vaccine research. At the same time, a better understanding of schistosome immune biology may provide opportunities to evaluate parasite-derived molecules as potential therapeutic agents. In this regard, continued investigation of schistosome–host interactions is important not only for advancing strategies to control schistosomiasis, but also for assessing their possible relevance in the development of novel immunomodulatory approaches applicable to a wider range of human diseases.
Statements
Author contributions
AT: Writing – original draft. CC: Writing – review & editing. CN: Writing – review & editing. AC: Writing – review & editing. FS: Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
Anderson TJC Enabulele EE . Schistosoma mansoni. Trends Parasitol. (2021) 37:176–7. doi: 10.1016/j.pt.2020.06.003
2
Buonfrate D Ferrari TCA Adegnika AA Russell Stothard J Gobbi FG . Human schistosomiasis. Lancet Lond Engl. (2025) 405:658–70. doi: 10.1016/S0140-6736(24)02814-9
3
WHO . Ending the Neglect to Attain the Sustainable Development Goals: A Road Map for Neglected Tropical Diseases 2021-2030. 1st ed. Geneva: World Health Organization (2021). p. 1.
4
King CH . Parasites and poverty: The case of schistosomiasis. Acta Trop. (2010) 113:95–104. doi: 10.1016/j.actatropica.2009.11.012
5
Masdor NA Kandayah T Amsah N Othman R Hassan MR Rahim SSSA et al . Systematic review with meta-analysis: Prevalence, risk factors, and challenges for urinary schistosomiasis in children (USC). PloS One. (2023) 18:e0285533. doi: 10.1371/journal.pone.0285533
6
Gazzinelli A Velasquez-Melendez G Crawford SB LoVerde PT Correa-Oliveira R Kloos H . Socioeconomic determinants of schistosomiasis in a poor rural area in Brazil. Acta Trop. (2006) 99:260–71. doi: 10.1016/j.actatropica.2006.09.001
7
Kouadio JN Giovanoli Evack J Sékré JBK Achi LY Ouattara M Hattendorf J et al . Prevalence and risk factors of schistosomiasis and hookworm infection in seasonal transmission settings in northern Côte d’Ivoire: A cross-sectional study. PloS Negl Trop Dis. (2023) 17:e0011487. doi: 10.1371/journal.pntd.0011487
8
Gruninger SK Rasamoelina T Rakotoarivelo RA Razafindrakoto AR Rasolojaona ZT Rakotozafy RM et al . Prevalence and risk distribution of schistosomiasis among adults in Madagascar: a cross-sectional study. Infect Dis Poverty. (2023) 12:44. doi: 10.1186/s40249-023-01094-z
9
Gomes DS de Oliveira BL Coelho PRS Mendonça Severino A de J de Oliveira NMT Thiengo SC et al . Mapping risk factors and spatial clusters of schistosomiasis mansoni in rural communities from Brazil: three cross-sectional studies between 2014 and 2022. Parasitol Int. (2026) 110:103145. doi: 10.1016/j.parint.2025.103145
10
Ndum NC Trippler L Mohammed UA Ali AS Hattendorf J Utzinger J et al . Capacities and needs of health care facilities for schistosomiasis diagnosis and management in elimination settings. Parasit Vectors. (2024) 17:263. doi: 10.1186/s13071-024-06311-8
11
Mazigo HD Uisso C Kazyoba P Mwingira UJ . Primary health care facilities capacity gaps regarding diagnosis, treatment and knowledge of schistosomiasis among healthcare workers in North-western Tanzania: a call to strengthen the horizontal system. BMC Health Serv Res. (2021) 21:529. doi: 10.1186/s12913-021-06531-z
12
Piotrowski H Oluwole A Fapohunda VO Adejobi JB Nebe OJ Soneye I et al . Mixed-methods evaluation of integrating female genital schistosomiasis management within primary healthcare: a pilot intervention in Ogun State, Nigeria. Int Health. (2023) 15:i18–29. doi: 10.1093/inthealth/ihac073
13
Kihumuro RB Atimango L Kintu TM Makai C Kanyike AM Bazira J . Exploring healthcare professionals’ perspectives on neglected tropical diseases in Eastern Uganda: a qualitative study with a focus on schistosomiasis and soil-transmitted helminths. Trans R Soc Trop Med Hyg. (2024) 118:781–9. doi: 10.1093/trstmh/trae043
14
Eastham G Fausnacht D Becker MH Gillen A Moore W . Praziquantel resistance in schistosomes: a brief report. Front Parasitol. (2024) 3:1471451. doi: 10.3389/fpara.2024.1471451
15
Wang W Wang L Liang YS . Susceptibility or resistance of praziquantel in human schistosomiasis: a review. Parasitol Res. (2012) 111:1871–7. doi: 10.1007/s00436-012-3151-z
16
Cotton JA Doyle SR . A genetic TRP down the channel to praziquantel resistance. Trends Parasitol. (2022) 38:351–2. doi: 10.1016/j.pt.2022.02.006
17
Woellner-Santos D Tahira AC Malvezzi JVM Mesel V Morales-Vicente DA Trentini MM et al . Schistosoma mansoni vaccine candidates identified by unbiased phage display screening in self-cured rhesus macaques. NPJ Vaccines. (2024) 9:5. doi: 10.1038/s41541-023-00803-x
18
Nogueira RA Lira MGS Licá ICL Frazão GCCG Dos Santos VAF Filho ACCM et al . Praziquantel: An update on the mechanism of its action against schistosomiasis and new therapeutic perspectives. Mol Biochem Parasitol. (2022) 252:111531. doi: 10.1016/j.molbiopara.2022.111531
19
LoVerde PT . Schistosomiasis. Adv Exp Med Biol. (2019) 1154:45–70. doi: 10.1007/978-3-030-18616-6_3
20
Nelwan ML . Schistosomiasis: life cycle, diagnosis, and control. Curr Ther Res Clin Exp. (2019) 91:5–9. doi: 10.1016/j.curtheres.2019.06.001
21
Araújo MI Hoppe BS Medeiros M Carvalho EM . Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases. Mem Inst Oswaldo Cruz. (2004) 99:27–32. doi: 10.1590/s0074-02762004000900005
22
Brink LH McLaren DJ Smithers SR . Schistosoma mansoni : a comparative study of artificially transformed schistosomula and schistomula recoverd after cercarial penetration of isolated skin. Parasitology. (1977) 74:73–86. doi: 10.1017/s0031182000047545
23
Crabtree JE Wilson RA . Schistosoma mansoni: an ultrastructural examination of pulmonary migration. Parasitology. (1986) 92:343–54. doi: 10.1017/S0031182000064118
24
Nation CS Da’dara AA Marchant JK Skelly PJ . Schistosome migration in the definitive host. PloS Negl Trop Dis. (2020) 14:e0007951. doi: 10.1371/journal.pntd.0007951
25
Hams E Aviello G Fallon PG . The schistosoma granuloma: friend or foe? Front Immunol. (2013) 4:89/abstract. doi: 10.3389/fimmu.2013.00089/abstract
26
Peterková K Konečný L Macháček T Jedličková L Winkelmann F Sombetzki M et al . Winners vs. losers: Schistosoma mansoni intestinal and liver eggs exhibit striking differences in gene expression and immunogenicity. PloS Pathog. (2024) 20:e1012268. doi: 10.1371/journal.ppat.1012268
27
Llanwarne F Helmby H . Granuloma formation and tissue pathology in Schistosoma japonicum versus Schistosoma mansoni infections. Parasite Immunol. (2021) 43:e12778. doi: 10.1111/pim.12778
28
Paveley RA Aynsley SA Cook PC Turner JD Mountford AP . Fluorescent imaging of antigen released by a skin-invading helminth reveals differential uptake and activation profiles by antigen presenting cells. PloS Negl Trop Dis. (2009) 3:e528. doi: 10.1371/journal.pntd.0000528
29
Hansell E Braschi S Medzihradszky KF Sajid M Debnath M Ingram J et al . Proteomic analysis of skin invasion by blood fluke larvae. PloS Negl Trop Dis. (2008) 2:e262. doi: 10.1371/journal.pntd.0000262
30
Ingram JR Rafi SB Eroy-Reveles AA Ray M Lambeth L Hsieh I et al . Investigation of the proteolytic functions of an expanded cercarial elastase gene family in Schistosoma mansoni. PloS Negl Trop Dis. (2012) 6:e1589. doi: 10.1371/journal.pntd.0001589
31
Dvorák J Mashiyama ST Braschi S Sajid M Knudsen GM Hansell E et al . Differential use of protease families for invasion by schistosome cercariae. Biochimie. (2008) 90:345–58. doi: 10.1016/j.biochi.2007.08.013
32
Zhu B Luo F Shen Y Yang W Sun C Wang J et al . Schistosoma japonicum cathepsin B2 (SjCB2) facilitates parasite invasion through the skin. PloS Negl Trop Dis. (2020) 14:e0008810. doi: 10.1371/journal.pntd.0008810
33
Da’dara AA Krautz-Peterson G . New insights into the reaction of Schistosoma mansoni cercaria to the human complement system. Parasitol Res. (2014) 113:3685–96. doi: 10.1007/s00436-014-4033-3
34
Wang W Kirschfink M Ruppel A . Schistosoma japonicum and S. mansoni cercariae: different effects of protein in medium, of mechanical stress, and of an intact complement system on in vitro transformation to schistosomula. Parasitol Res. (2006) 99:269–74. doi: 10.1007/s00436-006-0150-y
35
Inclan-Rico JM Napuri CM Lin C Hung LY Ferguson AA Liu X et al . MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33. Nat Immunol. (2024) 25:2068–84. doi: 10.1038/s41590-024-01982-y
36
Inclan-Rico JM Stephenson A Napuri CM Rossi HL Hung LY Pastore CF et al . TRPV1+ neurons promote cutaneous immunity against Schistosoma mansoni. Immunology. (2025) 214:2700–2714. doi: 10.1101/2025.02.06.636930
37
Redpath SA Fonseca NM Perona-Wright G . Protection and pathology during parasite infection: IL -10 strikes the balance. Parasite Immunol. (2014) 36:233–52. doi: 10.1111/pim.12113
38
Turner JD Meurs L Dool P Bourke CD Mbow M Dièye TN et al . Schistosome infection is associated with enhanced whole-blood IL -10 secretion in response to cercarial excretory/secretory products. Parasite Immunol. (2013) 35:147–56. doi: 10.1111/pim.12028
39
Winkel BMF Dalenberg MR De Korne CM Feijt C Langenberg MCC Pelgrom L et al . Early induction of human regulatory dermal antigen presenting cells by skin-penetrating schistosoma mansoni cercariae. Front Immunol. (2018) 9:2510. doi: 10.3389/fimmu.2018.02510
40
Ramaswamy K Kumar P He YX . A role for parasite-induced PGE2 in IL-10-mediated host immunoregulation by skin stage schistosomula of Schistosoma mansoni. J Immunol. (2000) 165:4567–74. doi: 10.4049/jimmunol.165.8.4567
41
Prendergast CT Sanin DE Cook PC Mountford AP . CD4+ T Cell Hyporesponsiveness after Repeated Exposure to Schistosoma mansoni Larvae Is Dependent upon Interleukin-10. Infect Immun. (2015) 83:1418–30. doi: 10.1128/IAI.02831-14
42
Sanin DE Prendergast CT Bourke CD Mountford AP . Helminth infection and commensal microbiota drive early IL-10 production in the skin by CD4+ T cells that are functionally suppressive. PloS Pathog. (2015) 11:e1004841. doi: 10.1371/journal.ppat.1004841
43
Chen L Rao KVN He YX Ramaswamy K . Skin-stage schistosomula of schistosoma mansoni produce an apoptosis-inducing factor that can cause apoptosis of T cells. J Biol Chem. (2002) 277:34329–35. doi: 10.1074/jbc.M201344200
44
Hervé M Angeli V Pinzar E Wintjens R Faveeuw C Narumiya S et al . Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion. Eur J Immunol. (2003) 33:2764–72. doi: 10.1002/eji.200324143
45
Angeli V Faveeuw C Roye O Fontaine J Teissier E Capron A et al . Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal langerhans cell migration during schistosomiasis infection. J Exp Med. (2001) 193:1135–48. doi: 10.1084/jem.193.10.1135
46
Paveley RA Aynsley SA Turner JD Bourke CD Jenkins SJ Cook PC et al . The Mannose Receptor (CD206) is an important pattern recognition receptor (PRR) in the detection of the infective stage of the helminth Schistosoma mansoni and modulates IFNγ production. Int J Parasitol. (2011) 41:1335–45. doi: 10.1016/j.ijpara.2011.08.005
47
Shiels J Cwiklinski K Alvarado R Thivierge K Cotton S Gonzales Santana B et al . Schistosoma mansoni immunomodulatory molecule Sm16/SPO-1/SmSLP is a member of the trematode-specific helminth defence molecules (HDMs). PloS Negl Trop Dis. (2020) 14:e0008470. doi: 10.1371/journal.pntd.0008470
48
Sanin DE Mountford AP . Sm16, a major component of Schistosoma mansoni cercarial excretory/secretory products, prevents macrophage classical activation and delays antigen processing. Parasit Vectors. (2015) 8:1. doi: 10.1186/s13071-014-0608-1
49
Meyer S Van Liempt E Imberty A Van Kooyk Y Geyer H Geyer R et al . DC-SIGN mediates binding of dendritic cells to authentic pseudo-lewisY glycolipids of schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J Biol Chem. (2005) 280:37349–59. doi: 10.1074/jbc.M507100200
50
Jenkins SJ Mountford AP . Dendritic cells activated with products released by schistosome larvae drive th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation. Infect Immun. (2005) 73:395–402. doi: 10.1128/IAI.73.1.395-402.2005
51
Cook PC Aynsley SA Turner JD Jenkins GR Van Rooijen N Leeto M et al . Multiple helminth infection of the skin causes lymphocyte hypo-responsiveness mediated by th2 conditioning of dermal myeloid cells. PloS Pathog. (2011) 7:e1001323. doi: 10.1371/journal.ppat.1001323
52
Iriarte C Marks DH . Cutaneous schistosomiasis: epidemiological and clinical characteristics in returning travelers. Int J Dermatol. (2023) 62:376–86. doi: 10.1111/ijd.16389
53
Macháček T Turjanicová L Bulantová J Hrdý J Horák P Mikeš L . Cercarial dermatitis: a systematic follow-up study of human cases with implications for diagnostics. Parasitol Res. (2018) 117:3881–95. doi: 10.1007/s00436-018-6095-0
54
Burke ML McGarvey L McSorley HJ Bielefeldt-Ohmann H McManus DP Gobert GN . Migrating Schistosoma japonicum schistosomula induce an innate immune response and wound healing in the murine lung. Mol Immunol. (2011) 49:191–200. doi: 10.1016/j.molimm.2011.08.014
55
Amer EI El-Azzouni MZ El-Bannan RT Shalaby TI El-Achy SN Gomaa MM . Schistosomiasis mansoni: A new therapeutic target for ubiquinol, a natural inhibitor of neutral magnesium-dependent sphingomyelinase in murine model. Acta Trop. (2022) 226:106231. doi: 10.1016/j.actatropica.2021.106231
56
Xu L Liu Q Zeng Q Wu P Yu Q Gu K et al . Radicicol, a Novel Lead Compound against the Migratory-Stage Schistosomula of Schistosoma japonicum. Antimicrob Agents Chemother. (2021) 65:e01781–20. doi: 10.1128/AAC.01781-20
57
Nowacki FC Swain MT Klychnikov OI Niazi U Ivens A Quintana JF et al . Protein and small non-coding RNA-enriched extracellular vesicles are released by the pathogenic blood fluke Schistosoma mansoni. J Extracell Vesicles. (2015) 4:28665. doi: 10.3402/jev.v4.28665
58
Cao X Fu Z Zhang M Han Y Han Q Lu K et al . Excretory/secretory proteome of 14-day schistosomula, Schistosoma japonicum. J Proteomics. (2016) 130:221–30. doi: 10.1016/j.jprot.2015.10.001
59
Egesa M Lubyayi L Tukahebwa EM Bagaya BS Chalmers IW Wilson S et al . Schistosoma mansoni schistosomula antigens induce Th1/Pro-inflammatory cytokine responses. Parasite Immunol. (2018) 40:e12592. doi: 10.1111/pim.12592
60
El Ridi R Tallima H . Schistosoma mansoni ex vivo lung-stage larvae excretory-secretory antigens as vaccine candidates against schistosomiasis. Vaccine. (2009) 27:666–73. doi: 10.1016/j.vaccine.2008.11.039
61
Faveeuw C Mallevaey T Paschinger K Wilson IBH Fontaine J Mollicone R et al . Schistosome N-glycans containing core alpha 3-fucose and core beta 2-xylose epitopes are strong inducers of Th2 responses in mice. Eur J Immunol. (2003) 33:1271–81. doi: 10.1002/eji.200323717
62
Afifi MA El-Wakil HSI Abdel-Ghaffar MM Mohamed RT . Application of adult worm and lung-stage antigens to immunize against Schistosoma mansoni using cytokines as adjuvants. J Egypt Soc Parasitol. (2006) 36:351–62.
63
de Oliveira Fraga LA Lamb EW Moreno EC Chatterjee M Dvořák J Delcroix M et al . Rapid induction of IgE responses to a worm cysteine protease during murine pre-patent schistosome infection. BMC Immunol. (2010) 11:56. doi: 10.1186/1471-2172-11-56
64
Aly R Acharya R Upadhyay KK . Severe hypertriglyceridemia in an infant on chronic hemodialysis. Hemodialysis Int. (2023) 27:E1–4. doi: 10.1111/hdi.13049
65
Sotillo J Pearson M Becker L Mulvenna J Loukas A . A quantitative proteomic analysis of the tegumental proteins from Schistosoma mansoni schistosomula reveals novel potential therapeutic targets. Int J Parasitol. (2015) 45:505–16. doi: 10.1016/j.ijpara.2015.03.004
66
Wuhrer M Dennis RD Doenhoff MJ Bickle Q Lochnit G Geyer R . Immunochemical characterisation of Schistosoma mansoni glycolipid antigens. Mol Biochem Parasitol. (1999) 103:155–69. doi: 10.1016/S0166-6851(99)00123-1
67
Smit CH van Diepen A Nguyen DL Wuhrer M Hoffmann KF Deelder AM et al . Glycomic analysis of life stages of the human parasite schistosoma mansoni reveals developmental expression profiles of functional and antigenic glycan motifs. Mol Cell Proteomics MCP. (2015) 14:1750–69. doi: 10.1074/mcp.M115.048280
68
Smit CH Kies CL McWilliam HEG Meeusen ENT Hokke CH Van Diepen A . Local antiglycan antibody responses to skin stage and migratory schistosomula of schistosoma japonicum. Infect Immun. (2016) 84:21–33. doi: 10.1128/IAI.00954-15
69
Cha H Xie H Jin C Feng Y Xie S Xie A et al . Adjustments of γδ T cells in the lung of schistosoma japonicum-infected C56BL/6 mice. Front Immunol. (2020) 11:1045. doi: 10.3389/fimmu.2020.01045
70
Kuipers ME Nguyen DL van Diepen A Mes L Bos E Koning RI et al . Life stage-specific glycosylation of extracellular vesicles from Schistosoma mansoni schistosomula and adult worms drives differential interaction with C-type lectin receptors DC-SIGN and MGL. Front Mol Biosci. (2023) 10:1125438. doi: 10.3389/fmolb.2023.1125438
71
Kuipers ME Nolte-’t Hoen ENM van der Ham AJ Ozir-Fazalalikhan A Nguyen DL de Korne CM et al . DC-SIGN mediated internalisation of glycosylated extracellular vesicles from Schistosoma mansoni increases activation of monocyte-derived dendritic cells. J Extracell Vesicles. (2020) 9:1753420. doi: 10.1080/20013078.2020.1753420
72
Teixeira de Melo T Michel de Araujo J Do Valle Durães F Caliari MV Oliveira SC Coelho PMZ et al . Immunization with newly transformed Schistosoma mansoni schistosomula tegument elicits tegument damage, reduction in egg and parasite burden. Parasite Immunol. (2010) 32:749–59. doi: 10.1111/j.1365-3024.2010.01244.x
73
Angeli V Faveeuw C Delerive P Fontaine J Barriera Y Franchimont N et al . Schistosoma mansoni induces the synthesis of IL-6 in pulmonary microvascular endothelial cells: role of IL-6 in the control of lung eosinophilia during infection. Eur J Immunol. (2001) 31:2751–61. doi: 10.1002/1521-4141(200109)31:9<2751::AID-IMMU2751>3.0.CO;2-4
74
Marinho FV Alves CC De Souza SC Da Silva CMG Cassali GD Oliveira SC et al . Schistosoma mansoni tegument (Smteg) induces IL-10 and modulates experimental airway inflammation. PloS One. (2016) 11:e0160118. doi: 10.1371/journal.pone.0160118
75
Li Z Zhang W Luo F Li J Yang W Zhu B et al . Allergen-specific treg cells upregulated by lung-stage S. japonicum infection alleviates allergic airway inflammation. Front Cell Dev Biol. (2021) 9:678377. doi: 10.3389/fcell.2021.678377
76
Tallima H El Ridi R . Methyl-beta-Cyclodextrin treatment and filipin staining reveal the role of cholesterol in surface membrane antigen sequestration of Schistosoma mansoni and S. haematobium lung-stage larvae. J Parasitol. (2005) 91:720–5. doi: 10.1645/GE-439R
77
El Ridi R Tallima H . Equilibrium in lung schistosomula sphingomyelin breakdown and biosynthesis allows very small molecules, but not antibody, to access proteins at the host-parasite interface. J Parasitol. (2006) 92:730–7. doi: 10.1645/GE-745R1.1
78
Xiao S Shen B Chollet J Utzinger J Tanner M . Tegumental alterations in juvenile Schistosoma haematobium harboured in hamsters following artemether treatment. Parasitol Int. (2001) 50:175–83. doi: 10.1016/S1383-5769(01)00076-9
79
van Beek AE Jeanguenat H Häberli C Pouw RB Lamers C Pál G et al . Praziquantel and factor H recruitment differentially affect the susceptibility of Schistosoma mansoni to complement-mediated damage. Front Immunol. (2024) 15:1474358. doi: 10.3389/fimmu.2024.1474358
80
Karmakar S Zhang W Ahmad G Alam MU Winn R Torben W et al . Complement plays a minimal role in Sm-p80-mediated protection against Schistosoma mansoni. Hum Vaccines Immunother. (2014) 10:640–7. doi: 10.4161/hv.27576
81
Migliardo F Tallima H El Ridi R . Is there a sphingomyelin-based hydrogen bond barrier at the mammalian host-schistosome parasite interface? Cell Biochem Biophys. (2014) 68:359–67. doi: 10.1007/s12013-013-9716-3
82
Migliardo F Tallima H El Ridi R . Rigidity and resistance of larval- and adult schistosomes-medium interface. Biochem Biophys Res Commun. (2014) 446:255–60. doi: 10.1016/j.bbrc.2014.02.100
83
Elzoheiry M Da’dara AA Nation CS El-Beshbishi SN Skelly PJ . Schistosomes can hydrolyze proinflammatory and prothrombotic polyphosphate (polyP) via tegumental alkaline phosphatase, SmAP. Mol Biochem Parasitol. (2019) :232:111190. doi: 10.1016/j.molbiopara.2019.111190
84
Elzoheiry M Da’dara AA Bhardwaj R Wang Q Azab MS El-Kholy ESI et al . Intravascular Schistosoma mansoni Cleave the Host Immune and Hemostatic Signaling Molecule Sphingosine-1-Phosphate via Tegumental Alkaline Phosphatase. Front Immunol. (2018) 9:1746. doi: 10.3389/fimmu.2018.01746
85
Ranasinghe SL Fischer K Gobert GN McManus DP . Functional expression of a novel Kunitz type protease inhibitor from the human blood fluke Schistosoma mansoni. Parasit Vectors. (2015) 8:408. doi: 10.1186/s13071-015-1022-z
86
Inal JM Schifferli JA . Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2. J Immunol Baltim Md 1950. (2002) 168:5213–21. doi: 10.4049/jimmunol.168.10.5213
87
Neves LX Sanson AL Wilson RA Castro-Borges W . What’s in SWAP? Abundance of the principal constituents in a soluble extract of Schistosoma mansoni revealed by shotgun proteomics. Parasit Vectors. (2015) 8:337. doi: 10.1186/s13071-015-0943-x
88
Sepulveda J Tremblay JM DeGnore JP Skelly PJ Shoemaker CB . Schistosoma mansoni host-exposed surface antigens characterized by sera and recombinant antibodies from schistosomiasis-resistant rats. Int J Parasitol. (2010) 40:1407–17. doi: 10.1016/j.ijpara.2010.04.019
89
Zeng T Cai L Zeng Q Yang S Yu R Li Y et al . Immunization of mice with cells from juvenile worms of Schistosoma japonicum provides immunoprotection against schistosomiasis. Sci China C Life Sci. (2007) 50:822–30. doi: 10.1007/s11427-007-0100-7
90
El-Faham MH Eissa MM Igetei JE Amer EI Liddell S El-Azzouni MZ et al . Treatment of Schistosoma mansoni with miltefosine in vitro enhances serological recognition of defined worm surface antigens. PloS Negl Trop Dis. (2017) 11:e0005853. doi: 10.1371/journal.pntd.0005853
91
Joseph S Jones FM Walter K Fulford AJ Kimani G Mwatha JK et al . Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel. J Infect Dis. (2004) 190:835–42. doi: 10.1086/422604
92
Zhang W Li J Duke M Jones MK Kuang L Zhang J et al . Inconsistent protective efficacy and marked polymorphism limits the value of Schistosoma japonicum tetraspanin-2 as a vaccine target. PloS Negl Trop Dis. (2011) 5:e1166. doi: 10.1371/journal.pntd.0001166
93
Cai P Bu L Wang J Wang Z Zhong X Wang H . Molecular characterization of Schistosoma japonicum tegument protein tetraspanin-2: sequence variation and possible implications for immune evasion. Biochem Biophys Res Commun. (2008) 372:197–202. doi: 10.1016/j.bbrc.2008.05.042
94
Zhang M Hong Y Han Y Han H Peng J Qiu C et al . Proteomic analysis of tegument-exposed proteins of female and male Schistosoma japonicum worms. J Proteome Res. (2013) 12:5260–70. doi: 10.1021/pr400476a
95
Reamtong O Simanon N Thiangtrongjit T Limpanont Y Chusongsang P Chusongsang Y et al . Proteomic analysis of adult Schistosoma mekongi somatic and excretory-secretory proteins. Acta Trop. (2020) 202:105247. doi: 10.1016/j.actatropica.2019.105247
96
Kenney ET Mann VH Ittiprasert W Rosa BA Mitreva M Bracken BK et al . Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke, schistosoma mansoni. Front Parasitol. (2022) 1:950744. doi: 10.3389/fpara.2022.950744
97
Gobert GN Stenzel DJ McManus DP Jones MK . The ultrastructural architecture of the adult Schistosoma japonicum tegument. Int J Parasitol. (2003) 33:1561–75. doi: 10.1016/S0020-7519(03)00255-8
98
Krautz-Peterson G Debatis M Tremblay JM Oliveira SC Da’dara AA Skelly PJ et al . Schistosoma mansoni infection of mice, rats and humans elicits a strong antibody response to a limited number of reduction-sensitive epitopes on five major tegumental membrane proteins. PloS Negl Trop Dis. (2017) 11:e0005306. doi: 10.1371/journal.pntd.0005306
99
Cardoso FC Macedo GC Gava E Kitten GT Mati VL De Melo AL et al . Schistosoma mansoni Tegument Protein Sm29 Is Able to Induce a Th1-Type of Immune Response and Protection against Parasite Infection. PloS Negl Trop Dis. (2008) 2:e308. doi: 10.1371/journal.pntd.0000308
100
Ranasinghe SL Duke M Harvie M McManus DP . Kunitz-type protease inhibitor as a vaccine candidate against schistosomiasis mansoni. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. (2018) 66:26–32. doi: 10.1016/j.ijid.2017.10.024
101
Karmakar S Zhang W Ahmad G Torben W Alam MU Le L et al . Use of an Sm-p80-based therapeutic vaccine to kill established adult schistosome parasites in chronically infected baboons. J Infect Dis. (2014) 209:1929–40. doi: 10.1093/infdis/jiu031
102
Mansour JM McCrossan MV Bickle QD Mansour TE . Schistosoma mansoni phosphofructokinase: immunolocalization in the tegument and immunogenicity. Parasitology. (2000) 120:501–11. doi: 10.1017/S0031182099005648
103
Farias LP Cardoso FC Miyasato PA Montoya BO Tararam CA Roffato HK et al . Schistosoma mansoni Stomatin like protein-2 is located in the tegument and induces partial protection against challenge infection. PloS Negl Trop Dis. (2010) 4:e597. doi: 10.1371/journal.pntd.0000597
104
Piao X Wang Y Jiang N Cai P Duan J Liu S et al . Schistosoma japonicum cathepsin L1: A potential target for anti-schistosomiasis strategies. PloS Negl Trop Dis. (2025) 19:e0013241. doi: 10.1371/journal.pntd.0013241
105
Griffith Q Liang Y Whitworth P Rodriguez-Russo C Gul A Siddiqui AA et al . Immuno-evasive tactics by schistosomes identify an effective allergy preventative. Exp Parasitol. (2015) 153:139–50. doi: 10.1016/j.exppara.2015.03.012
106
Walter K Fulford AJC McBeath R Joseph S Jones FM Kariuki HC et al . Increased human IgE induced by killing Schistosoma mansoni in vivo is associated with pretreatment Th2 cytokine responsiveness to worm antigens. J Immunol Baltim Md 1950. (2006) 177:5490–8. doi: 10.4049/jimmunol.177.8.5490
107
Booth M Shaw MA Carpenter D Joseph S Kabatereine NB Kariuki HC et al . Carriage of DRB1*13 is associated with increased posttreatment IgE levels against Schistosoma mansoni antigens and lower long-term reinfection levels. J Immunol Baltim Md 1950. (2006) 176:7112–8. doi: 10.4049/jimmunol.176.11.7112
108
Leenstra T Acosta LP Wu HW Langdon GC Solomon JS Manalo DL et al . T-helper-2 cytokine responses to Sj97 predict resistance to reinfection with Schistosoma japonicum. Infect Immun. (2006) 74:370–81. doi: 10.1128/IAI.74.1.370-381.2006
109
Wilson S Jones FM Fofana HKM Doucouré A Landouré A Kimani G et al . Rapidly boosted Plasma IL-5 induced by treatment of human Schistosomiasis haematobium is dependent on antigen dose, IgE and eosinophils. PloS Negl Trop Dis. (2013) 7:e2149. doi: 10.1371/journal.pntd.0002149
110
Tweyongyere R Namanya H Naniima P Cose S Tukahebwa EM Elliott AM et al . Human eosinophils modulate peripheral blood mononuclear cell response to Schistosoma mansoni adult worm antigen in vitro. Parasite Immunol. (2016) 38:516–22. doi: 10.1111/pim.12336
111
Wilson MS Cheever AW White SD Thompson RW Wynn TA . IL-10 blocks the development of resistance to re-infection with schistosoma mansoni. PloS Pathog. (2011) 7:e1002171. doi: 10.1371/journal.ppat.1002171
112
Sadler CH Rutitzky LI Stadecker MJ Wilson RA . IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur J Immunol. (2003) 33:880–8. doi: 10.1002/eji.200323501
113
Resende SD Magalhães FC Rodrigues-Oliveira JL Castro VN Souza CSA Oliveira EJ et al . Modulation of allergic reactivity in humans is dependent on schistosoma mansoni parasite burden, low levels of IL-33 or TNF-α and high levels of IL-10 in serum. Front Immunol. (2018) 9:3158. doi: 10.3389/fimmu.2018.03158
114
Van Der Vlugt LEPM Labuda LA Ozir-Fazalalikhan A Lievers E Gloudemans AK Liu KY et al . Schistosomes induce regulatory features in human and mouse CD1dhi B cells: inhibition of allergic inflammation by IL-10 and regulatory T cells. PloS One. (2012) 7:e30883. doi: 10.1371/journal.pone.0030883
115
Koopman JPR Houlder EL Janse JJ Casacuberta-Partal M Lamers OAC Sijtsma JC et al . Safety and infectivity of female cercariae in Schistosoma-naïve, healthy participants: a controlled human Schistosoma mansoni infection study. EBioMedicine. (2023) 97:104832. doi: 10.1016/j.ebiom.2023.104832
116
Langenberg MCC Hoogerwerf MA Koopman JPR Janse JJ Kos-van Oosterhoud J Feijt C et al . A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics. Nat Med. (2020) 26:326–32. doi: 10.1038/s41591-020-0759-x
117
Sombetzki M Reinholdt C Winkelmann F Rabes A Koslowski N Reisinger EC . A one-year unisexual Schistosoma mansoni infection causes pathologic organ alterations and persistent non-polarized T cell-mediated inflammation in mice. Front Immunol. (2022) 13:1010932. doi: 10.3389/fimmu.2022.1010932
118
Sombetzki M Koslowski N Rabes A Seneberg S Winkelmann F Fritzsche C et al . Host defense versus immunosuppression: unisexual infection with male or female schistosoma mansoni differentially impacts the immune response against invading cercariae. Front Immunol. (2018) 9:861. doi: 10.3389/fimmu.2018.00861
119
Sombetzki M Rabes A Bischofsberger M Winkelmann F Koslowski N Schulz C et al . Preventive CTLA-4-ig treatment reduces hepatic egg load and hepatic fibrosis in Schistosoma mansoni -infected mice. BioMed Res Int. (2019) 2019:1–11. doi: 10.1155/2019/1704238
120
Everts B Adegnika AA Kruize YCM Smits HH Kremsner PG Yazdanbakhsh M . Functional impairment of human myeloid dendritic cells during Schistosoma haematobium infection. PloS Negl Trop Dis. (2010) 4:e667. doi: 10.1371/journal.pntd.0000667
121
van den Biggelaar AHJ Grogan JL Filié Y Jordens R Kremsner PG Koning F et al . Chronic schistosomiasis: dendritic cells generated from patients can overcome antigen-specific T cell hyporesponsiveness. J Infect Dis. (2000) 182:260–5. doi: 10.1086/315662
122
van der Kleij D Latz E Brouwers JFHM Kruize YCM Schmitz M Kurt-Jones EA et al . A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J Biol Chem. (2002) 277:48122–9. doi: 10.1074/jbc.M206941200
123
Floudas A Cluxton CD Fahel J Khan AR Saunders SP Amu S et al . Composition of the Schistosoma mansoni worm secretome: Identification of immune modulatory Cyclophilin A. PloS Negl Trop Dis. (2017) 11:e0006012. doi: 10.1371/journal.pntd.0006012
124
Chen L He B Hou W He L . Cysteine protease inhibitor of Schistosoma japonicum - A parasite-derived negative immunoregulatory factor. Parasitol Res. (2017) 116:901–8. doi: 10.1007/s00436-016-5363-0
125
Assunção LS Magalhães KG Carneiro AB Molinaro R Almeida PE Atella GC et al . Schistosomal-derived lysophosphatidylcholine triggers M2 polarization of macrophages through PPARγ dependent mechanisms. Biochim Biophys Acta BBA - Mol Cell Biol Lipids. (2017) 1862:246–54. doi: 10.1016/j.bbalip.2016.11.006
126
Skelly PJ Da’dara AA . Generation of immune modulating small metabolites—Metabokines—By adult schistosomes. Pathogens. (2025) 14:526. doi: 10.3390/pathogens14060526
127
Schwartz C Fallon PG . Schistosoma ‘Eggs-iting’ the host: granuloma formation and egg excretion. Front Immunol. (2018) 9:2492. doi: 10.3389/fimmu.2018.02492
128
Silva TD Gonçalves-Santos E Gonçalves RV Souza RLM Caetano JE Caldas IS et al . Matrix metalloproteinases inhibition reveals the association between inflammation, collagen accumulation and intestinal translocation of Schistosoma mansoni eggs in vivo. Int Immunopharmacol. (2024) 127:111353. doi: 10.1016/j.intimp.2023.111353
129
Karanja DMS Colley DG Nahlen BL Ouma JH Secor WE . Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with schistosoma mansoni and human immunodeficiency virus coinfections. Am J Trop Med Hyg. (1997) 56:515–21. doi: 10.4269/ajtmh.1997.56.515
130
Takaki KK Rinaldi G Berriman M Pagán AJ Ramakrishnan L . Schistosoma mansoni eggs modulate the timing of granuloma formation to promote transmission. Cell Host Microbe. (2021) 29:58–67. doi: 10.1016/j.chom.2020.10.002
131
Zhu J Xu Z Chen X Zhou S Zhang W Chi Y et al . Parasitic antigens alter macrophage polarization during Schistosoma japonicum infection in mice. Parasit Vectors. (2014) 7:122. doi: 10.1186/1756-3305-7-122
132
Xu J Zhang H Chen L Zhang D Ji M Wu H et al . Schistosoma japonicum infection induces macrophage polarization. J BioMed Res. (2014) 28:299–308. doi: 10.7555/JBR.27.20130072
133
Hoffmann KF Cheever AW Wynn TA . IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol Baltim Md 1950. (2000) 164:6406–16. doi: 10.4049/jimmunol.164.12.6406
134
Rutitzky LI Hernandez HJ Stadecker MJ . Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc Natl Acad Sci. (2001) 98:13243–8. doi: 10.1073/pnas.231258498
135
Pearce EJ MacDonald AS . The immunobiology of schistosomiasis. Nat Rev Immunol. (2002) 2:499–511. doi: 10.1038/nri843
136
Wynn TA Eltoum I Oswald IP Cheever AW Sher A . Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. (1994) 179:1551–61. doi: 10.1084/jem.179.5.1551
137
Costain AH Phythian-Adams AT Colombo SAP Marley AK Owusu C Cook PC et al . Dynamics of host immune response development during Schistosoma mansoni infection. Front Immunol. (2022) 13:906338. doi: 10.3389/fimmu.2022.906338
138
Lundy SK Lerman SP Boros DL . Soluble egg antigen-stimulated T helper lymphocyte apoptosis and evidence for cell death mediated by FasL(+) T and B cells during murine Schistosoma mansoni infection. Infect Immun. (2001) 69:271–80. doi: 10.1128/IAI.69.1.271-280.2001
139
Kane CM Cervi L Sun J McKee AS Masek KS Shapira S et al . Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol Baltim Md 1950. (2004) 173:7454–61. doi: 10.4049/jimmunol.173.12.7454
140
Van der Kleij D Van Remoortere A Schuitemaker JHN Kapsenberg ML Deelder AM Tielens AGM et al . Triggering of innate immune responses by schistosome egg glycolipids and their carbohydrate epitope GalNAc beta 1-4(Fuc alpha 1-2Fuc alpha 1-3)GlcNAc. J Infect Dis. (2002) 185:531–9. doi: 10.1086/338574
141
Schramm G Gronow A Knobloch J Wippersteg V Grevelding CG Galle J et al . IPSE/alpha-1: a major immunogenic component secreted from Schistosoma mansoni eggs. Mol Biochem Parasitol. (2006) 147:9–19. doi: 10.1016/j.molbiopara.2006.01.003
142
Everts B Perona-Wright G Smits HH Hokke CH van der Ham AJ Fitzsimmons CM et al . Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J Exp Med. (2009) 206:1673–80. doi: 10.1084/jem.20082460
143
Kuijk LM Klaver EJ Kooij G van der Pol SMA Heijnen P Bruijns SCM et al . Soluble helminth products suppress clinical signs in murine experimental autoimmune encephalomyelitis and differentially modulate human dendritic cell activation. Mol Immunol. (2012) 51:210–8. doi: 10.1016/j.molimm.2012.03.020
144
Almeida L van Roey R Patente TA Otto F Veldhuizen T Ghorasaini M et al . High-mannose glycans from Schistosoma mansoni eggs are important for priming of Th2 responses via Dectin-2 and prostaglandin E2. Front Immunol. (2024) 15:1372927. doi: 10.3389/fimmu.2024.1372927
145
Mukendi JPK Nakamura R Uematsu S Hamano S . Interleukin (IL)-33 is dispensable for Schistosoma mansoni worm maturation and the maintenance of egg-induced pathology in intestines of infected mice. Parasit Vectors. (2021) 14:70. doi: 10.1186/s13071-020-04561-w
146
McKee AS MacLeod M White J Crawford F Kappler JW Marrack P . Gr1+IL-4-producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses. Int Immunol. (2008) 20:659–69. doi: 10.1093/intimm/dxn025
147
Haeberlein S Obieglo K Ozir-Fazalalikhan A Chayé MAM Veninga H van der Vlugt LEPM et al . Schistosome egg antigens, including the glycoprotein IPSE/alpha-1, trigger the development of regulatory B cells. PloS Pathog. (2017) 13:e1006539. doi: 10.1371/journal.ppat.1006539
148
Liao Y Zhu Z Liu Y Wu J Li D Li Z et al . Schistosome egg-derived extracellular vesicles deliver Sja-miR-71a inhibits host macrophage and neutrophil extracellular traps via targeting Sema4D. Cell Commun Signal CCS. (2023) 21:366. doi: 10.1186/s12964-023-01395-8
149
Wang B Liang S Wang Y Zhu XQ Gong W Zhang HQ et al . Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSL KO mice. PloS Negl Trop Dis. (2015) 9:e0003434. doi: 10.1371/journal.pntd.0003434
150
Sertorio M Hou X Carmo RF Dessein H Cabantous S Abdelwahed M et al . IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections. Hepatol Baltim Md. (2015) 61:1321–31. doi: 10.1002/hep.27629
151
Scopelliti F Cattani C Gimmelli R Dimartino V Lalli C Papoff G et al . Profiling of human IL-22+ T cell clones from patients affected with Schistosoma mansoni: Insights into macrophage regulation and liver fibrosis. PloS Negl Trop Dis. (2025) 19:e0013132. doi: 10.1371/journal.pntd.0013132
152
Friedman SL . Mechanisms of hepatic fibrogenesis. Gastroenterology. (2008) 134:1655–69. doi: 10.1053/j.gastro.2008.03.003
153
Cheever AW Williams ME Wynn TA Finkelman FD Seder RA Cox TM et al . Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol. (1994) 153:753–9. doi: 10.4049/jimmunol.153.2.753
154
Barner M Mohrs M Brombacher F Kopf M . Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr Biol CB. (1998) 8:669–72. doi: 10.1016/s0960-9822(98)70256-8
155
Chiaramonte M . Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. (2001) 34:273–82. doi: 10.1053/jhep.2001.26376
156
Fallon PG Richardson EJ McKenzie GJ McKenzie AN . Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol Baltim Md 1950. (2000) 164:2585–91. doi: 10.4049/jimmunol.164.5.2585
157
Turner JD Jenkins GR Hogg KG Aynsley SA Paveley RA Cook PC et al . CD4+CD25+ regulatory cells contribute to the regulation of colonic Th2 granulomatous pathology caused by schistosome infection. PloS Negl Trop Dis. (2011) 5:e1269. doi: 10.1371/journal.pntd.0001269
158
Maestas DR Chung L Han J Wang X Sommerfeld SD Kelly SH et al . Helminth egg derivatives as proregenerative immunotherapies. Proc Natl Acad Sci U S A. (2023) 120:e2211703120. doi: 10.1073/pnas.2211703120
159
Wang L Yu Z Wan S Wu F Chen W Zhang B et al . Exosomes derived from dendritic cells treated with schistosoma japonicum soluble egg antigen attenuate DSS-induced colitis. Front Pharmacol. (2017) 8:651. doi: 10.3389/fphar.2017.00651
160
Hasby EA Hasby Saad MA Shohieb Z El Noby K . FoxP3+ T regulatory cells and immunomodulation after Schistosoma mansoni egg antigen immunization in experimental model of inflammatory bowel disease. Cell Immunol. (2015) 295:67–76. doi: 10.1016/j.cellimm.2015.02.013
161
La Flamme AC Canagasabey K Harvie M Bäckström BT . Schistosomiasis protects against multiple sclerosis. Mem Inst Oswaldo Cruz. (2004) 99:33–6. doi: 10.1590/s0074-02762004000900006
162
Liu F Cheng W Pappoe F Hu X Wen H Luo Q et al . Schistosoma japonicum cystatin attenuates murine collagen-induced arthritis. Parasitol Res. (2016) 115:3795–806. doi: 10.1007/s00436-016-5140-0
163
Osada Y Shimizu S Kumagai T Yamada S Kanazawa T . Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators. Int J Parasitol. (2009) 39:457–64. doi: 10.1016/j.ijpara.2008.08.007
164
Song X Shen J Wen H Zhong Z Luo Q Chu D et al . Impact of Schistosoma japonicum infection on collagen-induced arthritis in DBA/1 mice: a murine model of human rheumatoid arthritis. PloS One. (2011) 6:e23453. doi: 10.1371/journal.pone.0023453
165
Tang CL Yu XH Li Y Zhang RH Xie J Liu ZM . Schistosoma japonicum Soluble Egg Antigen Protects Against Type 2 Diabetes in Lepr db/db Mice by Enhancing Regulatory T Cells and Th2 Cytokines. Front Immunol. (2019) 10:1471. doi: 10.3389/fimmu.2019.01471
166
Tang CL Gao YR Wang LX Zhu YW Pan Q Zhang RH et al . Role of regulatory T cells in Schistosoma-mediated protection against type 1 diabetes. Mol Cell Endocrinol. (2019) 491:110434. doi: 10.1016/j.mce.2019.04.014
167
Zhang W Li L Zheng Y Xue F Yu M Ma Y et al . Schistosoma japonicum peptide SJMHE1 suppresses airway inflammation of allergic asthma in mice. J Cell Mol Med. (2019) 23:7819–29. doi: 10.1111/jcmm.14661
168
Cardoso LS Oliveira SC Araujo MI . Schistosoma mansoni antigens as modulators of the allergic inflammatory response in asthma. Endocr Metab Immune Disord Drug Targets. (2012) 12:24–32. doi: 10.2174/187153012799278929
169
Chaponda MM Lam HYP . Schistosoma antigens: A future clinical magic bullet for autoimmune diseases? Parasite. (2024) 31:68. doi: 10.1051/parasite/2024067
170
Houlder EL da Silva LF van Diepen A Amaral MS Wilson RA Hokke CH et al . Pre-clinical studies of Schistosoma mansoni vaccines: A scoping review. PloS Negl Trop Dis. (2025) 19:e0012956. doi: 10.1371/journal.pntd.0012956
171
Ly AT Diop D Diop M Schacht AM Mbengue A Diagne R et al . The Sm14+GLA-SE Recombinant Vaccine Against Schistosoma mansoni and S. haematobium in Adults and School Children: Phase II Clinical Trials in West Africa. Vaccines. (2025) 13:316. doi: 10.3390/vaccines13030316
172
Santini-Oliveira M MaChado Pinto P Santos TD Vilar MM Grinsztejn B Veloso V et al . Development of the sm14/GLA-SE schistosomiasis vaccine candidate: an open, non-placebo-controlled, standardized-dose immunization phase ib clinical trial targeting healthy young women. Vaccines. (2022) 10:1724. doi: 10.3390/vaccines10101724
173
Santini-Oliveira M Coler RN Parra J Veloso V Jayashankar L Pinto PM et al . Schistosomiasis vaccine candidate Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male adults. Vaccine. (2016) 34:586–94. doi: 10.1016/j.vaccine.2015.10.027
174
Siddiqui AA Siddiqui SZ . Sm-p80-based schistosomiasis vaccine: preparation for human clinical trials. Trends Parasitol. (2017) 33:194–201. doi: 10.1016/j.pt.2016.10.010
175
Riveau G Schacht AM Dompnier JP Deplanque D Seck M Waucquier N et al . Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children. PloS Negl Trop Dis. (2018) 12:e0006968. doi: 10.1371/journal.pntd.0006968
176
Diemert DJ Correa-Oliveira R Fraga CG Talles F Silva MR Patel SM et al . A randomized, controlled Phase 1b trial of the Sm-TSP-2 Vaccine for intestinal schistosomiasis in healthy Brazilian adults living in an endemic area. PloS Negl Trop Dis. (2023) 17:e0011236. doi: 10.1371/journal.pntd.0011236
177
Keitel WA Potter GE Diemert D Bethony J El Sahly HM Kennedy JK et al . A phase 1 study of the safety, reactogenicity, and immunogenicity of a Schistosoma mansoni vaccine with or without glucopyranosyl lipid A aqueous formulation (GLA-AF) in healthy adults from a non-endemic area. Vaccine. (2019) 37:6500–9. doi: 10.1016/j.vaccine.2019.08.075
178
Jackson LA Coler RN Deye GA Carter D Gray SA Pecor T et al . Safety and immunogenicity of the Sm-p80 GLA-SE schistosomiasis vaccine. NPJ Vaccines. (2025) 10:247. doi: 10.1038/s41541-025-01261-3
179
Eyayu T Zeleke AJ Worku L . Current status and future prospects of protein vaccine candidates against Schistosoma mansoni infection. Parasite Epidemiol Control. (2020) 11:e00176. doi: 10.1016/j.parepi.2020.e00176
180
Molehin AJ Rojo JU Siddiqui SZ Gray SA Carter D Siddiqui AA . Development of a schistosomiasis vaccine. Expert Rev Vaccines. (2016) 15:619–27. doi: 10.1586/14760584.2016.1131127
181
Merrifield M Hotez PJ Beaumier CM Gillespie P Strych U Hayward T et al . Advancing a vaccine to prevent human schistosomiasis. Vaccine. (2016) 34:2988–91. doi: 10.1016/j.vaccine.2016.03.079
182
Al-Naseri A Al-Absi S El Ridi R Mahana N . A comprehensive and critical overview of schistosomiasis vaccine candidates. J Parasit Dis Off Organ Indian Soc Parasitol. (2021) 45:557–80. doi: 10.1007/s12639-021-01387-w
183
Siddiqui AJ Bhardwaj J Saxena J Jahan S Snoussi M Bardakci F et al . A critical review on human malaria and schistosomiasis vaccines: current state, recent advancements, and developments. Vaccines. (2023) 11:792. doi: 10.3390/vaccines11040792
Summary
Keywords
immune organs, immunity, immunology, immunomodulation, schistosoma, schistosomiasis
Citation
Torsello A, Cattani C, Napoli C, Cavani A and Scopelliti F (2026) From cercariae to chronic inflammation: understanding schistosome infection and host immune responses. Front. Immunol. 16:1729394. doi: 10.3389/fimmu.2025.1729394
Received
21 October 2025
Revised
22 December 2025
Accepted
22 December 2025
Published
13 January 2026
Volume
16 - 2025
Edited by
Malcolm Scott Duthie, HDT Biotech Corporation, United States
Reviewed by
Josephine Schlosser-Brandenburg, Robert Koch Institute (RKI), Germany
Namrata Anand, University of Chicago Medical Center, United States
Updates
Copyright
© 2026 Torsello, Cattani, Napoli, Cavani and Scopelliti.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Fernanda Scopelliti, fernanda.scopelliti@inmp.it
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.