Perspective Chapter: Molecular Crosstalk and Signal Transduction between Platyhelminths and Their Hosts

Abstract

Parasitic infection is an intimate relationship between host and parasite with exchange of signal and complex signaling systems involved in these organisms’ molecular crosstalk. With the advances of knowledge due to the genomic and transcriptomic projects in the last two decades, several genes and the molecular mechanism involved in the biological function of platyhelminths have been described. Cytokines, hormones, and other molecules from the host have influenced the growth, development, and reproduction of platyhelminths. We are going to review the effects of host cytokines (IL-1, IL-4, IL-12, IL-7, TGF-β, TNF-α) and hormones (T4, estrogen, progesterone, and androgens) that directly or indirectly affect parasites’ development and reproduction, and the possible associated signaling pathway. These are excellent models for system biology studies, and the generated knowledge may be helpful in the development of new strategies to combat these helminthiases.

1. Introduction

Parasitism is a complex relationship between two organisms and requires several adaptations at the molecular level to establish successful interactions throughout evolution. Intricate signaling systems are necessary to transduce each signal from host to pathogen and vice versa. These systems or networks are relevant because they capture various signals from the environment in which the parasite lives (host), release stimuli, and send signals between different organs and tissues to regulate complex biological processes.

Many host signals (molecules) modulate the development and growth of parasites and directly or indirectly interfere in the course of parasitic infection. It is as important to understand the mechanism of action of these molecules to improve the knowledge of the basic biology of parasitism as the description of the effects itself is necessary.

With the development of sequencing technologies, the difficulties and costs of sequencing a genome or transcriptome have been reduced significantly; consequently, the number of sequences available dramatically increased [1], including the sequences from platyhelminth genomes [2, 3, 4, 5, 6] and transcriptomes [7, 8, 9, 10, 11, 12]. This data collection allowed the scientific community to perform evolutive studies and investigate the signaling elements such as receptor, kinase and phosphatase proteins, and transcription factors [13, 14, 15, 16]. These advances reflect the understanding of the molecular crosstalk mechanism between host and parasites. Studying the signaling elements is essential to comprehend parasitism, parasite development and identify new targets for developing strategies against these diseases (Figure 1) [17, 18].

Figure 1.

Molecular cross-talk between parasite and host. Schematic representation of parasite and host cells, signaling pathways, and molecules secreted (potential ligands) by both organisms. The ellipses represent signaling elements as indicated in the figure and the different colors represent distinct signaling pathways; the hexagons represent second messengers, and the arrows indicate the sequential interaction between proteins of the signaling pathways that culminate in the activation of transcription of target genes that will trigger various cellular processes. Potential molecular targets for drugs and vaccines are highlighted in red circles.

This chapter reviews the host molecules (cytokines and hormones) and their effects and signals transduction pathways in platyhelminths. The most studied model of platyhelminth is Schistosoma mansoni (S. mansoni) and most of the information available in this chapter refers to this parasite.

2. Host cytokines’ effects on platyhelminths

Cytokines are small proteins (5–25 kDa) produced by many cells (especially from the immune system), which exert a signaling effect (at an autocrine, paracrine, or endocrine level) in a broad range of tissues [19]. Generally, cytokine studies focus on the immune system’s regulation when faced with an infection; however, we will describe how the host cytokines can modulate platyhelminths’ biological/physiological processes and their possible signaling pathways.

2.1 Interleukins (12, 2, 7, 4, and 1)

Interleukin-7 (IL-7) is a cytokine secreted by bone-marrow, endothelial, and epithelial-stromal cells essential in the hematopoietic system for the proliferation, differentiation, and development of B cells [20]. It is also involved in the thymic development of mature T lymphocytes, natural killer (NK), and lymphokine-activated killer (LAK) cells [21].

IL-7 interferes in the development of S. mansoni (in murine infection) [22]. Female knockout mice for the IL-7 gene (IL-7−/−) infected with S. mansoni showed significant differences in parasite development, egg-induced pathology, and worm recovery rate. It was also observed that fewer eggs were laid in vivo, and more dead eggs were detected without IL-7. The decreasing egg burden ameliorated the liver pathology, and morphological differences in the length of male and female worms in the IL-7−/− mice were observed [22].

Studies with radiolabeled IL-7 suggested that this cytokine did not bind directly on the parasite surface; hence, the observed effects of IL-7 deficient mice could be attributed to the cytokine’s interactions with the host’s immune and or endocrine responses [23, 24].

Interleukin-2 (IL-2) is a cytokine with autocrine and paracrine effects secreted by activated T-CD4 + cells [25]. Further investigations interrogated the modulation of S. mansoni development by IL-7 and IL-2 through the influence of these cytokines on CD4+ T (T helper) cells [26]. With the use of knockout mice for IL-7 receptor (IL-7Rα−/−) and IL-2 (IL-2−/−) for S. mansoni infection, the morphology of adult worms is affected. In both knockout mice, the infected mice produced smaller male worms than the control group. In the IL-7 receptor knockout mice, the parasite’s egg production was drastically reduced [26]. Studies with IL-2 receptor knockout mice (IL-2Rα−/−) infected with S. mansoni revealed a similar impact on the parasite’s development, using the knockout mice for the cytokine. Thus, it could be concluded that the modulation of IL-7 and IL-2 in S. mansoni development (adult growth and egg-laying and granuloma formation) is indirect; the cytokines act on the host’s CD4+ T cells [26].

Interleukin-12 (IL-12) and interleukin-4 (IL-4) reciprocally regulate differentiation of naïve CD4+ T lymphocytes and directly promote the development of CD4+ Th1 cells and the CD4+ T-cell differentiation in the Th2 phenotype (which also produces IL-4). In 2012, Cheng et al. [27] used an approach with hybridoma cells injected into different mice groups to evaluate the effect of monoclonal antibodies against IL-12 and IL-4 on parasite infection. The effect of IL-12 and IL-4 on worm development and granuloma formation in a murine infection by Schistosoma japonicum (S. japonicum) was evaluated. It was observed that, 24 days post-infection, the group of anti-IL-12 had a significant increase in the number of eggs per couple and eggs in the liver. The granuloma size and fibrosis in the liver in the anti-IL-12 mice were significantly more prominent on day 42. The decreasing of T helper 1 (Th1) cytokine expression through the blocking of IL-12 promotes the T helper 2 (Th2) cytokine expression and reduces Interferon-γ (IFN-γ) and Interferon-α (IFN-α) cytokine levels.

The length of worms in the anti-IL-12 group was increased; however, the degree of increase was different in males and females. The female size was higher in anti-IL-12 than in anti-IL-4 and control groups at 28 and 42 days post-infection, while the male size was higher just at 28 days in the anti-IL-12 [27]. The data in this study suggest that IL-12 deficiency benefits S. japonicum worm development in the early days of infection, indicating the action of cytokine against the schistosome. At the same time, its effect was reduced at 42 days post-infection, revealing a transitory effect. It is important to note that IL-12 promotes a Th1 response.

Finally, interleukin-1 (IL-1) from Biomphalaria glabrata (B. glabrata), the intermediate host of S. mansoni, also affects the parasite. In the vertebrate’s immune system, the cytokine IL-1 mediates cytotoxic, humoral, and inflammatory responses, induces leukocyte recruitment to the inflammation site, and is involved in the cytotoxic reactive oxygen intermediate (ROI) production mechanism in the effector cells [28]. In the immune defense system of the invertebrate B. glabrata, molecules with functional homology to the vertebrate IL-1 (SnaIL-1) have been detected and isolated. It was observed that, in response to schistosome infection’s primary sporocysts, susceptible snail strains exhibit a decrease in plasmatic SnaIL-1 levels, while the SnaIL-1 cytokine levels rise in resistant strains. Also, when the susceptible snails are treated with a recombinant human Interleukin-1β (rhIL-1β), there is a rapid phagocytosis activation and ROI production at the same levels found in the resistant snail strains [29].

In 1998, Connors et al. [30] investigated if the treatment of two strands of susceptible B. glabrata with rhIL-1β had effect on the infection of the invertebrate host (directly or mediating by hemocyte’s activity). After 15 days of exposure, the authors observed a significant decrease of 50% in the number of counted miracidia on snails from both treated groups. Histological analysis of snail tentacles performed 3 days after exposure revealed a significantly higher percentage of dead or disrupted parasites compared to the control. In-vitro assays using hemocytes-free cultured parasites in contact with the plasma from rhIL-1β -injected snails showed an immediate killing effect on the parasites.

These results imply that the cytokine may stimulate in-vivo induction of a cell-free killing mechanism in the B. glabrata. Parasites’ killing seems to have no connection with the hemocyte’s encapsulation of the parasites, suggesting the presence of both a humoral cytotoxic molecule and a cellular signaling mechanism. Injection of the recombinant human IL-1β on the susceptible snails has activated the otherwise reduced cytotoxic capabilities of the snail’s immune system; however, other factors such as reduced number of hemocytes compared to resistant strains may limit the killing of the parasites. Further, invertebrates’ cytokine-like activity may occur in molecules with substantially different structures from their mammalian counterparts, obviating the need for more analysis of the elements involved in the host-parasite signaling mechanisms.

2.2 Transforming growth factor-β (TGF-β)

TGF-β plays an essential role in wound healing, angiogenesis, immunoregulation, and cancer development. These cytokine’s effects are dual-sided, contributing to the differentiation of regulatory (suppressive) T cells (Tr cells) and inflammatory Th17 cells. In mammals, all leukocytes produce at least one isoform of TGF-β [31]. TGF-β is locally produced by the host’s immune system cells in response to the presence of helminth parasites.

In the genome of Taenia solium (T. solium) and Taenia crassiceps (T. crassiceps, a canine tapeworm), protein-coding genes for the pivotal signaling elements were identified [32]. TsTGFβR1, TsTGFβR2, TGF-β Type I, Bone Morphogenetic Protein (BMP) Type-I receptor Tr-3, and activin (TGF-ligand) were identified and had a high identity with Echinococcus sp. The expression of TsTGFβR1, TsTGFβR2 at mRNA, and protein level was detected in T. solium and T. crassiceps cysticerci. It showed that both TGF receptors are expressed in the parasite’s teguments more prominently in the tegument of T. crassiceps and the periphery of T. solium cysticerci from the brain than in the cysticerci from skeletal muscle of infected pigs. It is interesting because the TGF-β levels in the cerebrospinal fluid are higher than in serum, suggesting that the exposure to the host’s molecule could be involved in cysticerci growth and differentiation [32].

It is interesting to note that T. solium and T. crassiceps cysticerci were in vitro exposed to three concentrations of recombinant human TGFβ-1 (0.001, 0.01, and 0.1 ng/mL). The human cytokine caused a significant increment in the size of cysticerci in T. crassiceps. In the T. solium cysticerci, a considerable improvement in the survival rate was observed with no effect on its size. The parasite could internalize the host’s TGF-β via endocytosis as a regulatory event. However, these effects may be mediated by the direct interaction of the host’s cytokine with the parasite receptors. The results observed on the parasites in an in vitro treatment and the antibody recognition of receptors are lower when TGF- β incubation occurs. The lower antibody recognition of both Type-I and Type-II parasite receptors when cysticerci were cultured with increasing levels of TGF-β suggests that TGF-βcould bind the Type-II receptor (avoiding the recognition of antibody), then the complex TGF-β-TsTGFβR2 receptor would recruit the Type-I receptor, forming a complex which would prevent the bounding of Type-I receptor antibody. These results point to hTGF-β as a factor in cysticerci growth and survival, which could also play a role in the lack of effectiveness of cysticidal treatment of patients.

In S. mansoni, several TGF-β signaling pathway elements have been identified and described, including two TGF-β receptors (SmTβR1 and SmTβR2), one homolog gene to Inhinbin/Activin (SmInAct), a homolog to the BMP (SmBMP), Smp300/CBP, Smad2, and Smad4. In female worms, these elements could play a role in vitelline cell development and egg embryogenesis, as these molecules’ expression is detected in these organs (reviewed in [33].

Oliveira et al. [34] studied the effects of the human TGF-β (hTGF-β) on the gene expression profile of S. mansoni adult worms. Microarray experiments were performed with RNA extracted from adult worms that were in vitro treated with the human cytokine. This experiment revealed that changes in the expression influence the pattern of treated worms. With this approach, 381 genes were detected as differentially expressed, with 316 down-regulated and 65 up-regulated. These genes are related to biological functions such as muscular system development and function, tissue morphology, cellular assembly and organization, organ development, tissue development and cellular growth, and proliferation. Some functions, such as contractile fiber and myosin complex, hydrolase activity, and adenyl ribonucleotide binding, are related to the down-regulated genes. It correlates with the already described TGF-β induction of cytoskeleton remodeling through the myosin chain and Rho GTPase [35, 36].

Figure 2 summarizes host cytokines’ direct or indirect effect on the parasites.

Figure 2.

Influences of mammals and invertebrate host’s cytokines on platyhelminths. (A) Cytokines. (B) Vertebrate immune system cells. (C) Platyhelminthes. (D) Cytokine. (E) Invertebrate effector cells. (F) S. mansoni primary sporocysts. Some cytokines (TNF-α and TGF-β) exert direct effects on the parasite; on the other hand, other cytokines (such as interleukins) exert effects on immune system cells and these cells regulate parasites´ biological processes.

2.3 The example of human Tumor Necrosis Factor-α (TNF- α) on S. mansoni

Human TNF-α and its effect on S. mansoni are excellent examples of how the comprehension of the molecular crosstalk between host and pathogen has increased in the last decades. Some studies have described the influence of the pro-inflammatory cytokine TNF-α on the fecundity and metabolism of the parasite S. mansoni. Amiri et al. [37] described that human TNF-α induces the formation of granulomas and causes a positive effect on the parasite’s egg-laying. Controversially, it was shown that egg-laying decreases and induces changes in the uptake of tyrosine [38] and methionine [39] on S. mansoni in the presence of the human cytokine. It was also documented that parasites’ egg-laying and fecundity occurred later when immunodeficient mice (SCID) were used for infection with the parasite [40]. Finally, Davies et al. [41] reported that host TNF-α promotes the parasite survival and the development of adult worms.

In this context, the molecular mechanism started to be elucidated by searching for S. mansoni homologous gene to the human TNF-α receptor. A homolog gene was identified and characterized (SmTNFR) [42] and generated a transcript of 1967 nucleotides that encodes a receptor composed of 599 amino acids. The predicted protein has an extracellular portion that contains four TNF-α conserved domains (cysteine-rich domains), the main characteristic of the TNF receptor family. Extracellular domains’ modular architecture is similar to the neural growth factor receptor (NGFR). The first analysis of the intracellular portion revealed no conserved domains, which is not expected in a homologous gene to NGFR characterized by Death Domain (DD), which makes it similar to TNF-R2, a non-death domain. The transcript expression level (mRNA) is detected in all developmental stages, but the highest expression level is detected in cercaria [42].

Parallel to the description of SmTNFR, other homolog genes for a possible signaling pathway were also identified. It is interesting to highlight that all elements required and activated by the human TNF-R2 signaling pathway (which does not have DD and, therefore, is not related to the activation of apoptosis) were found [42].

Recently, through in-silico analysis, 29 genes of homologous receptors to SmTNFR in other species of parasitic flatworms were identified. The homologs may evidence conservation of the TNF-α signaling pathway in a part of helminths. Additionally, highly conserved homologs of endogenous TNF-α ligands only in free-living flatworms were also identified. This suggests that the loss of the endogenous ligand (observed in parasitic flatworms) and the consequent use of the host’s ligand was an event that occurred throughout the evolutionary process, as a cause or consequence of the parasitism [43].

Further, TNFR homologs identified in platyhelminths had conserved DD, which was concluded after the analysis of the secondary structure of intracellular regions. The intracellular portion of all receptors was reanalyzed, and evidence of the presence of DD was found in most SmTNFR homologs in platyhelminths but with different levels of conservation. Generally, cestodes have a more conserved DD than trematodes. This urges us to rethink the possible signaling pathway triggered by SmTNFR, since this receiver was initially classified as without DD [42].

Parallelly, Oliveira et al. [42] investigated the effect of human TNF-α on the gene expression profile in newly transformed schistosomula (NTS) and adult worms. NTSs (3 h after transformation) were treated with human TNF-α for 1 h (at the concentration of 20 ng/mL), and adult worms treated with human TNF-α for 1 h and 24 h. Microarray experiments revealed 548 genes with altered expression in NTSs after treatment with the human cytokine (309 up-regulated and 239 down-regulated). These genes are involved in biological functions related to the regulation of gene expression, cell proliferation and growth, and cell development. Two groups of differentially expressed genes were identified in adult worms treated for 1 h and 24 h. One group had transient changes in expression, that is, an inverse change pattern within 24 h compared to the pattern obtained within 1h. This group comprises 1365 genes, 821 of which have their expression level increased in 1 h of treatment and decreased in 24 h, and 544 have the opposite expression pattern. The second group has sustained changes in its expression level in 1 h and 24 h; this group comprises 492 genes, 337 being with the expression level increased by treatment with human TNF-α and 155 with the expression level decreased. These differentially expressed genes were organized in gene expression networks, and the most significantly enriched network interacts with TNF-α in other organisms. The network suggests that the parasite response to the human cytokine is conserved and similar to the reaction in humans [42]. Interestingly, the enzyme lactate dehydrogenase (responsible for producing lactate) was differentially expressed in schistosomula and adult worms treated with human TNF-α.

Thus, it was described that human TNF-α induces the phosphorylation of different proteins in adult male worms after in vitro treatment for 15 min. Differentially phosphorylated proteins were related to muscle contraction, cytoskeletal remodeling, cell signaling, and metabolism. Lactate dehydrogenase and a subunit of ATP synthase are differentially phosphorylated proteins. These results indicate that this enzyme, in the glycolytic pathway of the parasite, is being potentially regulated by the host’s TNF-α in its expression level (mRNA) and activity [44].

Since the literature description of egg-laying is contradictory, and lactate dehydrogenase is differentially expressed and phosphorylated, the effect of TNF-α on egg-laying and metabolism was investigated in the adult parasites, in an in vitro treatment with doses of the human cytokine (5, 20, and 40 ng/mL) during 5 days [45].

The average number of eggs/couple increased on the second day in the treatment with 40 ng/mL. On the third day, there was a significant decrease in the average of eggs/couple for the treatments with 20 and 40 ng/mL; besides, there was a decrease for the doses of 5 and 40 ng/mL on the fourth day of incubation with the cytokine. The most important observation is that the total number of eggs was not different between treatments and control over the 5 days of treatment. The conclusion is that although egg-laying dynamics were affected, the fecundity was not. The host’s TNF-α causes a decrease in the half-life of the egg-laying; therefore, when faced with the stimulus, couples lay eggs more quickly, but not in greater or lesser amounts than the respective negative control [45].

The TNF-α treatment induced significant changes in lactate concentration or possibly the glucose uptake when there was also a change in egg-laying. On the third day of treatment, for example, when lactate production decreased, the number of eggs laid was also reduced, indicating that energy metabolism is a relevant actor regulated by human TNF-α and interferes in the production dynamics and egg-laying [45].

In addition, the increase in the accumulation of adenosine triphosphate (ATP) in adult worms on the fifth day was observed. The compromised egg-laying can explain it at this time: the high demand for ATP is destined for oogenesis and, when not necessary, this molecule can accumulate, especially against the modulation induced by the human cytokine [45]. It is also interesting to note that one subunit of ATP synthase is regulated by human TNF-α [44].

Figure 3 summarizes the history of the characterization of the effects of TNF-α on Schistosoma mansoni. It is an exciting example of how a cytokine effect can be elucidated like a puzzle, piece by piece.

Figure 3.

Timeline of main discoveries described in the literature about host TNF-α and its effects on S. mansoni.

3. Host hormones influences in metabolism, development, and viability of platyhelminths

The interaction between host and parasite depends on the ability of the parasite to successfully adapt to the host’s microenvironment, allowing for a complete life cycle and parasite development [46]. That relationship suffers interference from age, sex, and reproductive status of the host and influences the hormonal profile [47]. Hormones, especially sex steroids, are fundamental for many biological processes such as reproduction, growth, development, and immunity. Parasites can evade the immune system. They can also exploit the host’s hormones to improve their growth and reproduction, demonstrating that these organisms have mechanisms to interact with the host’s molecules [48, 49].

Female supremacy is an older concept that assumes that female mammals suffer less parasitism than males. The statement that supports this paradigm implies that sexual dimorphism to parasite infections is based, principally, on the host immune system and has less interference of direct effects of hormones on parasites. Analysis of literature contests this paradigm, showing that publications represent few host-parasite systems, most of which have a medical bias, exploring, in general, human infections. Furthermore, there is no definition of infection and the immune parameters that contribute to host resistance or susceptibility to parasitism, casting doubt on the protective effect of those immune indicators. There are several exceptions to female supremacy: in malaria, toxoplasmosis, and cysticercosis, females are more affected by parasite infections than males [50].

Another line of discussion focuses on the influence of host sex in the genetic diversity of parasites. In this study of 2006, the researchers showed that independent of sex, schistosomes have more genetic diversity in male hosts. The authors postulated three hypotheses that explain the genetic variability of schistosomes: the relationship between rat-sex and duration of infection by cercaria; a combination of rat sex and specific habitat on host males that can contribute to more genetic diversity in parasites; a host sex bias in immunocompetence that select more diverse clones in male rats [51].

Together, these pieces of evidence raise new questions about the participation of host hormones in the host-parasite relationship. Do differences in concentrations of sex hormones between males and females have a significant role in the susceptibility to parasite infections? Can host hormones directly affect parasite biology? Do the parasites exploit the host hormones for their growth? Here in this topic, we aim to review the interaction between host hormones and platyhelminths, especially in S. mansoni, T. crassiceps, and T. solium.

As previously mentioned, hormones are important for the modulation of immune responses. The influence of host sex on resistance and susceptibility to parasitism in CBAJ/mice infected with S. mansoni showed the following results: females and castrated males had the worst survival rates, with 80% dead after 16 weeks of infection, compared to under 40% of infected males that died. In another experiment, investigators revealed that schistosomula grow better in the low testosterone level group, as noticed by the higher recovery rates of adult worms per cercaria. A possible explanation is the differences promoted by testosterone in the decline of infection effects, represented by a more pronounced organomegaly in the liver and spleen in females and castrated males, which are early pre-mortality indicators. These results start a discussion about the relationship between the host sex and differences in the parasite infection [52, 53].

When it comes to cestodes, we also see the effects of hormones on immunity. To test the influence of androgens in the parasite loads, the researchers investigated the effect of testosterone, dihydrotestosterone (DHT), and 17β-estradiol in castrated female and male mice infected with T. crassiceps. The castration triplicated the parasite burden in males and had the opposite effect in females, decreasing the number of parasites by 45%. The treatment with testosterone and DHT reduces de parasite loads in both genders, respectively, 60% and 70%. However, estradiol treatment increases the parasite number in female and male mice three times. Another experiment shows that parasite infection in male mice results in a high level of estradiol, a lower 90% testosterone, and a 95% decrease in DHT [54].

The antibodies’ and cytokines’ production is also affected by the sex steroids levels. In general, testosterone and DHT have no effect on the production of IgG, IL-6, and IL-10 in both sexes. On the other hand, the production of IL-2 and IFN-γ increases significantly in both sexes, and DHT promotes 70% recovery of the cytokines in males. Estradiol increases levels of anti-parasite IgG by 60% and duplicates IL-6 and IL-10 production in males and females. Those results demonstrated that androgens increase the cellular response in T. crassiceps infection with a specifically TH1 pattern. Oppositely, estrogens produce a TH2 immune response, which has no value in stopping the parasite’s growth [54].

The effect of progesterone is also investigated in T. crassiceps and T. solium cysticercosis. In T. crassiceps treatment with progesterone, the number of parasites increases by three folds in male and two folds in female mice. Estradiol is increased two times in both genders, suggesting that progesterone is metabolized in the gonad. The cytokines, IL-4, IL-6, and IL-10 levels increase under the infection, with no change after progesterone treatment. In addition, IL-2, TNF-α, and IFN-γ concentration in the spleen is not modified with infection and treatment, but IL-2 is undetected in both sexes infected, and IFN-γ and TNF-α are increasing in progesterone-treated mice. Moving to T. solium, progesterone treatment decreases tapeworm length and increases IL-4, IL-6, and TNF-α in the duodenum, combined with a polymorphonuclear leukocytes infiltration. Once again, these results show that progesterone modulates TH1 immune response in T. crassiceps and improves intestinal mucosal immunity [55, 56].

Host hormones also directly affect the biology of parasites. Previous experiments showed that dehydroepiandrosterone (DHEA) and DHEA-S have a protected effect on mice infected with S. mansoni [57]. Another study demonstrated a negative correlation between DHEAS and intensity of parasitism, and this decline of S. mansoni infection also correlated to age [58]. Researchers investigated the effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on S. mansoni, including DHEA. Cercariae are more affected than schistosomula and adults, with 100% dead after 48 h of culture, showing a concentration- and time-dependence.

Interestingly, males and paired worms are more resistant to the harmful effects of DHEA than females and separated worms. This fact suggests a beneficial effect of the relationship between female and male worms [59]. T. crassiceps is negatively affected by DHEA treatment with lower reproduction, motility, and viability [60].

17β-estradiol (E2), progesterone (P4), testosterone (T4), and dihydrotestosterone (DHT) also modulate the parasite physiology. Estrogens stimulated the reproduction and viability of T. crassiceps, with E2 being more effective than P4. These hormones are also involved in a high expression of genes c-fos and c-jun of the parasite, correlated to differentiation, reproduction, and apoptosis, showing a relative impact on viability changes. Since this parasite expressed estrogen and androgen receptors (excluding P4), sex steroids can bind these specific receptors and directly affect reproduction [61]. E2 and P4 also increase the expression of actin, tubulin, and myosin, major components of flame cells of the excretory system, benefiting the growth of T. crassiceps [62]. Progesterone also affects the development of T. solium by promoting evagination, maintaining motility, and inducing growth of the worms by two times [63].

In contrast to the positive effects of estrogens, T4 and DHT have deleterious actions, inhibiting the reproduction and reducing the viability of parasites. Additionally, they reduce the expression of c-fos and c-jun, explaining the changes in reproduction and growth of T. crassiceps. This data also agrees that cysticerci grow better in female and castrated males, proposing that the differences in sex steroids’ concentrations in males and females are involved [61]. Moreover, T4 and DHT reduce the viability of the parasite by almost 90%, disrupting tegument and changing the structure of flame cells, with direct interaction with actin, tubulin, and myosin, without changes in their expression. This interaction results in the intoxication of the parasite, which explains the significant reduction in viability [64].

These findings improve the critical role of host sex hormones on the host-parasite relationship. Those sex hormones can determine the course of infection by direct effects like modulation in growth, reproduction, and viability or indirect effects such as changes in gene expression and immune system of the host, which sometimes benefit the host and other, permitting the parasite to exploit the microenvironment (Figure 4). The knowledge that estrogens and progesterone are related to positive effects on parasites and androgens protecting the host can urge the investigation of the beneficial use of sex steroids as new therapeutic targets to the parasitic infections. It is currently known that taximofen, an antiestrogen, and RU486, a progesterone antagonist, can negatively affect the reproduction and growth of T. crassiceps and T. solium, respectively [50, 63]. In this way, more discovery of the crosstalk between parasites and sex hormones can change the scenario about antiparasitic drugs, permitting a faster development process with high efficacy and low toxicity [65].

Figure 4.

Effects of sex steroids in parasites S. mansoni, T. crassiceps, and T. solium. Estrogens like E2 and P4 have positive effects on parasites and also modulate the immune response to the Th2 pattern. In contrast, testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) decrease parasite growth and reproduction and increase Th1 cytokines, which protect the host.

Figure 4 summarizes the effect of host hormones in the platyhelminths.

4. Conclusions and perspectives

We have reviewed some host molecules and their effects on the parasite. It is interesting to note how many distinct molecules produced along with the immune response (cytokines, pro or anti-inflammatory) or regularly produced by the endocrine system (such as sexual hormones) may interfere with parasites’ development and fecundity. The study of molecular targets of this signaling is relevant to understanding how the evolution prepares the parasite’s genome to respond and adapt to different signals from the environment and the hosts.

These biological models are exciting for system biology sciences and drug and vaccines discoveries; however, for a better understanding, functional genomic approaches must be improved to be applied in platyhelminths models to clarify the contribution of the signaling elements in the transduction and regulation of parasites’ biological process.

As technologies have been developed and adapted, much information will be obtained from these particularly complex and challenging biological models. As information increases, new solutions for combating parasitic diseases will be elaborated and applied.