Signal transduction regulates schistosome reproductive biology
Introduction
Blood flukes of the genus Schistosoma infect over 200 million people in 76 countries [1]. Schistosomes have a complex life cycle involving both a snail intermediate and a vertebrate definitive host. Schistosome parasites have coevolved an intricate relationship with their human and snail hosts as well as a novel interplay between the adult male and female parasites.
Eggs produced by worm pairs are important in the transmission of the parasite and responsible for pathogenesis. For S. mansoni, worm pairs produce approximately 300 eggs per day. Approximately half of the deposited eggs reach the outside environment in the excreta, to continue the life cycle. The other 50% are swept into the circulation and filter out in the periportal tracts of the liver eliciting granulomatous inflammatory reactions that can lead to periportal fibrosis, portal hypertension, and the serious sequelae of intestinal schistosomiasis such as hepatosplenomegaly and esophageal and gastric varicies [2]. Thus, understanding the molecular basis for male–female interactions that lead to female reproductive development should offer targets to prevent egg production and thus prevent both transmission of the parasite and morbidity because of the eggs. In this review we focus on the biological interplay between the male and female parasites, in particular the recent developments in signal transduction that contribute to reproductive development and subsequent egg production.
Section snippets
Male–female interplay
To develop into a reproductively active female worm and to maintain reproductive activity and egg production, the female worm is dependent on the presence of a mature male worm [3, 4, 5, 6, 7] (Figure 1). Female schistosomes from single-sex infections are underdeveloped in that they are stunted in size and exhibit an immature reproductive system. In particular, the vitellaria, whose cells produce the eggshell precursors and nutrients for the egg, are not developed. The nature of the stimuli for
Role of TGFβ signaling pathway in male–female interactions
Schistosomes have evolved an interesting biological interplay among the male and female parasites such that male schistosomes via an unknown stimulus regulate female-specific gene expression and thus female reproductive development and egg production. Signaling pathways are prime candidates for the transduction of the male stimulus to the vitelline cells of the female parasite.
Current data argue for multiple (pleiotropic) roles for the TGFβ signaling pathway throughout the schistosome life
Identification of SmGCP as a S. mansoni TGFβ target gene that is regulated in response to worm pairing
A gynecophoral canal protein (SmGCP) has been demonstrated to be involved in promoting intimate contact of the female with the tegument of the gynecophoric canal of the male [9••, 22•]. SmGCP localizes to the surface of the gynecophoric canal of the male (the site of interaction between the mating pair) and to the entire surface of the en copula female but not to nonmated males nor to immature females [23, 24]. SmGCP shows homology to beta-ig-h3 (β-induced gene-Human clone 3) whose expression
Role of TGFβ signaling in female reproductive development and egg production
Two TGFβ ligands from S. mansoni have been identified; an Inhibin/Activin-like molecule (SmInACT) and a BMP-like molecule (SmBMP) [10•, 26••, 27]. As regards a role in female reproductive development and egg production, the S. mansoni TGFβ ligand, SmInAct has been demonstrated to play a significant role in female reproduction and egg embryogenesis by demonstrating that in mature (bisexual) female worms, the SmInAct transcript is highly expressed and localizes to the vitellaria and eggs. The
Role of tyrosine kinases in female reproductive development and egg production
Tyrosine kinases are critical factors in the regulation of female reproductive development and egg production, especially cytoplasmic tyrosine kinases (CTKs) of the Src class, SmTK3 and SmTK5 [28•, 29, 30].
SmTK3 and SmTK5 are expressed among other places in the vitellaria, ovary, and spermatocytes indicating a role in adult reproductive activity. Src kinases among their multiple functions regulate cell proliferation and differentiation in response to growth factor stimulation ([31] for review).
Conclusions
A model is emerging in which signals that originate from worm pairing may involve a male-derived stimulus or an initiating signal from a female residing in the gynecophoric canal that would induce the male to send a signal, in either case, with the end result reproductive development and egg production (see [3] for discussion). This could be a single signal that has a number of effects such as with the TGFβ pathway in which a single signal is converted into programs of gene regulation and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (41)
- et al.
Cytokine-mediated host responses during schistosome infections; walking the fine line between immunological control and immunopathology
Adv Parasitol
(2002) - et al.
Schistosome female reproductive development
Parasitol Today
(1991) Schistosome male–female interaction: induction of germ-cell differentiation
Trends Parasitol
(2001)- et al.
Herbimycin A suppresses mitotic activity and egg production of female Schistosoma mansoni
Int J Parasitol
(2006) - et al.
Signaling cross-talk between TGF-beta/BMP and other pathways
Cell Res
(2009) - et al.
A divergent member of the transforming growth factor beta receptor family from Schistosoma mansoni is expressed on the parasite surface membrane
J Biol Chem
(1998) - et al.
Cytological and biochemical evidence for a gonad-preferential interplay of SmFKBP12 and SmTbetaR-I in Schistosoma mansoni
Mol Biochem Parasitol
(2004) - et al.
Identification and characterization of a Smad2 homologue from Schistosoma mansoni, a transforming growth factor-beta signal transducer
J Biol Chem
(2001) - et al.
Expression of functional Schistosoma mansoni Smad4: role in Erk-mediated transforming growth factor beta (TGF-beta) down-regulation
J Biol Chem
(2004) - et al.
Identification and characterization of a R-Smad orthologue (SmSmad1B) from Schistosoma mansoni
FEBS J
(2007)
Human transforming growth factor-beta activates a receptor serine/threonine kinase from the intravascular parasite Schistosoma mansoni
J Biol Chem
Functional conservation of Schistosoma mansoni Smads in TGF beta signaling
Mol Biochem Parasitol
Molecular cloning of a Schistosoma mansoni protein expressed in the gynecophoral canal of male worms
Mol Biochem Parasitol
A bone morphogenetic protein homologue in the parasitic flatworm, Schistosoma mansoni
Int J Parasitol
Identification, isolation and characterisation of a Fyn-like tyrosine kinase from Schistosoma mansoni
Parasitology
A novel Syk-family tyrosine kinase from Schistosoma mansoni which is preferentially transcribed in reproductive organs
Gene
Evaluation of Schistosoma mansoni retinoid X receptor (SmRXR1 and SmRXR2) activity and tissue distribution
Mol Biochem Parasitol
Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice
Nature
Early variations of host thyroxine and interleukin-7 favor Schistosoma mansoni development
J Parasitol
Diversification of the insulin receptor family in the helminth parasite Schistosoma mansoni
FEBS J
Cited by (65)
Comparative proteomic profiles of Schistosoma japonicum male worms derived from single-sex and bisexual infections
2022, International Journal for ParasitologyCitation Excerpt :A SF worm is underdeveloped with stunting and an immature reproductive system. In SF worms, the vitelline glands that produce the eggshell precursors and nutrients for the egg are not developed (LoVerde et al., 2009; Zhong et al., 2022b). The results of our previous work confirmed that MF worms were fully developed at 25 days p.i., while SF worms were undeveloped with no ovary enlargement (Li et al., 2020).
Review: Schistosoma mansoni phosphatidylinositol 3 kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway
2021, Comparative Biochemistry and Physiology Part - B: Biochemistry and Molecular BiologyThe effect of fs800 on female egg production in Schistosoma mansoni
2021, Molecular and Biochemical ParasitologyCitation Excerpt :Differentiation, maturation, and maintenance of the female reproductive system requires continuous male-female pairing. This interplay between male and female worms results in a series of changes that include differentiation of germ cells in females into vitellocytes [11–14]. Several genes have been characterized during this process [15–18].
Schistosome TRP channels: An appraisal
2020, International Journal for Parasitology: Drugs and Drug ResistanceFailure of in vitro-cultured schistosomes to produce eggs: how does the parasite meet its needs for host-derived cytokines such as TGF-β?
2019, International Journal for Parasitology