Complementing previous transcriptomic work [e.g. 13], the eagerly-awaited S. mansoni and S. japonicum genomes were published in July 2009 1415; together, these have provided an invaluable resource for the schistosome research community, although genome studies on S. haematobium are badly needed 16. Analyses of the existing genomes and predicted proteomes have revealed a wealth of information highlighting mechanisms by which the parasite might exploit host nutrients and cell signalling molecules to support growth, and revealing the nature of schistosome neuropeptides, kinases, ion-channels, metabolic pathways, and proteolytic enzymes required for host invasion and haemoglobin degradation 1415. The availability of sequence data has since supported research projects spanning a wide spectrum of schistosome biology from studies into miracidial cilia beat 17, regulation of spermatogenesis and oogenesis 18, gender-specific gene expression 19, and histamine signalling 20 in adult worms, through to vaccine discovery using immunomics 10 and characterization of genes encoding small RNA regulatory pathway components 21. In addition, a detailed functional annotation of the S. mansoni kinome comprising 252 eukaryotic protein kinases 22 has recently been enabled, paving the way for further research into schistosome kinases; such research is particularly pertinent to research on schistosome development and survival and modulation of schistosome cell signalling pathways by host molecules. In silico approaches, reliant upon genome data, have also recently been employed to prioritize potential S. mansoni drug targets 23. Thus, through supporting basic research that integrates experimental and bioinformatic approaches, it is anticipated that the genome will help deliver novel anti-schistosome drug and/or vaccine candidates. In addition, the availability of the schistosome genome and predicted proteome will also bring huge benefit to research in comparative biology and the evolution of parasitism, with the future assembly of the genome of the free-living flatworm Schmidtea mediterranea 24 being particularly important to this endeavour.

The tegument of schistosomula and adult worms is intriguing. It includes a single multinucleated cytoplasmic layer (syncytium) that covers the entire worm and is linked to underlying nucleated cell bodies by cytoplasmic connections that span the musculature (reviewed in 25; see poster). The apical surface of the tegument undergoes dynamic turnover and has a unique architecture comprising two closely aligned lipid bilayers, the plasma membrane and the host-proximal membranocalyx. This surface plays a vital function in immune evasion/modulation and nutrient uptake thus ensuring schistosome survival; in addition, it has recently been proposed that the tegument functions in the removal of waste lactate from adult schistosomes 26. During the last decade, advances in proteomic/genomic technologies have enabled studies into the identification of proteins present in the tegument of adult schistosomes. The rationale for much of this work is that tegument proteins might represent useful drug/vaccine targets given their close proximity to host blood. In 2006, proteomic analysis of S. mansoni proteins obtained by differential solubilization of an apical membrane preparation identified 51proteins based on homology with known proteins in other organisms 27. Among these were enolase involved in energy metabolism; the molecular chaperone heat shock proteins 19, 17 and 20, calmodulin; various cytoskeletal and molecular motor proteins including actin, severin and dynein light chains; mitochondrial proteins such as ATP synthase; vesicle proteins, and plasma membrane transporters; enzymes and structural molecules such as calcium ATPase, glucose transport protein, alkaline phosphatase, annexin and tetraspanins A, B, and C 27. This study advanced knowledge from that achieved a year earlier which identified 43 tegument proteins that included those possibly present within the syncitium 28. In 2010, by first biotinylating proteins on the surface of live adult S. japonicum and subsequent capture using streptavidin beads, 54 proteins were identified by tandem mass spectrometry (MS/MS), the majority of which are putatively surface-exposed 29. Comparative analysis of the results obtained with those of other studies revealed that many of these identified proteins are commonly expressed in both S. mansoni and S. japonicum 29. More recently, by employing trypsin to release the most accessible surface proteins from live S. mansoni, analysis by MS/MS revealed the presence of host complement proteins C3 and C4, the leukocyte marker CD44 and various schistosome proteins including annexins IV, V and VI, the membrane protease calpain, and Sm200 and Sm25, proteins of unknown function 30. In addition, release of GPI-anchored proteins using phosphatidylinositol-specific phospholipase C revealed the presence of schistosome Sm29, CD59a and b, Sm200, carbonic anhydrase, alkaline phosphatase, and ADP-ribosyl cyclase 30. These studies highlight the power of proteomics and subsequent data mining in identifying important molecules present at the host-parasite interface and the ingenious approaches used by researchers to obtain relevant fractions for study. Other proteins were found during these proteomic studies that lack homology to proteins expressed in other organisms including humans; these unique proteins are therefore ripe for further investigation as in addition to being potential therapeutic targets understanding their function might yield valuable insight into the specific nature of schistosome-host interactions.

Schistosomes possess separate sexes. An interesting feature of schistosome conjugal biology is that sustained pairing occurs between males and females. Molecular signalling between them is essential for complete development of the female reproductive apparatus including the ovary and vitellaria, and separation of worm couples reverses this maturation process. Between 2001 and 2007 strong evidence emerged for the transforming growth factor β (TGFβ) signalling pathway playing an important part in female reproductive development and egg embryogenesis; this pathway involves TGFβ growth factors that activate serine/threonine kinase transmembrane receptors (TβRI/TβRII) which in turn signal to downstream elements of the Smad pathway [reviewed in 3132]. Both TGFβ and bone morphogenic protein (BMP) subfamily members have been discovered in schistosomes with S. mansoni BMP characterized recently 33. Importantly, RNA interference-mediated knockdown of the TGFβ superfamily member Inhibin/Activin in eggs aborts their development highlighting a crucial role for this molecule in schistosome embryogenesis 34. In addition, other studies highlighted that Src, Src/Fyn and Syk cytoplasmic tyrosine kinases probably govern reproductive development in a distinct manner with SmTK3/SmTK5 expressed in the ovary, vitellaria and testes, and SmTK4/SmTK6 in ovary and testes but not in the vitellaria 32. Interestingly, SmTK3 was recently found to interact with the formin-homology protein SmDia which also binds the small GTPase SmRho1 in male and female worm gonads; given the role of such components in other organisms it is considered that these co-operative pathways might organize reproductive cytoskeletal events 35. A polo-like kinase, SmPlk1, has also been found to play a major role in S. mansoni reproduction; not only were SmPlK1 transcripts detected in the female vitelline cells and oocytes and in male spermatocytes, but a novel Plk1 inhibitor disrupted the gonads resulting in defective oogenesis and spermatogenesis 36. Finally, in S. japonicum, a Frizzled member (SjFz9) representing a novel receptor of the evolutionarily conserved Wnt developmental signalling pathway has been found to be predominantly expressed in the testes of male worms and the ovary and vitellaria of the female worm 37, providing tantalizing opportunities for investigating the role of this protein in the development of these tissues. Taken together, these findings demonstrate some of the excellent progress made to decipher factors governing reproductive development of schistosomes and thus egg production. Such work will undoubtedly influence the direction of schistosome reproductive research within the coming decade, providing a springboard for the development of effective drugs that target key proteins involved in egg production by adult worms.

Our overall knowledge of the molecular control of schistosome development remains poor. The large morphological and physiological differences that exist between each of the schistosome life-stages means that identification of important drivers of development, particularly those that govern key life-stage transitions, will be a major task. Such work needs to be considered in the context of changing environments, both within a host and between hosts, and the different metabolic milieux present. For example, the importance of human and snail growth factors to development of the requisite life-stages need to be evaluated and the mechanisms by which host-derived molecular signals are communicated to the parasite to benefit this process understood. Despite such challenges, we do have some insight into the changes in gene expression that occur during schistosome development 3839 and of potential regulators of reproductive development (above). In addition, knowledge gleaned from studies into the regulation of development of early post-embryonic snail-host life-stages 4041 could inform similar research on definitive-host stages and vice-versa. As with other organisms, molecular regulation of schistosome development will be complex, but studies this area are important to develop a complete understanding of schistosome developmental biology, crucial for drug development work, and to inform research in comparative developmental biology including that on other trematode parasites such as Fasciola spp.

What are the cellular mechanisms used by schistosomes to sense the presence of the intermediate and definitive hosts? What mechanisms enable them to respond to environmental cues and migrate within their hosts to their sites of final development? What mechanisms enable immature adult worms to recognize each other, couple, and sustain their intimate association? All of these fascinating questions relating to schistosome sensory biology remain ripe for investigation. Sensory structures exist on the surface of adult schistosomes and on various regions (e.g. the terebratorium) of certain larval stages, but how signals received at the parasite surface modulate the behaviour of the parasite remains largely unknown. There has however been excellent progress in understanding various aspects of the schistosome neuronal system, particularly in relation to the presence of neurotransmitters 4243 and some G-protein coupled receptors 2043. Molecular communication between such components will be vital to behavioural responses such as schistosome muscle contraction and motility of schistosome larvae, but how such signals are integrated to provide a co-ordinated response remains to be explored. Although this represents a substantial research challenge, understanding the molecular control of schistosome behaviour is crucial to developing a detailed knowledge of schistosome functional biology.

While parasites such as Plasmodium falciparum and Trypanosoma brucei are well known to use polymorphism and protein variation to evade host immune responses 4445, the extent to which a schistosome varies its molecular appearance via genetic mechanisms to facilitate survival in its host is little understood. It has however recently been shown that, in the snail host, S. mansoni produces mucins coded by a multi-gene family whose members frequently recombine; multiple splice variants also exist for each gene and as a consequence mucin polymorphism occurs 46. Moreover in S. japonicum, the tegument protein tetraspanin-2 has been found to be diverse with sequence variation occurring on the surface of the molecule 47, and more recently a mechanism of protein variation generated by differential splicing of micro-exon gene transcripts has been elucidated in S. mansoni 48. Understanding the nature of protein variation and polymorphism in schistosomes has major implications for the development of vaccines against these parasites and studies such as these pave the way for novel investigations into schistosome immune evasion strategies.