Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development

Abstract

During infection of their human definitive host, schistosomes transform rapidly from free-swimming infective cercariae in freshwater to endoparasitic schistosomules. The ‘somules’ next migrate within the skin to access the vasculature and are surrounded by host molecules that might activate intracellular pathways that influence somule survival, development and/or behaviour. However, such ‘transactivation’ by host factors in schistosomes is not well defined. In the present study, we have characterized and functionally localized the dynamics of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) activation during early somule development in vitro and demonstrate activation of these protein kinases by human epidermal growth factor, insulin, and insulin-like growth factor I, particularly at the parasite surface. Further, we provide evidence that support the existence of specialized signalling domains called lipid rafts in schistosomes and propose that correct signalling to ERK requires proper raft organization. Finally, we show that modulation of PKC and ERK activities in somules affects motility and reduces somule survival. Thus, PKC and ERK are important mediators of host-ligand regulated transactivation events in schistosomes, and represent potential targets for anti-schistosome therapy aimed at reducing parasite survival in the human host.

Deep phosphoproteome analysis of Schistosoma mansoni leads development of a kinomic array that highlights sex-biased differences in adult worm protein phosphorylation

“…The five protein kinases selected for interactome phosphorylation analysis were all TDR targets: Smp_093930 (EGFR; SER), Smp_128480 (PKCβ), Smp_047900 (ERK2), Smp_073930.2 (Akt), Smp_152330 (PKA), with associated Target IDs 282997, 290399, 283994, 324234, and 286928, respectively. These protein kinases were also chosen due to their recognised importance to schistosome biology, particularly in relation to host-parasite interactions [13,45,46], reproduction and development [14,47,48], glucose uptake [15], and motor activity and survival [49,50]. Analysis of the five networks revealed a high proportion of phosphorylated partners within each interactome.…”

“…The interactomes of five selected S. mansoni protein kinases were next investigated to establish the extent of phosphorylation between high-confidence interacting partners (Fig 8 and S9 Table). These kinases were chosen due to their known importance to schistosome biology: a) epidermal growth factor receptor (EGFR, SER), which binds human EGF and induces signalling in the worm [45,46]; b) PKCβ, which plays an important role in schistosome larval development and possibly regulates pairing and egg release of adults [14,47]; c) extracellular signal-regulated kinase 2 (ERK2), which together with ERK1, regulates the maintenance of the ovaries and thus egg production [48]; d) Akt, which plays an important role in glucose uptake in adult worms [15]; and e) PKA, which is important in schistosome motor activity and survival [49,50]. For each of these five networks, the identified phosphoproteins comprised between 37-53% of the predicted interactome (Fig 8).…”

“…japonicum, or obstructive and inflammatory disease in the urinary system in the case of S. haematobium [7]. The parasite (both larval and adult stages) is highly adapted to thrive in the human host; it feeds on host blood and possesses a complex tegument thought to play an important role in host immune evasion, osmoregulation, excretion and glucose uptake [8][9][10][11], and can respond to host growth factors and other signalling molecules [12][13][14][15]. Ultimately, the exquisite biology of the schistosome underpins its fecundity and longevity-surviving on average for five to 10 years [16], but possibly up to 30 years [7]-in the human host.…”

NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner

“…Schistosoma japonicum ( S. japonicum ), is one of the three main species of schistosome responsible for human infections, and is the only human blood fluke that occurs in China 4 , 5 . Once a person is infected with S. japonicum , the cercariae penetrate the human skin, transform into schistosomula and migrate through the circulatory system to reach the portal system 6 . Here they mature into adult worms and lay eggs.…”

Glucose Uptake in the Human Pathogen Schistosoma mansoni Is Regulated Through Akt/Protein Kinase B Signaling

“…Next, we functionally mapped Akt signaling in intact somules/adults using our published approaches that use immunohistochemistry and confocal microscopy [ 32 , 33 ]. On slides, some “somules” had retained their tails.…”