Abstract
Eukaryotic protein kinases (ePKs) are good medical targets for drug development in different biological systems. ePKs participate in many cellular processes, including the p38 MAPK regulation of homeostasis upon oxidative stress. We propose to assess the role of Smp38 MAPK signaling pathway in Schistosoma mansoni development and protection against oxidative stress, parasite survival, and also to elucidate which target genes have their expression regulated by Smp38 MAPK. After a significant reduction of up to 84% in the transcription level by Smp38 MAPK gene knockdown, no visible phenotypic changes were reported in schistosomula in culture. The development of adult worms was tested in vivo in mice infected with the Smp38 knocked-down schistosomula. It was observed that Smp38 MAPK has an essential role in the transformation and survival of the parasites as a low number of adult worms was recovered. Smp38 knockdown also resulted in decreased egg production, damaged adult worm tegument, and underdeveloped ovaries in females. Furthermore, only ~13% of the eggs produced developed into mature eggs. Our results suggest that inhibition of the Smp38 MAPK activity interfere in parasites protection against reactive oxygen species. Smp38 knockdown in adult worms resulted in 80% reduction in transcription levels on the 10th day, with consequent reduction of 94.4% in oviposition in vitro. In order to search for Smp38 MAPK pathway regulated genes, we used an RNASeq approach and identified 1,154 DEGs in Smp38 knockdown schistosomula. A substantial proportion of DEGs encode proteins with unknown function. The results indicate that Smp38 regulates essential signaling pathways for the establishment of parasite homeostasis, including genes related to antioxidant defense, structural composition of ribosomes, spliceosomes, cytoskeleton, as well as, purine and pyrimidine metabolism pathways. Our data show that the Smp38 MAPK signaling pathway is a critical route for parasite development and may present attractive therapeutic targets for the treatment and control of schistosomiasis.
Highlights
Protein kinases (PKs) have been developed as drug targets, with several inhibitors already registered for clinical trials [1]
The expression profile of Smp38 in developmental stages of S. mansoni was investigated by quantitative PCR
Many extracellular stimuli are converted into specific cellular responses through the activation of mitogen-activated protein kinases (MAPKs)
Summary
Protein kinases (PKs) have been developed as drug targets, with several inhibitors already registered for clinical trials [1]. Several cellular processes, including growth, metabolism, apoptosis, and immune responses are regulated by kinases of the family of mitogen-activated protein kinases (MAPKs) [2,3,4]. MAPK signaling pathways are evolutionally highly conserved and respond to a variety of extracellular stimuli, such as growth factors and environmental stresses. MAPK signaling pathways are well-conserved and include members of four subfamilies: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), Nemo-like kinase (NLK), and p38 MAP kinase [6]. The p38 subfamily has four isoforms identified (p38 α/β/γ/δ) that interact with a diverse number of regulatory mechanisms [7,8,9], many of which are related to stress responses, inflammation, and apoptosis [10, 11]
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