BackgroundProtein kinases are proven targets for drug development with an increasing number of eukaryotic Protein Kinase (ePK) inhibitors now approved as drugs. Mitogen-activated protein kinase (MAPK) family members connect cell-surface receptors to regulatory targets within cells and influence a number of tissue-specific biological activities such as cell proliferation, differentiation and survival. However, the contributions of members of the MAPK pathway to schistosome development and survival are unclear.Methodology/Principal FindingsWe employed RNA interference (RNAi) to elucidate the functional roles of five S. mansoni genes (SmCaMK2, SmJNK, SmERK1, SmERK2 and SmRas) involved in MAPK signaling pathway. Mice were injected with post-infective larvae (schistosomula) subsequent to RNAi and the development of adult worms observed. The data demonstrate that SmJNK participates in parasite maturation and survival of the parasites, whereas SmERK are involved in egg production as infected mice had significantly lower egg burdens with female worms presenting underdeveloped ovaries. Furthermore, it was shown that the c-fos transcription factor was overexpressed in parasites submitted to RNAi of SmERK1, SmJNK and SmCaMK2 indicating its putative involvement in gene regulation in this parasite's MAPK signaling cascade.ConclusionsWe conclude that MAPKs proteins play important roles in the parasite in vivo survival, being essential for normal development and successful survival and reproduction of the schistosome parasite. Moreover SmERK and SmJNK are potential targets for drug development.
BackgroundSchistosoma mansoni is one of the causative agents of schistosomiasis, a neglected tropical disease that affects about 237 million people worldwide. Despite recent efforts, we still lack a general understanding of the relevant host-parasite interactions, and the possible treatments are limited by the emergence of resistant strains and the absence of a vaccine. The S. mansoni genome was completely sequenced and still under continuous annotation. Nevertheless, more than 45% of the encoded proteins remain without experimental characterization or even functional prediction. To improve our knowledge regarding the biology of this parasite, we conducted a proteome-wide evolutionary analysis to provide a broad view of the S. mansoni’s proteome evolution and to improve its functional annotation.ResultsUsing a phylogenomic approach, we reconstructed the S. mansoni phylome, which comprises the evolutionary histories of all parasite proteins and their homologs across 12 other organisms. The analysis of a total of 7,964 phylogenies allowed a deeper understanding of genomic complexity and evolutionary adaptations to a parasitic lifestyle. In particular, the identification of lineage-specific gene duplications pointed to the diversification of several protein families that are relevant for host-parasite interaction, including proteases, tetraspanins, fucosyltransferases, venom allergen-like proteins, and tegumental-allergen-like proteins. In addition to the evolutionary knowledge, the phylome data enabled us to automatically re-annotate 3,451 proteins through a phylogenetic-based approach rather than solely sequence similarity searches. To allow further exploitation of this valuable data, all information has been made available at PhylomeDB (http://www.phylomedb.org).ConclusionsIn this study, we used an evolutionary approach to assess S. mansoni parasite biology, improve genome/proteome functional annotation, and provide insights into host-parasite interactions. Taking advantage of a proteome-wide perspective rather than focusing on individual proteins, we identified that this parasite has experienced specific gene duplication events, particularly affecting genes that are potentially related to the parasitic lifestyle. These innovations may be related to the mechanisms that protect S. mansoni against host immune responses being important adaptations for the parasite survival in a potentially hostile environment. Continuing this work, a comparative analysis involving genomic, transcriptomic, and proteomic data from other helminth parasites, other parasites, and vectors will supply more information regarding parasite’s biology as well as host-parasite interactions.
Schistosoma mansoni is one of the three main causative agents of human schistosomiasis, a major health problem with a vast socio-economic impact. Recent advances in the proteomic analysis of schistosomes have revealed that peptidases are the main virulence factors involved in the pathogenesis of this disease. In this context, evolutionary studies can be applied to identify peptidase families that have been expanded in genomes over time in response to different selection pressures. Using a phylogenomic approach, we searched for expanded endopeptidase families in the S. mansoni predicted proteome with the aim of contributing to the knowledge of such enzymes as potential therapeutic targets. We found three endopeptidase families that comprise leishmanolysins (metallopeptidase M8 family), cercarial elastases (serine peptidase S1 family) and cathepsin D proteins (aspartic peptidase A1 family). Our results suggest that the Schistosoma members of these families originated from successive gene duplication events in the parasite lineage after its diversification from other metazoans. Overall, critical residues are conserved among the duplicated genes/proteins. Furthermore, each protein family displays a distinct evolutionary history. Altogether, this work provides an evolutionary view of three S. mansoni peptidase families, which allows for a deeper understanding of the genomic complexity and lineage-specific adaptations potentially related to the parasitic lifestyle.Key words: phylogenomics -maximum likelihood analysis -homology predictionfunctional annotation -proteases -paralogous families -parasite genomics S. mansoni peptidase families • Larissa Lopes Silva et al. 865et al. 2010). In general, cysteine peptidases have cysteine and histidine residues forming their "catalytic dyad". Meanwhile, other active site residues have been found. Glutamic peptidases have glutamic acid residues as their primary catalytic residues, which are probably the nucleophilic attack mediators involved in the catalysis (Fujinaga et al. 2004, Rawlings et al. 2010. In metallopeptidases, the catalytic mechanism usually involves a single catalytic zinc ion tetrahedrally coordinated by one glutamate and two histidine residues (Rawlings et al. 2010). Serine peptidases have serine residues at their active sites, which together with two other variable amino acids constitute the "catalytic triad" (Hedstrom 2002, Rawlings et al. 2010. Threonine peptidases have threonine residues as their nucleophiles during catalysis. For unknown peptidases, the active site residues have not yet been determined. Evolutionary analyses have been applied to a broad range of studies, which include the identification of gene/protein families that have expanded in a specific lineage over evolutionary time and possibly indicate the existence of selective pressure (Irving et al. 2003, Sargeant et al. 2006, Nahum & Pereira 2008, Robinson et al. 2008, Wu et al. 2009, Huzurbazar et al. 2010. The availability of faster and more powerful computers combined with the development of...
In Brazil, there are near 20 genera and almost 120 species of scorpions of which 95% reproduce sexually. Parthenogenetic reproduction, however, may also take place. To gain insight into useful molecular markers in parthenogenetic scorpion species, we studied DNA polymorphism using two molecular approaches: simple sequence repeat anchored polymerase chain reaction (SSR-PCR) and sequencing of the cytochrome C oxidase subunit I of the mitochondrial genome, mtDNA (COXI), of Tityus serrulatus. Three different groups were used: group 1, composed of 1 female and 14 descendants; group 2 with 1 female and 17 descendants, both from the city of Uberlândia, State of Minas Gerais (MG), Brazil, and the third group that consisted of three adult scorpions from the city of Belo Horizonte, MG. The profiles generated by SSR-PCR were identical for all specimens, while partial sequencing of COXI showed the presence of SNPs. After aligning COXI contigs, one of the groups presented 18 SNPs and the second 8 SNPs. The two groups were differentiated by two diagnostic SNPs. We did not find evidence of mitochondrial recombination. The results are in agreement with the parthenogenetic mode of reproduction of this species and sequencing of the COXI gene enabled the separation of scorpions groups.
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