Parasite Cathepsin D-Like Peptidases and Their Relevance as Therapeutic Targets

Sojka, Daniel; Hartmann, David J.; Bartošová-Sojková, Pavla; Dvořák, Jan

doi:10.1016/j.pt.2016.05.015

Cited by 28 publications

(32 citation statements)

References 95 publications

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“…Hba_17394 is identified to have an aspartic peptidase motif. While further functional investigation is necessary for an exact identity, aspartic peptidases are known to have a range of functions from the digestion of peptides to the production of active proteins from precursor proteins [29, 30]. Within parasites, such a peptidase could be secreted for use as a virulence factor.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate infection genes from the model entomopathogenic nematode Heterorhabditis bacteriophora

et al. 2017

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BackgroundDespite important progress in the field of innate immunity, our understanding of host immune responses to parasitic nematode infections lags behind that of responses to microbes. A limiting factor has been the obligate requirement for a vertebrate host which has hindered investigation of the parasitic nematode infective process. The nematode parasite Heterorhabditis bacteriophora offers great potential as a model to genetically dissect the process of infection. With its mutualistic Photorhabdus luminescens bacteria, H. bacteriophora invades multiple species of insects, which it kills and exploits as a food source for the development of several nematode generations. The ability to culture the life cycle of H. bacteriophora on plates growing the bacterial symbiont makes it a very exciting model of parasitic infection that can be used to unlock the molecular events occurring during infection of a host that are inaccessible using vertebrate hosts.ResultsTo profile the transcriptional response of an infective nematode during the early stage of infection, we performed next generation RNA sequencing on H. bacteriophora IJs incubated in Manduca sexta hemolymph plasma for 9 h. A subset of up-regulated and down-regulated genes were validated using qRT-PCR. Comparative analysis of the transcriptome with untreated controls found a number of differentially expressed genes (DEGs) which cover a number of different functional categories. A subset of DEGs is conserved across Clade V parasitic nematodes revealing an array of candidate parasitic genes.ConclusionsOur analysis reveals transcriptional changes in the regulation of a large number of genes, most of which have not been shown previously to play a role in the process of infection. A significant proportion of these genes are unique to parasitic nematodes, suggesting the identification of a group of parasitism factors within nematodes. Future studies using these candidates may provide functional insight into the process of nematode parasitism and also the molecular evolution of parasitism within nematodes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3468-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Identification of candidate infection genes from the model entomopathogenic nematode Heterorhabditis bacteriophora

et al. 2017

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“…Proteolytic enzymes are receiving increasing attention as potential therapeutic targets or as diagnostic markers for various diseases [ 34 – 36 ]. In helminths, they have been implicated in a broad range of biological process [ 35 , 37 – 39 ]. Very little is known about the function of proteolytic enzymes in A .…”

Section: Discussionmentioning

confidence: 99%

“…Aspartic peptidases are a group of evolutionarily conserved proteolytic enzymes that have been characterized in many parasites [ 35 , 46 , 47 ]. Aspartic peptidases trigger a multienzyme cooperative cascade of hemoglobin proteolysis inside the guts of nematodes and other parasites.…”

Section: Discussionmentioning

confidence: 99%

Activity profiling of peptidases in Angiostrongylus costaricensis first-stage larvae and adult worms

et al. 2018

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BackgroundAngiostrongylus costaricensis is a relatively uncharacterized nematode that causes abdominal angiostrongyliasis in Latin America, a human parasitic disease. Currently, no effective pharmacological treatment for angiostrongyliasis exists. Peptidases are known to be druggable targets for a variety of diseases and are essential for several biological processes in parasites. Therefore, this study aimed to systematically characterize the peptidase activity of A. costaricensis in different developmental stages of this parasitic nematode.Methodology/Principal findingsA library of diverse tetradecapeptides was incubated with cellular lysates from adult worms and from first-stage larvae (L1) and cleaved peptide products were identified by mass spectrometry. Lysates were also treated with class specific peptidase inhibitors to determine which enzyme class was responsible for the proteolytic activity. Peptidase activity from the four major mechanistic classes (aspartic, metallo, serine and cysteine) were detected in adult worm lysate, whereas aspartic, metallo and serine-peptidases were found in the larval lysates. In addition, the substrate specificity profile was found to vary at different pH values.Conclusions/SignificanceThe proteolytic activities in adult worm and L1 lysates were characterized using a highly diversified library of peptide substrates and the activity was validated using a selection of fluorescent substrates. Taken together, peptidase signatures for different developmental stages of this parasite has improved our understanding of the disease pathogenesis and may be useful as potential drug targets or vaccine candidates.

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“…Cathepsin D evolved to an enzyme with digestive function in invertebrates like insects (Srp et al, 2016), mites (Wajahat Mahmood et al, 2013) and bloodsucking parasites as part of a multienzyme proteolytic complex (Sojka et al, 2016) and in vertebrates like bloodsucking fish (Xiao et al, 2015). How a typical intra-cellular lysosomal enzyme can appear in the gastric fluid of crustacea and act there as an extra-cellular enzyme (Rojo et al, 2010a) may be answered by the function and cytology of the digestive organs.…”

Section: Discussionmentioning

confidence: 99%

“…Cathepsin D evolved to an enzyme with digestive function in invertebrates like insects (Srp et al, 2016), mites (Wajahat Mahmood et al, 2013) and bloodsucking parasites as part of a multienzyme proteolytic complex (Sojka et al, 2016) and in vertebrates like bloodsucking fish (Xiao et al, 2015) and now we found it in crustaceans (Navarrete del Rojo et al, 2010a). The presence of cathepsin D in the gastric fluid of clawed lobsters that contributes to the extracellular digestion (Rojo et al, 2010b) raises the question whether this situation is unique within the genus of clawed lobsters (Homarus sp.)…”

Section: Introductionmentioning

confidence: 99%

Is digestive cathepsin D the rule in decapod crustaceans?

Martinez-Alarcon

Saborowski

Rojo‐Arreola

et al. 2018

Comparative Biochemistry and Physiology Part B: Biochemistry an

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A B S T R A C TCathepsin D is an aspartic endopetidase with typical characteristics of lysosomal enzymes. Cathepsin D activity has been reported in the gastric fluid of clawed lobsters where it acts as an extracellular digestive enzyme. Here we investigate whether cathepsin D is unique in clawed lobsters or, instead, common in decapod crustaceans. Eleven species of decapods belonging to six infraorders were tested for cathepsin D activity in the midgut gland, the muscle tissue, the gills, and when technically possible, in the gastric fluid. Cathepsin D activity was present in the midgut gland of all 11 species and in the gastric fluid from the seven species from which samples could be taken. All sampled species showed higher activities in the midgut glands than in non-digestive organs and the activity was highest in the clawed lobster. Cathepsin D mRNA was obtained from tissue samples of midgut gland, muscle, and gills. Analyses of deduced amino acid sequence confirmed molecular features of lysosomal cathepsin D and revealed high similarity between the enzymes from Astacidea and Caridea on one side, and the enzymes from Penaeoidea, Anomura, and Brachyura on the other side. Our results support the presence of cathepsin D activity in the midgut glands and in the gastric fluids of several decapod species suggesting an extracellular function of this lysosomal enzyme. We discuss whether cathepsin D may derive from the lysosomal-like vacuoles of the midgut gland B-cells and is released into the gastric lumen upon secretion by these cells.

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Parasite Cathepsin D-Like Peptidases and Their Relevance as Therapeutic Targets

Cited by 28 publications

References 95 publications

Identification of candidate infection genes from the model entomopathogenic nematode Heterorhabditis bacteriophora

Identification of candidate infection genes from the model entomopathogenic nematode Heterorhabditis bacteriophora

Activity profiling of peptidases in Angiostrongylus costaricensis first-stage larvae and adult worms

Is digestive cathepsin D the rule in decapod crustaceans?

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