The silencing of cysteine proteases in Fasciola hepatica newly excysted juveniles using RNA interference reduces gut penetration

McGonigle, Louise; Mousley, Angela; Marks, Nikki J.; Brennan, Gerard; Dalton, John P.; Spithill, Terry W.; Day, Tim A.; Maule, Aaron G.

doi:10.1016/j.ijpara.2007.10.007

Cited by 158 publications

(145 citation statements)

References 22 publications

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“…hepatica (24). In the latter trematode, these proteins are proposed to play an important role in the evasion of host immune responses, which likely relates to the protection of the parasite from reactive oxygen species released by host immune cells (82)(83)(84)(85), an inhibition of the proliferative potential of spleen cells (e.g. in rats) (86), and/or the recruitment and alternative activation of macrophages (86 -88).…”

Section: Discussionmentioning

confidence: 99%

A Deep Exploration of the Transcriptome and “Excretory/Secretory” Proteome of Adult Fascioloides magna

Cantacessi

Mulvenna

Young

et al. 2012

Molecular & Cellular Proteomics

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Parasitic liver flukes of the family Fasciolidae are responsible for major socioeconomic losses worldwide. However, at present, knowledge of the fundamental molecular biology of these organisms is scant. Here, we characterize, for the first time, the transcriptome and secreted proteome of the adult stage of the "giant liver fluke," Fascioloides magna, using Illumina sequencing technology and one-dimensional SDS-PAGE and OFFGEL protein electrophoresis, respectively. A total of ϳ54,000,000 reads were generated and assembled into ϳ39,000 contiguous sequences (contigs); ϳ20,000 peptides were predicted and classified based on homology searches, protein motifs, gene ontology, and biological pathway mapping. From the predicted proteome, 48.1% of proteins could be assigned to 384 biological pathway terms, including "spliceosome," "RNA transport," and "endocytosis." Putative proteins involved in amino acid degradation were most abundant. Of the 835 secreted proteins predicted from the transcriptome of F. magna, 80 were identified in the excretory/secretory products from this parasite. Highly represented were antioxidant proteins, followed by peptidases (particularly cathepsins) and proteins involved in carbohydrate metabolism. The integration of transcriptomic and proteomic datasets generated herein sets the scene for future studies aimed at exploring the potential role(s) that molecules might play at the hostparasite interface and for establishing novel strategies for the treatment or control of parasitic fluke infections. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

A Deep Exploration of the Transcriptome and “Excretory/Secretory” Proteome of Adult Fascioloides magna

Cantacessi

Mulvenna

Young

et al. 2012

Molecular & Cellular Proteomics

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“…Asparaginyl endopeptidases are likely to be essential for the rapid trans-processing and activation of the stored zymogens of cathepsins L and B, and hence it is probable that one of the first steps in activation of the dormant larvae is the switching on of the genes encoding these enzymes. A role for cathepsin L and B proteases in the penetration of the host by NEJ was recently demonstrated using RNA interference methods by McGonigle et al (67). Knockdown of both cathepsin L and cathepsin B transcripts in NEJ parasites blocked the ability of the larvae to penetrate and traverse the intestinal wall of a rodent host.…”

Section: Relative Expression Levels Of Fasciola Proteases and Relatiomentioning

confidence: 99%

An Integrated Transcriptomics and Proteomics Analysis of the Secretome of the Helminth Pathogen Fasciola hepatica

Robinson

Menon

Donnelly

et al. 2009

Molecular & Cellular Proteomics

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249

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To infect their mammalian hosts, Fasciola hepatica larvae must penetrate and traverse the intestinal wall of the duodenum, move through the peritoneum, and penetrate the liver. After migrating through and feeding on the liver, causing extensive tissue damage, the parasites move to their final niche in the bile ducts where they mature and produce eggs. Here we integrated a transcriptomics and proteomics approach to profile Fasciola secretory proteins that are involved in host-pathogen interactions and to correlate changes in their expression with the migration of the parasite. Prediction of F. hepatica secretory proteins from 14,031 expressed sequence tags (ESTs) available from the Wellcome Trust Sanger Centre using the semiautomated EST2Secretome pipeline showed that the major components of adult parasite secretions are proteolytic enzymes including cathepsin L, cathepsin B, and asparaginyl endopeptidase cysteine proteases as well as novel trypsinlike serine proteases and carboxypeptidases. Proteomics analysis of proteins secreted by infective larvae, immature flukes, and adult F. hepatica showed that these proteases are developmentally regulated and correlate with the passage of the parasite through host tissues and its encounters with different host macromolecules. Proteases such as FhCL3 and cathepsin B have specific functions in larvae activation and intestinal wall penetration, whereas FhCL1, FhCL2, and FhCL5 are required for liver penetration and tissue and blood feeding. Besides proteases, the parasites secrete an array of antioxidants that are also highly regulated according to their migration through host tissues. However, whereas the proteases of F. hepatica are secreted into the parasite gut via a classical endoplasmic reticulum/Golgi pathway, we speculate that the antioxidants, which all lack a signal sequence, are released via a non-classical trans-tegumental pathway. Fasciola hepatica is a helminth (worm) parasite with a worldwide distribution. Although traditionally regarded as a parasite of livestock, particularly sheep and cattle, that results in a large economic loss to the agricultural community it has recently emerged as an important human infection in many regions of the world, including South America, Iran, Egypt, and mainland South-East Asia (1). Dormant larvae contained within cysts adhere to vegetation and emerge as infective juveniles (newly excysted juveniles (NEJs)) 1 in the duodenum following ingestion by animals or humans. They infect their hosts by rapidly penetrating the intestinal wall and entering the peritoneal cavity where they break through the liver capsule. After 8 -12 weeks of consistent burrowing, feeding, and growth within the liver parenchyma they move to their final destination within the bile ducts where they mature and produce enormous numbers of eggs (2). The two distinct clinical phases of fasciolosis are directly related to the migration of the parasites: acute fasciolosis, which manifests as fever, abdominal pain, weight loss, and hepatomegaly, is associated with...

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“…07 % concentrated HCl and 0 . 006 % l-cysteine for up to 3 h at 37 xC (McGonigle et al 2008). Excysted juveniles are maintained in nutritive culture medium, such as RPMI 1640, supplemented with penicillin and streptomycin and possibly serum or red blood cells (Ibarra and Jenkins, 1984).…”

Section: F Hepatica In Vitro Assaysmentioning

confidence: 99%

In vitroandin vivotrematode models for chemotherapeutic studies

2009

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Schistosomiasis and food-borne trematodiases are chronic parasitic diseases affecting millions of people mostly in the developing world. Additional drugs should be developed as only few drugs are available for treatment and drug resistance might emerge. In vitro and in vivo whole parasite screens represent essential components of the trematodicidal drug discovery cascade. This review describes the current state-of-the-art of in vitro and in vivo screening systems of the blood fluke Schistosoma mansoni, the liver fluke Fasciola hepatica and the intestinal fluke Echinostoma caproni. Examples of in vitro and in vivo evaluation of compounds for activity are presented. To boost the discovery pipeline for these diseases there is a need to develop validated, robust high-throughput in vitro systems with simple readouts.

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The silencing of cysteine proteases in Fasciola hepatica newly excysted juveniles using RNA interference reduces gut penetration

Cited by 158 publications

References 22 publications

A Deep Exploration of the Transcriptome and “Excretory/Secretory” Proteome of Adult Fascioloides magna

A Deep Exploration of the Transcriptome and “Excretory/Secretory” Proteome of Adult Fascioloides magna

An Integrated Transcriptomics and Proteomics Analysis of the Secretome of the Helminth Pathogen Fasciola hepatica

In vitroandin vivotrematode models for chemotherapeutic studies

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