The cathepsin-like cysteine peptidases of trematodes of the genus Fasciola

Cwiklinski, Krystyna; Donnelly, Sheila; Drysdale, Orla; Jewhurst, Heather; Smith, David W.; Veríssimo, Carolina De Marco; Pritsch, Izanara Cristine; O’Neill, Sandra M.; Dalton, John P.; Robinson, Mark W.

doi:10.1016/bs.apar.2019.01.001

Cited by 55 publications

(97 citation statements)

References 175 publications

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“…rely almost exclusively on cathepsin L and cathepsin B like cysteine proteases to facilitate tissue migration, feeding, and immune evasion/modulation [49, 50]. Analysis of the recently sequenced F. hepatica genome has confirmed that the large cathepsin L gene family has arisen following gene duplication, which based on current genome assemblies is comprised of 23 genes, followed by functional divergence [51]. In addition, a family of 11 cathepsin B gene sequences was identified within the F. hepatica genome that arose in similar fashion [51].…”

Section: Resultsmentioning

confidence: 99%

Complex and dynamic transcriptional changes allow the helminth Fasciola gigantica to adjust to its intermediate snail and definitive mammalian hosts

Zhang

Cwiklinski

et al. 2019

BMC Genomics

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Background The tropical liver fluke, Fasciola gigantica causes fasciolosis, an important disease of humans and livestock. We characterized dynamic transcriptional changes associated with the development of the parasite in its two hosts, the snail intermediate host and the mammalian definitive host. Results Differential gene transcription analysis revealed 7445 unigenes transcribed by all F. gigantica lifecycle stages, while the majority (n = 50,977) exhibited stage-specific expression. Miracidia that hatch from eggs are highly transcriptionally active, expressing a myriad of genes involved in pheromone activity and metallopeptidase activity, consistent with snail host finding and invasion. Clonal expansion of rediae within the snail correlates with increased expression of genes associated with transcription, translation and repair. All intra-snail stages (miracidia, rediae and cercariae) require abundant cathepsin L peptidases for migration and feeding and, as indicated by their annotation, express genes putatively involved in the manipulation of snail innate immune responses. Cercariae emerge from the snail, settle on vegetation and become encysted metacercariae that are infectious to mammals; these remain metabolically active, transcribing genes involved in regulation of metabolism, synthesis of nucleotides, pH and endopeptidase activity to assure their longevity and survival on pasture. Dramatic growth and development following infection of the mammalian host are associated with high gene transcription of cell motility pathways, and transport and catabolism pathways. The intra-mammalian stages temporally regulate key families of genes including the cathepsin L and B proteases and their trans-activating peptidases, the legumains, during intense feeding and migration through the intestine, liver and bile ducts. While 70% of the F. gigantica transcripts share homology with genes expressed by the temperate liver fluke Fasciola hepatica, gene expression profiles of the most abundantly expressed transcripts within the comparable lifecycle stages implies significant species-specific gene regulation. Conclusions Transcriptional profiling of the F. gigantica lifecycle identified key metabolic, growth and developmental processes the parasite undergoes as it encounters vastly different environments within two very different hosts. Comparative analysis with F. hepatica provides insight into the similarities and differences of these parasites that diverged > 20 million years ago, crucial for the future development of novel control strategies against both species.

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Section: Resultsmentioning

confidence: 99%

Complex and dynamic transcriptional changes allow the helminth Fasciola gigantica to adjust to its intermediate snail and definitive mammalian hosts

Zhang

Cwiklinski

et al. 2019

BMC Genomics

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“…Many molecules produced and secreted by NEJ are well characterized and are known to aid the parasite's tissue invasion and feeding activity [7][8][9]. These include several developmentally-regulated cathepsin L-and B-like cysteine proteases that are specially adapted to degrading host tissue proteins, such as collagen and fibronectin, and blood proteins such haemoglobin [10,11].…”

Section: Introductionmentioning

confidence: 99%

Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases

et al. 2020

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Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate proteases encountered during its development within vertebrate hosts. Interrogation of the F. hepatica genome identified a multi-gene serpin family of seven members that has expanded by gene duplication and divergence to create an array of inhibitors with distinct specificities. We investigated the molecular properties and functions of two representatives, FhSrp1 and FhSrp2, highly expressed in the invasive newly excysted juvenile (NEJ). Consistent with marked differences in the reactive centre loop (RCL) that executes inhibitor-protease complexing, the two recombinant F. hepatica serpins displayed distinct inhibitory profiles against an array of mammalian serine proteases. In particular, rFhSrp1 efficiently inhibited kallikrein (K i = 40 nM) whilst rFhSrp2 was a highly potent inhibitor of chymotrypsin (K i = 0.07 nM). FhSrp1 and FhSrp2 are both expressed on the NEJ surface, predominantly around the oral and ventral suckers, suggesting that these inhibitors protect the parasites from the harmful proteolytic effects of host proteases, such as chymotrypsin, during invasion. Furthermore, the unusual inhibition of kallikrein suggests that rFhSrp1 modulates host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. A vaccine combination of rFhSrp1 and rFhSrp2 formulated in the adjuvant Montanide ISA 206VG elicited modest but non-significant protection against a challenge infection in a rat model, but did induce some protection against liver pathogenesis when compared to a control group and a group vaccinated with two well-studied vaccine candidates, F. hepatica cathepsin L2 and L3. This work highlights the importance of F. hepatica serpins to regulate host responses that enables parasite survival during infection and, coupled with the vaccine data, encourages future vaccine trials in ruminants.

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“…This highly cationic molecule, cytotoxic to many parasites, is likely to bind with, and perhaps be inactivated by, the polyanionic glycocalyx components. Furthermore, the thick, labile and replaceable glycocalyx may help protect the parasite surface from host-gut-derived proteases and the secreted proteases (typically cathepsins B and L) originating from the developing gastrodermal epithelium of the parasite itself, and used to achieve penetration of the host tissues (Bennett, 1975;Cwiklinski et al, 2019). Later in the invasion process, or as a result of anamnestic response in an immunocompetent host, the parasite surface will become the target for the effectors of acquired immunity.…”

Section: Role Of the Glycocalyx In Innate And Acquired Immunitymentioning

confidence: 99%

Fasciola gigantica: Ultrastructural cytochemistry of the tegumental surface in newly- excysted metacercariae and in vitro-penetrated juvenile flukes informs a concept of parasite defence at the interface with the host

Hanna

Moffett

Robinson

et al. 2019

Veterinary Parasitology

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The cathepsin-like cysteine peptidases of trematodes of the genus Fasciola

Cited by 55 publications

References 175 publications

Complex and dynamic transcriptional changes allow the helminth Fasciola gigantica to adjust to its intermediate snail and definitive mammalian hosts

Complex and dynamic transcriptional changes allow the helminth Fasciola gigantica to adjust to its intermediate snail and definitive mammalian hosts

Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases

Fasciola gigantica: Ultrastructural cytochemistry of the tegumental surface in newly- excysted metacercariae and in vitro-penetrated juvenile flukes informs a concept of parasite defence at the interface with the host

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