Infection by the Helminth Parasite Fasciola hepatica Requires Rapid Regulation of Metabolic, Virulence, and Invasive Factors to Adjust to Its Mammalian Host

Abstract

The parasite Fasciola hepatica infects a broad range of mammals with impunity. Following ingestion of parasites (metacercariae) by the host, newly excysted juveniles (NEJ) emerge from their cysts, rapidly penetrate the duodenal wall and migrate to the liver. Successful infection takes just a few hours and involves negotiating hurdles presented by host macromolecules, tissues and micro-environments, as well as the immune system. Here, transcriptome and proteome analysis of ex vivo F. hepatica metacercariae and NEJ reveal the rapidity and multitude of metabolic and developmental alterations that take place in order for the parasite to establish infection. We found that metacercariae despite being encased in a cyst are metabolically active, and primed for infection. Following excystment, NEJ expend vital energy stores and rapidly adjust their metabolic pathways to cope with their new and increasingly anaerobic environment. Temperature increases induce neoblast proliferation and the remarkable up-regulation of genes associated with growth and development. Cysteine proteases synthesized by gastrodermal cells are secreted to facilitate invasion and tissue degradation, and tegumental transporters, such as aquaporins, are varied to deal with osmotic/salinity changes. Major proteins of the total NEJ secretome include proteases, protease inhibitors and anti-oxidants, and an array of immunomodulators that likely disarm host innate immune effector cells. Thus, the challenges of infection by F. hepatica parasites are met by rapid metabolic and physiological adjustments that expedite tissue invasion and immune evasion; these changes facilitate parasite growth, development and maturation. Our molecular analysis of the critical processes involved in host invasion has identified key targets for future drug and vaccine strategies directed at preventing parasite infection.

Modulation of the Functions of Goat Peripheral Blood Mononuclear Cells by Fasciola gigantica Thioredoxin Peroxidase In Vitro

“…Of particular importance to their survival is the ability of liver flukes to employ an anti–oxidant, redox-based system that protects the liver flukes against the reactive oxygen and nitrogen species produced by host immune cells and endogenous cellular metabolism [ 22 ]. Thioredoxin (FhTRx) and the related protein peroxiredoxin (FhPRx), key components of this anti–oxidant system, were amongst the most abundant proteins detected in the secretome of newly excysted juveniles (NEJ) of F. hepatica [ 23 ].…”

In silico analyses of protein glycosylating genes in the helminth Fasciola hepatica (liver fluke) predict protein-linked glycan simplicity and reveal temporally-dynamic expression profiles

“…In developmentally staged transcriptomes from intra-mammalian parasites 8 , 9 , we detected 101 glycogene transcripts (66% of total; Fig. 7 , Supplementary Dataset S2 ).…”

“…Exploring our previously published proteomic datasets for peptides relating to our glycosylation genes uncovered 29 genes represented by at least 2 unique peptides in one or more of these datasets (Supplementary Dataset S5 ) 9 , 14 , 62 . Notably, these datasets identified three glycosylating proteins within secreted proteome datasets.…”

“…As part of our analysis we exploited previously published datasets describing: (i) Developmentally-staged RNAseq datasets representing F . hepatica metacercariae, newly excysted juveniles (NEJs) maintained in vitro for 1 h, 3 h or 24 h post excystment, ex vivo parasites recovered from rat liver parenchyma 21-days post infection, and adult parasites recovered from cattle bile ducts at abattoir 8 , 9 ; (ii) Proteomic datasets representing N-glycoproteins from the adult tegument, excretory-secretory (ES) products from adults and NEJs, extracellular vesicles (EVs) from NEJs and somatic extracts from metacercariae and NEJs 8 , 9 , 14 . These datasets were processed and analysed as previously described 8 , 9 , 14 .…”

Calicophoron daubneyi—The Path Toward Understanding Its Pathogenicity and Host Interactions

“…Despite their prevalence, our knowledge of many aspects of basic rumen fluke biology, and how they interact with their hosts, is limited. This is in contrast to F. hepatica, the other major endemic trematode species in the UK, for which we have a very good understanding of the key metabolic, biochemical and molecular mechanisms underpinning invasion, virulence, and development, as well as a clear picture of the immune responses (in rodent and ruminant hosts) which define the cellular and molecular signatures of liver fluke infection (27)(28)(29)(30)(31).…”