TGF-β superfamily members from the helminth Fasciola hepatica show intrinsic effects on viability and development

Japa, Ornampai; Hodgkinson, Jane E.; Emes, Richard D.; Flynn, Robin J.

doi:10.1186/s13567-015-0167-2

Cited by 18 publications

(16 citation statements)

References 36 publications

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“…We have recently shown that the trematode parasite Fasciola hepatica contains three ligand members of the transforming growth factor superfamily [17]. These include two bone morphogenic proteins (BMPs) and an activin-like molecule which we have terms F .…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that FhTLM is selectively expressed within the newly excysted juvenile (NEJs) stage of F. hepatica infection [17]. NEJs are thought to be resident within the intestine for only a number of hours before entering the peritoneal cavity and continuing on their migration to the liver.…”

Section: Resultsmentioning

confidence: 99%

“…The macrophage response to surgery has been shown to tend towards alternative activation, thus attempting to analyse the immune phenotype in such circumstances may prove difficult. A second complicating factor are the parasite-intrinsic effects of FhTLM [17], knock-out of FhTLM may yield a near-lethal or lethal phenotype, for reasons unrelated to host immunity, again complicating the analysis. A system for conditional gene targeting within the parasite metacercariae would best allow for natural infection and thus a faithful analysis of the resulting immune response; however these tools do not yet exist.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously described the cloning and expression of FhTLM [17]. A pET28-based construct (Novagen) was used to express a 6XHis-Tagged protein in BL21 E .…”

Section: Methodsmentioning

confidence: 99%

“…We have recently demonstrated that the F . hepatica contains a TGF-like molecule which we termed FhTLM [17]. Previously we have shown that the expression of FhTLM was restricted to the NEJ stage.…”

Section: Introductionmentioning

confidence: 99%

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A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

et al. 2016

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The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allowing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF) superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL)-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory receptor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is dependent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs) in their evasion of antibody-dependent cell cytotoxicity (ADCC) by reducing the NO response of macrophages—again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for dampened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow for a reduced effector response targeting juvenile parasites which we demonstrate extends to an abrogation of the ADCC response. Thus suggesting that FhTLM is a stage specific evasion molecule that utilises host cytokine receptors. These findings are the first to clearly demonstrate the interaction of a helminth cytokine with a host receptor complex resulting in immune modifications that facilitate the non-protective chronic immune response which is characteristic of F. hepatica infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…We have previously described the cloning and expression of FhTLM [17]. A pET28-based construct (Novagen) was used to express a 6XHis-Tagged protein in BL21 E .…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

et al. 2016

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The omic approach to parasitic trematode research—a review of techniques and developments within the past 5 years

Haçarız

Sayers

2016

Parasitol Res

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The evolution of technologies to explore parasite biology at a detailed level has made significant advances in recent years, particularly with the development of omic-based strategies. Whilst extensive efforts have been made in the past to develop therapeutic and prophylactic control strategies for trematode parasites, only the therapeutic anthelmintic approach can be regarded as usable in clinical practice. Currently, there is no commercialised prophylactic strategy (such as vaccination) for protection of the definitive host against any trematode parasite. Since 2010 in particular, the integration of omic technologies, including liquid chromatography-mass spectrometry (LC-MS) and next-generation sequencing (NGS), has been increasingly reported in trematode-related studies. Both LC-MS and NGS facilitate a better understanding of the biology of trematodes and provide a promising route to identifying clinically important biological characteristics of parasitic trematodes. In this review, we focus on the application, advantages, and disadvantages of omic technologies (LC-MS and NGS) in trematode research within the past 5 years and explore the use and translation of the omic-based research results into practical tools to deal with infection.

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Identification and expression of a transforming growth factor beta (TGF-β) homologue in the tropical liver fluke Fasciola gigantica

2022

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TGF-β superfamily members from the helminth Fasciola hepatica show intrinsic effects on viability and development

Cited by 18 publications

References 36 publications

A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

The omic approach to parasitic trematode research—a review of techniques and developments within the past 5 years

Identification and expression of a transforming growth factor beta (TGF-β) homologue in the tropical liver fluke Fasciola gigantica

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