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

Sulaiman, Azad A.; Zolnierczyk, Katarzyna; Japa, Ornampai; Owen, Jonathan P.; Maddison, Ben C.; Emes, Richard D.; Hodgkinson, Jane E.; Gough, Kevin C.; Flynn, Robin J.


Azad A. Sulaiman

Katarzyna Zolnierczyk

Ornampai Japa

Jonathan P. Owen

Ben C. Maddison

Jane E. Hodgkinson

Professor of Biochemistry and Pathology

Robin J. Flynn


William C Gause


© 2016 Sulaiman et al. 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.


Sulaiman, A. A., Zolnierczyk, K., Japa, O., Owen, J. P., Maddison, B. C., Emes, R. D., …Flynn, R. J. (2016). A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes. PLoS Pathogens, 12(11), e1005991.

Journal Article Type Article
Acceptance Date Oct 11, 2016
Online Publication Date Nov 2, 2016
Publication Date Nov 2, 2016
Deposit Date Nov 7, 2016
Publicly Available Date Nov 7, 2016
Journal PLoS Pathogens
Print ISSN 1553-7366
Electronic ISSN 1553-7374
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 12
Issue 11
Article Number 1005991
Pages e1005991
Public URL
Publisher URL
Additional Information Sulaiman AA, Zolnierczyk K, Japa O, Owen JP, Maddison BC, Emes RD, et al. (2016) A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions
via Host Cytokine Receptor Complexes. PLoS Pathog 12(11): e1005991. doi:10.1371/journal. ppat.1005991


Sulaiman et al TLM.pdf (2.1 Mb)

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