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

ABSTRACT: 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-? 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-? 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-? 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-? 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.

SUBMITTER: Sulaiman AA

PROVIDER: S-EPMC5091765 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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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 AA Zolnierczyk Katarzyna K Japa Ornampai O Owen Jonathan P JP Maddison Ben C BC Emes Richard D RD Hodgkinson Jane E JE Gough Kevin C KC Flynn Robin J RJ

PLoS pathogens 20161102 11

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 ...[more]

PMID: 27806135

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Project description:BackgroundParasites can profoundly impact their hosts and are responsible for a plethora of debilitating diseases. To identify global changes in host gene expression related to parasite infection, we sequenced, assembled, and annotated the liver transcriptomes of Balb/cj mice infected with the trematode parasite Schistosoma mansoni and compared the results to uninfected mice. We used two different methodologies (i.e. de novo and reference guided) to evaluate the influence of parasite sequences on host transcriptome assembly.ResultsOur results demonstrate that the choice of assembly methodology significantly impacted the proportion of parasitic reads detected from the host library, yet the presence of non-target (xenobiotic) sequences did not create significant structural errors in the assembly. After removing parasite sequences from the mouse transcriptomes, we analyzed host gene expression under different parasite infection levels and observed significant differences in the associated immunologic and metabolic responses based on infection level. In particular, genes associated with T-helper type 1 (Th-1) and T-helper type 2 (Th-2) were up-regulated in infected mice whereas genes related to amino acid and carbohydrate metabolism were down-regulated in infected mice. These changes in gene expression scale with infection status and likely impact the evolutionary fitness of hosts.ConclusionsOverall, our data indicate that a) infected mice reduce the expression of key metabolic genes in direct proportion to their infection level; b) infected mice similarly increase the expression of key immune genes in response to infection; c) patterns of gene expression correspond to the pathological symptoms of schistosomiasis; and d) identifying and filtering out non-target sequences (xenobiotics) improves differential expression prediction. Our findings identify parasite targets for RNAi or other therapies and provide a better understanding of the pathology and host immune repertoire involved in response to S. mansoni infections.

Dataset Information

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

Publications

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

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