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Expansion of Host Regulatory T Cells by Secreted Products of the Tapeworm Echinococcus multilocularis.

ABSTRACT: Background:Alveolar echinococcosis (AE), caused by the metacestode larval stage of the fox-tapeworm Echinococcus multilocularis, is a chronic zoonosis associated with significant modulation of the host immune response. A role of regulatory T-cells (Treg) in generating an immunosuppressive environment around the metacestode during chronic disease has been reported, but the molecular mechanisms of Treg induction by E. multilocularis, particularly parasite immunoregulatory factors involved, remain elusive so far. Methodology/Principal Findings:We herein demonstrate that excretory/secretory (E/S) products of the E. multilocularis metacestode promote the formation of Foxp3+ Treg from CD4+ T-cells in vitro in a TGF-?-dependent manner, given that this effect was abrogated by treatment with antibody to mammalian TGF-?. We also show that host T-cells secrete elevated levels of the immunosuppressive cytokine IL-10 in response to metacestode E/S products. Within the E/S fraction of the metacestode we identified an E. multilocularis activin A homolog (EmACT) that displays significant similarities to mammalian Transforming Growth Factor-? (TGF-?/activin subfamily members. EmACT obtained from heterologous expression failed to directly induce Treg expansion from naïve T cells but required addition of recombinant host TGF-? to promote CD4+ Foxp3+ Treg conversion in vitro. Furthermore, like in the case of metacestode E/S products, EmACT-treated CD4+ T-cells secreted higher levels of IL-10. These observations suggest a contribution of EmACT to in vitro expansion of Foxp3+ Treg by the E. multilocularis metacestode. Using infection experiments we show that intraperitoneally injected metacestode tissue expands host Foxp3+ Treg, confirming the expansion of this cell type in vivo during parasite establishment. Conclusion/Significance:In conclusion, we herein demonstrate that E. multilocularis larvae secrete factors that induce the secretion of IL-10 by T-cells and contribute to the expansion of TGF-b-driven Foxp3+ Treg, a cell type that has been reported crucial for generating a tolerogenic environment to support parasite establishment and proliferation. Among the E/S factors of the parasite we identified a factor with structural and functional homologies to mammalian activin A which might play an important role in these activities.

SUBMITTER: Nono JK

PROVIDER: S-EPMC7225322 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Expansion of Host Regulatory T Cells by Secreted Products of the Tapeworm <i>Echinococcus multilocularis</i>.

Nono Justin Komguep JK Lutz Manfred B MB Brehm Klaus K

Frontiers in immunology 20200508

<h4>Background</h4>Alveolar echinococcosis (AE), caused by the metacestode larval stage of the fox-tapeworm <i>Echinococcus multilocularis</i>, is a chronic zoonosis associated with significant modulation of the host immune response. A role of regulatory T-cells (Treg) in generating an immunosuppressive environment around the metacestode during chronic disease has been reported, but the molecular mechanisms of Treg induction by <i>E. multilocularis</i>, particularly parasite immunoregulatory fac ...[more]

PMID: 32457746

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Project description:BackgroundAlveolar echinococcosis (AE), caused by the metacestode of the tapeworm Echinococcus multilocularis, is a lethal zoonosis associated with host immunomodulation. T helper cells are instrumental to control the disease in the host. Whereas Th1 cells can restrict parasite proliferation, Th2 immune responses are associated with parasite proliferation. Although the early phase of host colonization by E. multilocularis is dominated by a potentially parasitocidal Th1 immune response, the molecular basis of this response is unknown.Principal findingsWe describe EmTIP, an E. multilocularis homologue of the human T-cell immunomodulatory protein, TIP. By immunohistochemistry we show EmTIP localization to the intercellular space within parasite larvae. Immunoprecipitation and Western blot experiments revealed the presence of EmTIP in the excretory/secretory (E/S) products of parasite primary cell cultures, representing the early developing metacestode, but not in those of mature metacestode vesicles. Using an in vitro T-cell stimulation assay, we found that primary cell E/S products promoted interferon (IFN)-γ release by murine CD4+ T-cells, whereas metacestode E/S products did not. IFN-γ release by T-cells exposed to parasite products was abrogated by an anti-EmTIP antibody. When recombinantly expressed, EmTIP promoted IFN-γ release by CD4+ T-cells in vitro. After incubation with anti-EmTIP antibody, primary cells showed an impaired ability to proliferate and to form metacestode vesicles in vitro.ConclusionsWe provide for the first time a possible explanation for the early Th1 response observed during E. multilocularis infections. Our data indicate that parasite primary cells release a T-cell immunomodulatory protein, EmTIP, capable of promoting IFN-γ release by CD4+ T-cells, which is probably driving or supporting the onset of the early Th1 response during AE. The impairment of primary cell proliferation and the inhibition of metacestode vesicle formation by anti-EmTIP antibodies suggest that this factor fulfills an important role in early E. multilocularis development within the intermediate host.

Project description:BackgroundThe cestode Echinococcus multilocularis is the causative agent of human alveolar echinococcosis (AE). However, this life-threatening disease is still difficult to treat and control, due to the lack of efficient drugs and vaccines. Excretory/secretory (ES) proteins are crucial for parasite survival and represent potential preferred targets for novel intervention strategies. However, the ES protein features in this parasite have been poorly investigated until now. The current study was carried out to identify and characterise a repertoire of ES proteins in E. multilocularis at the genome-wide level.MethodsHere we predicted and functionally annotated the classical and non-classical ES proteins, and comprehensively compared the features and evolution of ES and non-ES proteins in E. multilocularis genome using an integration of bioinformatics tools. The intervention target and antigen potentials as well as the transcription information were also investigated.ResultsComputational analysis of the E. multilocularis proteins identified 673 putative ES proteins (6.4%), of which 617 (91.68%) could be supported by transcription analyses. The predicted ES proteins in E. multilocularis were mostly represented by molecular functions of protease inhibitors, proteases, glycoside hydrolases, immunoglobulin-like folds and growth factors. Analysis of the ratio between synonymous and non-synonymous substitution rates (dN/dS) revealed no significant difference of the evolution selection pressure on ES and non-ES protein coding genes. ES proteins showed higher antigenic density measured by AAR values as compared with the transmembrane proteins but had no significant difference of that feature with intracellular proteins. Additionally, 383 possible ideal drug targets were identified in ES proteins, of which four proteins have corresponding known drugs.ConclusionsThe present study is the first to identify a repertoire of predicted ES proteins at the genome-wide level in E. multilocularis. The comprehensive analysis provides some novel understanding of the parasite ES protein features and a valuable resource of potential targets for future experimental studies to develop new intervention tools against this parasite.

Project description:BackgroundThe metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood.ResultsUsing in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin.ConclusionsOur data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.

Dataset Information

Expansion of Host Regulatory T Cells by Secreted Products of the Tapeworm Echinococcus multilocularis.

Publications

Expansion of Host Regulatory T Cells by Secreted Products of the Tapeworm <i>Echinococcus multilocularis</i>.

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