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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:BackgroundAlveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E.multilocularis, by excretory/secretory (E/S)-products, specifically affects DC to deviate immune responses, little information is available on the molecular nature of respective E/S-products and their mode of action.Methodology/principal findingsWe established cultivation systems for exposing DC to live material from early (oncosphere), chronic (metacestode) and late (protoscolex) infectious stages. When co-incubated with Echinococcus primary cells, representing the invading oncosphere, or metacestode vesicles, a significant proportion of DC underwent apoptosis and the surviving DC failed to mature. In contrast, DC exposed to protoscoleces upregulated maturation markers and did not undergo apoptosis. After pre-incubation with primary cells and metacestode vesicles, DC showed a strongly impaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. While none of the larvae induced the secretion of pro-inflammatory IL-12p70, the production of immunosuppressive IL-10 was elevated in response to primary cell E/S-products. Finally, upon incubation with DC and naïve T-cells, E/S-products from metacestode vesicles led to a significant expansion of Foxp3+ T cells in vitro.ConclusionsThis is the first report on the induction of apoptosis in DC by cestode E/S-products. Our data indicate that the early infective stage of E. multilocularis is a strong inducer of tolerance in DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. The induction of CD4+CD25+Foxp3+ T cells through metacestode E/S-products suggests that these cells fulfill an important role for parasite persistence during chronic echinococcosis.

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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