EmTIP, a T-Cell immunomodulatory protein secreted by the tapeworm Echinococcus multilocularis is important for early metacestode development

PLoS Negl Trop Dis. 2014 Jan 2;8(1):e2632. doi: 10.1371/journal.pntd.0002632. eCollection 2014.


Background: Alveolar 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 findings: We 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.

Conclusions: We 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Helminth / immunology
  • Antigens, Helminth / metabolism*
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Echinococcus multilocularis / growth & development*
  • Echinococcus multilocularis / immunology
  • Helminth Proteins / immunology
  • Helminth Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Sequence Analysis, DNA
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*


  • Antigens, Helminth
  • Helminth Proteins
  • Interferon-gamma

Associated data

  • GENBANK/HF912277

Grants and funding

This work was supported by grant BR 2045/4-1 of the Deutsche Forschungsgemeinschaft as well as a personal grant from the Wellhöfer foundation (Fonds 827317) to KB. This publication was funded by the German Research Foundation (DFG) and the University of Würzburg in the funding program Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.