EmTIP, a T-Cell Immunomodulatory Protein Secreted by the Tapeworm Echinococcus multilocularis Is Important for Early Metacestode Development

Abstract

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.

Author Summary

E. multilocularis is a parasitic helminth causing the chronic human disease alveolar echinococcosis. Current disease control measures are very limited resulting in a high case-fatality rate. A transiently dominating Th1 immune response is mounted at the early phase of the infection, potentially limiting parasite proliferation and disease progression. Understanding the molecular basis of this early anti- Echinococcocus Th1 response would provide valuable information to improve disease control. The authors found that EmTIP, a T-cell immunomodulatory protein homologue, is secreted by the parasite early larva and promotes a Th1 response in host cells. Interestingly, EmTIP binding by antibodies impairs the development of the early parasite larva towards the chronic stage. Altogether the authors propose that E. multilocularis utilizes EmTIP for early larval development, but in the process, the factor is released by the parasite larva and influences host T-cells by directing a parasitocidal Th1 immune response. Therefore, the authors recommend EmTIP as a promising lead for future studies on the development of anti- Echinococcus intervention strategies.