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Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4+ CD25+ Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice.

AbstractBACKGROUND:
The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. We previously showed that Fibrinogen-like-protein 2 (FGL2), a novel CD4+CD25+ Treg effector molecule, was over-expressed in the liver of mice experimentally infected with E. multilocularis. However, little is known about its contribution to the control of this chronic helminth infection.
METHODS/FINDINGS:
Key parameters for infection outcome in E. multilocularis-infected fgl2-/- (AE-fgl2-/-) and wild type (AE-WT) mice at 1 and 4 month(s) post-infection were (i) parasite load (i. e. wet weight of parasitic metacestode tissue), and (ii) parasite cell proliferation as assessed by determining E. multilocularis 14-3-3 gene expression levels. Serum FGL2 levels were measured by ELISA. Spleen cells cultured with ConA for 48h or with E. multilocularis Vesicle Fluid (VF) for 96h were analyzed ex-vivo and in-vitro. In addition, spleen cells from non-infected WT mice were cultured with rFGL2/anti-FGL2 or rIL-17A/anti-IL-17A for further functional studies. For Treg-immune-suppression-assays, purified CD4+CD25+ Treg suspensions were incubated with CD4+ effector T cells in the presence of ConA and irradiated spleen cells as APCs. Flow cytometry and qRT-PCR were used to assess Treg, Th17-, Th1-, Th2-type immune responses and maturation of dendritic cells. We showed that AE-fgl2-/- mice exhibited (as compared to AE-WT-animals) (a) a significantly lower parasite load with reduced proliferation activity, (b) an increased T cell proliferative response to ConA, (c) reduced Treg numbers and function, and (d) a persistent capacity of Th1 polarization and DC maturation.
CONCLUSIONS:
FGL2 appears as one of the key players in immune regulatory processes favoring metacestode survival by promoting Treg cell activity and IL-17A production that contributes to FGL2-regulation. Prospectively, targeting FGL2 could be an option to develop an immunotherapy against AE and other chronic parasitic diseases.
AuthorsJunhua Wang, Dominique A Vuitton, Norbert Müller, Andrew Hemphill, Markus Spiliotis, Oleg Blagosklonov, Denis Grandgirard, Stephen L Leib, Itay Shalev, Gary Levy, Xiaomei Lu, Renyong Lin, Hao Wen, Bruno Gottstein
JournalPLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 9 Issue 5 Pg. e0003755 (May 2015) ISSN: 1935-2735 [Electronic] United States
PMID25955764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CD4 Antigens
  • Fgl2 protein, mouse
  • Interleukin-17
  • Concanavalin A
  • Fibrinogen
Topics
  • Animals
  • CD4 Antigens
  • Concanavalin A (immunology)
  • Dendritic Cells (cytology, immunology)
  • Echinococcosis
  • Echinococcosis, Hepatic (immunology, parasitology)
  • Echinococcus multilocularis (immunology)
  • Fibrinogen (genetics, immunology)
  • Flow Cytometry
  • Interleukin-17 (biosynthesis)
  • Mice
  • T-Lymphocytes, Regulatory (immunology)
  • Th1 Cells (immunology)
  • Th17 Cells (immunology)
  • Th2 Cells (immunology)

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