title: 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.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
authors.affiliation: Institute of Parasitology, University of Bern, Bern, Switzerland; State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; Department of Nuclear Medicine, University of Franche-Comté and Jean Minjoz University Hospital, Besançon, Franche-Comté, France.
authors.forename: Junhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: World Health Organization (WHO)-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, University of Franche-Comté and University Hospital, Besançon, Franche-Comté, France.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Vuitton
authors.affiliation: Institute of Parasitology, University of Bern, Bern, Switzerland.
authors.forename: Norbert
authors.initials: N
authors.lastname: Müller
authors.affiliation: Institute of Parasitology, University of Bern, Bern, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
authors.affiliation: Institute of Parasitology, University of Bern, Bern, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Spiliotis
authors.affiliation: Department of Nuclear Medicine, University of Franche-Comté and Jean Minjoz University Hospital, Besançon, Franche-Comté, France.
authors.forename: Oleg
authors.initials: O
authors.lastname: Blagosklonov
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Grandgirard
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Biology Division, Spiez Laboratory, Federal Office for Civil Protection (FOCP), Spiez, Switzerland.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
authors.affiliation: University of Toronto Transplantation Institute, Toronto, Ontario, Canada.
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.affiliation: University of Toronto Transplantation Institute, Toronto, Ontario, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Levy
authors.affiliation: State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Renyong
authors.initials: R
authors.lastname: Lin
authors.affiliation: State Key Lab Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wen
authors.affiliation: Institute of Parasitology, University of Bern, Bern, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gottstein
mesh_terms: D000818:Animals; D015704:CD4 Antigens; D003208:Concanavalin A / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004443:Echinococcosis; D004444:Echinococcosis, Hepatic / Q000276:immunology* / Q000469:parasitology; D048210:Echinococcus multilocularis / Q000276:immunology*; D005340:Fibrinogen / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D015704:CD4 Antigens; C490637:Fgl2 protein, mouse; D020381:Interleukin-17; D003208:Concanavalin A; D005340:Fibrinogen