title: A Trypanosoma brucei kinesin heavy chain promotes parasite growth by triggering host arginase activity.
abstract: BACKGROUND
  In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.
  
  
  RESULTS
  By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO) synthase activity. This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time.
  
  
  CONCLUSIONS
  A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity.
authors.affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: De Muylder
authors.forename: Sylvie
authors.initials: S
authors.lastname: Daulouède
authors.forename: Laurence
authors.initials: L
authors.lastname: Lecordier
authors.forename: Pierrick
authors.initials: P
authors.lastname: Uzureau
authors.forename: Yannick
authors.initials: Y
authors.lastname: Morias
authors.forename: Jan
authors.initials: J
authors.lastname: Van Den Abbeele
authors.forename: Guy
authors.initials: G
authors.lastname: Caljon
authors.forename: Michel
authors.initials: M
authors.lastname: Hérin
authors.forename: Philippe
authors.initials: P
authors.lastname: Holzmuller
authors.forename: Silla
authors.initials: S
authors.lastname: Semballa
authors.forename: Pierrette
authors.initials: P
authors.lastname: Courtois
authors.forename: Luc
authors.initials: L
authors.lastname: Vanhamme
authors.forename: Benoît
authors.initials: B
authors.lastname: Stijlemans
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Barlow
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Luke
authors.initials: L
authors.lastname: Barron
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
authors.forename: Philippe
authors.initials: P
authors.lastname: Vincendeau
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D016547:Kinesins / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D014346:Trypanosoma brucei brucei / Q000235:genetics / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001119:Arginase; D015815:Cell Adhesion Molecules; D016753:Interleukin-10; D016547:Kinesins; D037181:Lectins, C-Type; D009569:Nitric Oxide; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C556062:IL10 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C544448:Arg1 protein, mouse