• Géraldine De Muylder
  • Sylvie Daulouede
  • Laurence Lecordier
  • Pierrick Uzureau
  • Jan Van Den Abbeele
  • Michel Hérin
  • P Holzmuller
  • S. Semballa
  • Pierrette Courtois
  • Luc Vanhamme
  • Barrett Michael
  • Jillian Barlow
  • Andrew Mckenzie
  • Luke Barron
  • Wynn Thomas
  • Philippe Vincendeau
  • Etienne Pays
BACKGROUND:

In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.
METHODOLOGY/PRINCIPAL FINDINGS:

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-4R a -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.
CONCLUSION:

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.
Original languageEnglish
Pages (from-to)1003731
Number of pages1
JournalPLoS Pathogens
Volume9
Issue number10
Publication statusPublished - 31 Oct 2013

    Research areas

  • T. brucei i, SIGN-R1, TbKHC1

ID: 2412035