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.

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-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.

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.

• Authors: Géraldine De Muylder, Sylvie Daulouède, Laurence Lecordier, Pierrick Uzureau, Yannick Morias, Jan Van Den Abbeele, Guy Caljon, Michel Hérin, Philippe Holzmuller, Silla Semballa, Pierrette Courtois, Luc Vanhamme, Benoît Stijlemans, Patrick De Baetselier, Michael P Barrett, Jillian L Barlow, Andrew N J McKenzie, Luke Barron, Thomas A Wynn, Alain Beschin, Philippe Vincendeau, Etienne Pays
• Journal: PLoS pathogens (PLoS Pathog) Vol. 9 Issue 10 Pg. e1003731 (Oct 2013) ISSN: 1553-7374 [Electronic] United States
• PMID: 24204274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• DC-specific ICAM-3 grabbing nonintegrin
• IL10 protein, mouse
• Il4ra protein, mouse
• Lectins, C-Type
• Protozoan Proteins
• Receptors, Cell Surface
• Interleukin-10
• Nitric Oxide
• Arg1 protein, mouse
• Arginase
• Kinesins

Topics

• Animals
• Arginase (genetics, immunology)
• Cell Adhesion Molecules (genetics, immunology)
• Enzyme Activation (genetics, immunology)
• Interleukin-10 (genetics, immunology)
• Kinesins (genetics, immunology)
• Lectins, C-Type (genetics, immunology)
• Mice
• Mice, Knockout
• Nitric Oxide (genetics, immunology)
• Protozoan Proteins (genetics, immunology)
• Receptors, Cell Surface (genetics, immunology)
• Trypanosoma brucei brucei (genetics, immunology)
• Trypanosomiasis, African (genetics, immunology, pathology)