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A Trypanosoma brucei kinesin heavy chain promotes parasite growth by triggering host arginase activity.

De Muylder G, Daulouède S, Lecordier L, Uzureau P, Morias Y, Van Den Abbeele J, Caljon G, Hérin M, Holzmuller P, Semballa S, Courtois P, Vanhamme L, Stijlemans B, De Baetselier P, Barrett MP, Barlow JL, McKenzie AN, Barron L, Wynn TA, Beschin A, Vincendeau P, Pays E - PLoS Pathog. (2013)

Bottom Line: 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.This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.

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.

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Mechanism of arginase activity induction by T. brucei PRF and rTbKHC1.Myeloid cells from non-infected WT (A-D,F, G) or IL-4Rα KO (E) mice were incubated with PRF or rTbKHC1. (A) IL-10 production induced by PRF. (B) Arginase activity induced by PRF incubated with indicated antibodies or sugars. (C) Arginase activity and IL-10 secretion induced by rTbKHC1 incubated with indicated antibodies or sugars. (D–G) Relative expression level of M2 genes after incubation with rTbKHC1. In F, M2 IL-10-dependent genes are indicated, and in G, rTbKHC1 was incubated with the indicated antibodies. Data are means ± SEM of 3 individual mice of one representative from 3 independent experiments. * p<0.05 compared to non-stimulated (-) cells.
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ppat-1003731-g003: Mechanism of arginase activity induction by T. brucei PRF and rTbKHC1.Myeloid cells from non-infected WT (A-D,F, G) or IL-4Rα KO (E) mice were incubated with PRF or rTbKHC1. (A) IL-10 production induced by PRF. (B) Arginase activity induced by PRF incubated with indicated antibodies or sugars. (C) Arginase activity and IL-10 secretion induced by rTbKHC1 incubated with indicated antibodies or sugars. (D–G) Relative expression level of M2 genes after incubation with rTbKHC1. In F, M2 IL-10-dependent genes are indicated, and in G, rTbKHC1 was incubated with the indicated antibodies. Data are means ± SEM of 3 individual mice of one representative from 3 independent experiments. * p<0.05 compared to non-stimulated (-) cells.

Mentions: We screened for pathways altering the levels of PRF-induced arginase activity in myeloid cells. Co-incident with the induction of arginase activity, PRF induced myeloid cells to express the regulatory cytokine IL-10 (Fig. 3A). The arginase activity induced by PRF was inhibited by neutralizing anti-IL-10 antibody and by D-mannose, but not by D-galactose (Fig. 3B).


A Trypanosoma brucei kinesin heavy chain promotes parasite growth by triggering host arginase activity.

De Muylder G, Daulouède S, Lecordier L, Uzureau P, Morias Y, Van Den Abbeele J, Caljon G, Hérin M, Holzmuller P, Semballa S, Courtois P, Vanhamme L, Stijlemans B, De Baetselier P, Barrett MP, Barlow JL, McKenzie AN, Barron L, Wynn TA, Beschin A, Vincendeau P, Pays E - PLoS Pathog. (2013)

Mechanism of arginase activity induction by T. brucei PRF and rTbKHC1.Myeloid cells from non-infected WT (A-D,F, G) or IL-4Rα KO (E) mice were incubated with PRF or rTbKHC1. (A) IL-10 production induced by PRF. (B) Arginase activity induced by PRF incubated with indicated antibodies or sugars. (C) Arginase activity and IL-10 secretion induced by rTbKHC1 incubated with indicated antibodies or sugars. (D–G) Relative expression level of M2 genes after incubation with rTbKHC1. In F, M2 IL-10-dependent genes are indicated, and in G, rTbKHC1 was incubated with the indicated antibodies. Data are means ± SEM of 3 individual mice of one representative from 3 independent experiments. * p<0.05 compared to non-stimulated (-) cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814429&req=5

ppat-1003731-g003: Mechanism of arginase activity induction by T. brucei PRF and rTbKHC1.Myeloid cells from non-infected WT (A-D,F, G) or IL-4Rα KO (E) mice were incubated with PRF or rTbKHC1. (A) IL-10 production induced by PRF. (B) Arginase activity induced by PRF incubated with indicated antibodies or sugars. (C) Arginase activity and IL-10 secretion induced by rTbKHC1 incubated with indicated antibodies or sugars. (D–G) Relative expression level of M2 genes after incubation with rTbKHC1. In F, M2 IL-10-dependent genes are indicated, and in G, rTbKHC1 was incubated with the indicated antibodies. Data are means ± SEM of 3 individual mice of one representative from 3 independent experiments. * p<0.05 compared to non-stimulated (-) cells.
Mentions: We screened for pathways altering the levels of PRF-induced arginase activity in myeloid cells. Co-incident with the induction of arginase activity, PRF induced myeloid cells to express the regulatory cytokine IL-10 (Fig. 3A). The arginase activity induced by PRF was inhibited by neutralizing anti-IL-10 antibody and by D-mannose, but not by D-galactose (Fig. 3B).

Bottom Line: 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.This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.

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.

Show MeSH
Related in: MedlinePlus