A Trypanosoma brucei Kinesin Heavy Chain Promotes Parasite Growth by Triggering Host Arginase Activity

Abstract

BackgroundIn order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.Methodology/Principal findingsBy 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.ConclusionA 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.

A protective effect of the laminated layer on Echinococcus granulosus survival dependent on upregulation of host arginase

“…On the other hand, a Trypanosoma brucei protein named Kinesin Heavy Chain 1 (TbKHC1) induces arginase-1 through SIGNR1 signaling in myeloid cells (De Muylder et al, 2013). In this sense, the potential involvement of SIGNR1 in the LL effect may be suggested.…”

“…Moreover, interaction of a protein from Trypanosoma brucei with SIGNR1 promotes early trypanosome growth and favors parasite settlement in the host (De Muylder et al, 2013).…”

MIF Contributes to Trypanosoma brucei Associated Immunopathogenicity Development

“…Despite reduced pathogenicity, Mif −/− mice exhibit only a moderate increase in survival compared to WT mice, inferring that MIF-independent mechanisms determine survival of infected mice. Yet, so far the exact cause of death in murine African trypanosomiasis is unknown and is suggested to be due to Systemic Inflammatory Response Syndrome (SIRS), thus likely multifactorial [36] and going beyond the role of MIF.…”

African trypanosome control in the insect vector and mammalian host

“…The binding of TNF to TNF receptor 1 (TNF-R1) also triggers NO production. While both TNF and NO reduce the in vivo fitness of T. congolense, facilitating opsonization and clearance by myeloid cells, NO negatively affects parasitemia control in T. brucei-infected mice [39,40,[48][49][50][51]. Although myeloid cell-derived type I IFN aids in efficient initial parasite clearance, such a response when uncontrolled is detrimental to host resistance, possibly due to an antagonist effect on IFN-g production [52].…”

“…Arginase 1 also converts L-arginine to L-ornithine, which is then converted to polyamines. Combined, the production of polyamines triggered by TbKHC1 and the inhibition of NO production, known to impair T. brucei growth control, by TbKHC1 promote trypanosome settlement in body niches and decrease host resistance in acute infection [51]. In addition, by decreasing NO bioavailability TbKHC1 reduces tolerance during the chronic stage 3 of infection (Figure 2), thereby potentially decreasing vascular tone [51].…”