Trypanosoma musculi Infection in Mice Critically Relies on Mannose Receptor–Mediated Arginase Induction by a TbKHC1 Kinesin H Chain Homolog

Abstract

Arginase activity induction in macrophages is an escape mechanism developed by parasites to cope with the host's immune defense and benefit from increased host-derived growth factor production. We report that arginase expression and activity were induced in macrophages during mouse infection by , a natural parasite of this host. This induction was reproduced in vitro by excreted/secreted factors of the parasite. A mAb directed toKHC1, an orphan kinesin H chain from , inhibited excreted/secreted factor-mediated arginase induction. Anti-KHC1 Ab also inhibited growth, both in vitro and in vivo. Induction of arginase activity and parasite growth involved C-type lectin receptors, because mannose injection decreased arginase activity induction and parasite load in vitro and in vivo. Accordingly, the parasite load was reduced in mice lacking mannose receptor C-type 1. The KHC1 homolog showed high similarity with KHC1. Bioinformatics analysis revealed the presence of homologs of this gene in other trypanosomes, including pathogens for humans and animals. Host metabolism dysregulation represents an effective parasite mechanism to hamper the host immune response and modify host molecule production to favor parasite invasion and growth. Thus, this orphan kinesin plays an important role in promoting trypanosome infection, and its neutralization or the lock of its partner host molecules offers promising approaches to increasing resistance to infection and new developments in vaccination against trypanosomiasis.

CD209 C-Type Lectins Promote Host Invasion, Dissemination, and Infection of Toxoplasma gondii

“…On the contrary, previous studies using Yersinia pseudotuberculosis showed that partial inhibition of CD209 between the interaction of hDCS and Y. pseudotuberculosis was achieved only when the triple combination of inhibitors (antireceptor antibodies, mannan oligosaccharide, and purified LPS core) was employed. In this study, even the use of a single inhibitor provided partial protection against Toxoplasma infection as was also observed in Trypanosoma musculi infection (69).…”

“…Similar results were reported in a study involving T. musculi and T. cruzi whose results showed enhanced survival in macrophages, whereas receptor blockade decreased parasite growth (69). A number of studies using different antibodies and different strains of knock-out mice have yielded a wide array of contradicting results (11,(70)(71)(72)(73)(74).…”

Trypanosomatid Infections: How Do Parasites and Their Excreted–Secreted Factors Modulate the Inducible Metabolism of l-Arginine in Macrophages?

“…Treatment with mannose also reduced parasitemia in mice infected by T. musculi . However, whereas TbKHC1 facilitates Tbb parasitemia via the SIGN-R1 receptor, the MMR receptor was apparently the main target of T. musculi ES ( 138 ). This suggests that kinesin heavy chain-related proteins play similar roles in promoting infection in two genetically distant trypanosomes, via macrophage arginase induction, following distinct CLR targeting.…”

Trypanosoma brucei gambiense excreted/secreted factors impair lipopolysaccharide‐induced maturation and activation of human monocyte‐derived dendritic cells

“…The secretome, (excreted/secreted factors), of trypanosomes is a complex mixture of proteins, carbohydrates and lipids excreted from the surface of the parasite or secreted via exocytotic vesicles by a parasite‐specific organelle called the flagellar pocket . Some of these components are implicated in T brucei evasion of host innate response and others in the virulence process .…”

“…The secretome, (excreted/secreted factors), of trypanosomes is a complex mixture of proteins, carbohydrates and lipids excreted from the surface of the parasite or secreted via exocytotic vesicles by a parasite-specific organelle called the flagellar pocket. [12][13][14] Some of these components are implicated in T brucei evasion of host innate response 15,16 and others in the virulence process. [17][18][19][20][21] Because of the fundamental role of DCs during trypanosomiasis but limited human data, we investigated the effects of T gambiense and its secretome on human monocytes-derived DCs.…”