African trypanosomes can efficiently undermine the protective immune response of their hosts to favor their survival within the host and successful transmission by its vector. Excreted /secreted factors are among the first parasite molecules involved in the establishment of an environment favoring parasite settlement. We report here that factors released by the parasite promote the degradation of L-arginine through increase of arginase activity in macrophages/ myeloid cells, and antagonize NO synthases (NOS)· mediated conversion of L-arginine into NO in infected mice. Arginase induction appears to attenuate the innate response at the early stage of infection, and likely contributes to the synthesis or polyamines and the trypanosome anti-oxidant trypanothione, known to promote trypanosome growth and colonization of the host. During acute infection, a Trypanosoma brucei protein named Kinesin Heavy Chain 1 (TbKHCl) is released and sustains the development of the first (most prominent) peak or parasitaemia. TbKHCl is found to interact with SIGN-Rl at the surface of immune cells. TbKHCl modulates arginine/ NO metabolism via an IL-10-dependent induction of arginase 1 and down-regulation of iNOS activities. Consequently, IL-10/arginase 1 producing cells are impaired in their capacity to destroy the parasite, favoring parasite settlement. A kinesin modulating host arginine/NO metabolism is also detected in T. muscull, a natural murine parasite. Its neutralization during infection decreased parasite load. T. musculi kinesin showed high similarity with TbKHCl, and bioinformatics analysis revealed the presence of this gene in other trypanosomes. Thus, targeting TbKHCl may benefit the host protective immunity against T. brucei.