Kinetoplastid membrane protein-11 exacerbates infection with Leishmania amazonensis in murine macrophages

Abstract

In Leishmania amazonensis, kinetoplastid membrane protein-11 (KMP-11) expression increases during metacyclogenesis and is higher in amastigotes than in promastigotes, suggesting a role for this protein in the infection of the mammalian host. We show that the addition of KMP-11 exacerbates L. amazonensis infection in peritoneal macrophages from BALB/c mice by increasing interleukin (IL)-10 secretion and arginase activity while reducing nitric oxide (NO) production. The doses of KMP-11, the IL-10 levels and the intracellular amastigote loads were strongly, positively and significantly correlated. The increase in parasite load induced by KMP-11 was inhibited by anti-KMP-11 or anti-IL-10 neutralising antibodies, but not by isotype controls. The neutralising antibodies, but not the isotype controls, were also able to significantly decrease the parasite load in macrophages cultured without the addition of KMP-11, demonstrating that KMP-11-induced exacerbation of the infection is not dependent on the addition of exogenous KMP-11 and that the protein naturally expressed by the parasite is able to promote it. In this study, the exacerbating effect of KMP-11 on macrophage infection with Leishmania is for the first time demonstrated, implicating it as a virulence factor in L. amazonensis. The stimulation of IL-10 production and arginase activity and the inhibition of NO synthesis are likely involved in this effect

Immunomodulation in Human Dendritic Cells Leads to Induction of Interferon-Gamma Production byLeishmania donovaniDerived KMP-11 Antigen via Activation of NF-κB in Indian Kala-Azar Patients

“…LPS in recombinant protein KMP-11 was completely removed by passing through polymyxin B-agarose column (Sigma, USA) according to the manufacturer's instructions and confirmed by LAL test. The recombinant KMP-11 protein was then stored at −80°C for further use [17]. …”

Resolvin D1 drives establishment of Leishmania amazonensis infection

“…In vitro experiments have demonstrated that during Leishmania infection, there is increased production of arginase-I, transforming growth factor β (TGF-β) and HO-1 by infected macrophages, which has been associated with augmented intracellular parasite proliferation78910. Moreover, the role of these three important mediators in Leishmania infection has been further established in experiments using macrophages from mice genetically lacking HO-111, and pharmacological inhibition of arginase-I7 or antibody-mediated blockage of TGF-β12 in infected human macrophages.…”

Leishmania, the phagosome, and host responses: The journey of a parasite

“…Another Leishmania pathogenicity factor, the kinetoplastid membrane protein-11 (KMP-11), whose expression is increased during metacyclogenesis and in L. amazonensis amastigote stage, was shown to exacerbate BALB/c mice peritoneal macrophages infection by increasing IL-10 secretion [65,66]. KMP-11 was also shown to increase the macrophage arginase activity while reducing the nitric oxide production, thus promoting parasite survival [65].…”

“…KMP-11 was also shown to increase the macrophage arginase activity while reducing the nitric oxide production, thus promoting parasite survival [65]. KMP-11 is currently regarded as a potential vaccine target [67].…”