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Kinetoplastid Membrane Protein-11 as a Vaccine Candidate and a Virulence Factor in Leishmania
Sergio Coutinho Furtado de Mendonça1, Léa Cysne-Finkelstein1, Denise Cristina de Souza Matos2
1Laboratório de Imunoparasitologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz , Rio de Janeiro , Brazil.
Abstract:
Kinetoplastid membrane protein-11 (KMP-11), a protein present in all kinetoplastid protozoa, is considered a potential candidate for a leishmaniasis vaccine. In Leishmania amazonensis, KMP-11 is expressed in promastigotes and amastigotes. In both stages, the protein was found in association with membrane structures at the cell surface, flagellar pocket, and intracellular vesicles. More importantly, its surface expression is higher in amastigotes than in promastigotes and increases during metacyclogenesis. The increased expression of KMP-11 in metacyclic promastigotes, and especially in amastigotes, indicates a role for this molecule in the parasite relationship with the mammalian host. In this connection, we have shown that 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 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-neutralizing antibodies, but not by isotype controls. The neutralizing 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. All these data indicate that KMP-11 acts as a virulence factor in L. amazonensis infection.
Insights
Kinetoplastid membrane protein-11 (KMP-11) exacerbates Leishmania amazonensis infection by increasing parasite load and IL-10 secretion. This protein acts as a virulence factor, contributing to disease severity in mammalian hosts.
Area of Science:
- Parasitology
- Immunology
- Molecular Biology
Background:
- Kinetoplastid membrane protein-11 (KMP-11) is found in all kinetoplastid protozoa and is a potential vaccine candidate for leishmaniasis.
- KMP-11 is expressed in both promastigote and amastigote stages of Leishmania amazonensis, associated with membrane structures and intracellular vesicles.
- Surface expression of KMP-11 increases during metacyclogenesis and is higher in amastigotes, suggesting a role in host-parasite interactions.
Purpose of the Study:
- To investigate the role of KMP-11 in Leishmania amazonensis infection and its impact on the host immune response.
- To determine if KMP-11 functions as a virulence factor in L. amazonensis infections.
Main Methods:
- Addition of KMP-11 to peritoneal macrophages from BALB/c mice infected with L. amazonensis.
- Measurement of interleukin-10 (IL-10) and nitric oxide (NO) production, and arginase activity.
- Correlation analysis between KMP-11 doses, IL-10 levels, and intracellular amastigote loads.
- Inhibition assays using anti-KMP-11 and anti-IL-10 neutralizing antibodies.
Main Results:
- Exogenous KMP-11 exacerbated L. amazonensis infection, increasing IL-10 secretion and arginase activity while decreasing NO production.
- A significant positive correlation was observed between KMP-11 dose, IL-10 levels, and intracellular amastigote load.
- Neutralizing antibodies against KMP-11 or IL-10 inhibited KMP-11-induced exacerbation and reduced parasite load, even without exogenous KMP-11 addition.
Conclusions:
- Kinetoplastid membrane protein-11 (KMP-11) acts as a virulence factor in Leishmania amazonensis infections.
- Naturally expressed KMP-11 by the parasite promotes infection exacerbation.
- KMP-11 contributes to disease severity by modulating the host immune response, specifically through IL-10 induction.
