Abstract
Infection with the intracellular protozoan parasite Leishmania mexicana causes chronic disease in C57BL/6 mice, in which cutaneous lesions persist for many months with high parasite burdens (107–108 parasites). This chronic disease process requires host IL-10 and FcγRIII. When Leishmania amastigotes are released from cells, surface-bound IgG can induce IL-10 and suppress IL-12 production from macrophages. These changes decrease IFN-γ from T cells and nitric oxide production in infected cells, which are both required for Leishmania control. However, antibodies targets and the kinetics of antibody production are unknown. Several groups have been unsuccessful in identifying amastigote surface proteins that bind IgG. We now show that glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by mouse IgG1 by 6 weeks of infection, with a rapid increase between 12 and 16 weeks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcγRIII-deficient mice. A single prominent spot on TLC is recognized by IgG, and the glycolipid is a glycosyl phosphatidylinositol containing a branched mannose structure. We show that the lipid structure of the GIPL (the sn-2 fatty acid) is required for antibody recognition. This GIPL is abundant in L. mexicana amastigotes, rare in stationary-phase promastigotes, and absent in L. major, consistent with a role for antibodies to GIPLs in chronic disease. A mouse monoclonal anti-GIPL IgG recognizes GIPLs on the parasite surface, and induces IL-10 from macrophages. The current work also extends this mouse analysis to humans, finding that L. mexicana-infected humans with localized and diffuse cutaneous leishmaniasis have antibodies that recognize GIPLs, can bind to the surface of amastigotes, and can induce IL-10 from human monocytes. Further characterization of the target glycolipids will have important implications for drug and vaccine development and will elucidate the poorly understood role of glycolipids in the immunology of infections.
Highlights
Leishmania is an intracellular protozoan parasite that causes 2 million new infections yearly and is a major cause of death worldwide [1]
Antibodies on the surface of parasites lead to the production of a protein called interleukin-10 (IL-10), which blocks an effective immune response needed to kill parasites and resolve skin lesions
We have extended this work to humans by showing that people infected with this parasite make antibodies that bind to these glycolipids and to the surface of parasites, and that can induce IL-10 from human white blood cells
Summary
Leishmania is an intracellular protozoan parasite that causes 2 million new infections yearly and is a major cause of death worldwide [1]. Drug toxicity and the development of resistance have made leishmaniasis an ever-challenging set of diseases [2,3,4]. While a vaccine is likely the best way to deal with leishmaniasis, development has been hampered by our lack of understanding of factors needed to induce long-lasting cellmediated immunity. Leishmania are able to hide from antibodies in an intracellular location. When Leishmania amastigote stages, found in the mammalian host, are released from the cell to parasitize new host cells, the parasite is bound by antibodies and utilizes mechanisms to prevent lysis by complement [7,8]. Are antibodies not helpful, they can be pathogenic [9,10,11]
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