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 (10(7)-10(8) 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.