Abstract
Footpad infection of C3HeB/FeJ mice with Leishmania amazonensis leads to chronic lesions accompanied by large parasite loads. Co-infecting these animals with L. major leads to induction of an effective Th1 immune response that can resolve these lesions. This cross-protection can be recapitulated in vitro by using immune cells from L. major-infected animals to effectively activate L. amazonensis-infected macrophages to kill the parasite. We have shown previously that the B cell population and their IgG2a antibodies are required for effective cross-protection. Here we demonstrate that, in contrast to L. major, killing L. amazonensis parasites is dependent upon FcRγ common-chain and NADPH oxidase-generated superoxide from infected macrophages. Superoxide production coincided with killing of L. amazonensis at five days post-activation, suggesting that opsonization of the parasites was not a likely mechanism of the antibody response. Therefore we tested the hypothesis that non-specific immune complexes could provide a mechanism of FcRγ common-chain/NADPH oxidase dependent parasite killing. Macrophage activation in response to soluble IgG2a immune complexes, IFN-γ and parasite antigen was effective in significantly reducing the percentage of macrophages infected with L. amazonensis. These results define a host protection mechanism effective during Leishmania infection and demonstrate for the first time a novel means by which IgG antibodies can enhance killing of an intracellular pathogen.
Highlights
Infection of mice with the protozoal parasite Leishmania sp. is a useful model to understand the host-pathogen relationship
We previously demonstrated that CD4+ T cells and B cells, harvested from L. major-infected animals and restimulated with antigen ex vivo, provided the required immune factors to significantly enhance the microbicidal response of L. amazonensis-infected macrophages [31]
We show that when L. major-induced cross-protection against L. amazonensis infection is recapitulated in vitro, parasite killing is dependent, in part, upon Fc receptor c-common chain (FcRc)-common chain-mediated nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activation
Summary
Infection of mice with the protozoal parasite Leishmania sp. is a useful model to understand the host-pathogen relationship. Is a useful model to understand the host-pathogen relationship This system has defined host mechanisms required for an effective leishmanicidal response as well as how parasites limit host responses. In several different experimental models, infection with a Leishmania parasite to which the host mounts a healing immune response, such as L. major, induces a cross-protective immune response against a parasite to which the host is normally susceptible, such as L. amazonensis [5,6,7,8]. We find that nonspecific soluble immune complexes (ICs) promoted a NADPH oxidase-dependent leishmanicidal response post-infection. These results define a host protection mechanism effective during
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