Parasite interactions with dendritic cells and macrophages: Implications for cutaneous Leishmaniasis caused by Leishmania amazonensis




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Protozoan Leishmania is an important human pathogen that affects millions people worldwide. Investigation of experimental Leishmania infection in mice has been instrumental to our understanding of interactions between the parasite and the host immune system. Previous studies have established the model of Th1-Th2 paradigm: gamma interferon (IFN-g)-secreting Th1 cells protect the host from developing progressive diseases, while interleukin (IL)-4-producing Th2 cells drive the disease pathogenesis. Focused on L. amazonensis infection in mice, this dissertation study is mainly intended to understand the cellular mechanism underlying the generation of parasite-specific Th2 cells and to ascertain the role for IFN-g in parasite-macrophage interactions. We showed that L. amazonensis parasites infected and activated dendritic cells (DCs), a population of phagocytic antigen-presenting cells specialized in activating naïve T cells. We found that DCs from susceptible or resistant mice differentially responded to amastigotes in CD40-dependent cytokine production and that amastigote-infected DCs favor Th2 priming in susceptible but not resistant mice. IFN-g is believed to be crucial for activating macrophages to kill intracellular parasites such as L. major. However, we found that L. amazonensis amastigotes but not promastigotes could not only survive but also replicate better in IFN-g-activated macrophages. The promastigote was evidently killed in IFN-g-activated macrophages. On the other hand, macrophages activated with IFN-g and LPS were able to limit intracellular amastigote replication. When tested in vivo, endogenous IFN-g apparently exerted minimal effects on the course of amastigote infection. It is likely that IFN-g plays a bidirectional role during L. amazonensis infection: when optimally coupled with other factors, it can activate macrophages to control parasite infection; while in the absence of such synergy, it would promote amastigote propagation by itself. Collectively, results presented in this dissertation have pointed to the unique ability of L. amazonensis amastigotes to modulate host immune system to the advantage of their own survival.