title: Apoptotic-like Leishmania exploit the host's autophagy machinery to reduce T-cell-mediated parasite elimination.
abstract: Apoptosis is a well-defined cellular process in which a cell dies, characterized by cell shrinkage and DNA fragmentation. In parasites like Leishmania, the process of apoptosis-like cell death has been described. Moreover upon infection, the apoptotic-like population is essential for disease development, in part by silencing host phagocytes. Nevertheless, the exact mechanism of how apoptosis in unicellular organisms may support infectivity remains unclear. Therefore we investigated the fate of apoptotic-like Leishmania parasites in human host macrophages. Our data showed--in contrast to viable parasites--that apoptotic-like parasites enter an LC3(+), autophagy-like compartment. The compartment was found to consist of a single lipid bilayer, typical for LC3-associated phagocytosis (LAP). As LAP can provoke anti-inflammatory responses and autophagy modulates antigen presentation, we analyzed how the presence of apoptotic-like parasites affected the adaptive immune response. Macrophages infected with viable Leishmania induced proliferation of CD4(+) T-cells, leading to a reduced intracellular parasite survival. Remarkably, the presence of apoptotic-like parasites in the inoculum significantly reduced T-cell proliferation. Chemical induction of autophagy in human monocyte-derived macrophage (hMDM), infected with viable parasites only, had an even stronger proliferation-reducing effect, indicating that host cell autophagy and not parasite viability limits the T-cell response and enhances parasite survival. Concluding, our data suggest that apoptotic-like Leishmania hijack the host cells' autophagy machinery to reduce T-cell proliferation. Furthermore, the overall population survival is guaranteed, explaining the benefit of apoptosis-like cell death in a single-celled parasite and defining the host autophagy pathway as a potential therapeutic target in treating Leishmaniasis.
authors: a Division of Immunology ; Paul-Ehrlich-Institute ; Langen , Germany.
authors: Peter
authors: P
authors: Crauwels
authors: Rebecca
authors: R
authors: Bohn
authors: Meike
authors: M
authors: Thomas
authors: Stefan
authors: S
authors: Gottwalt
authors: Florian
authors: F
authors: Jäckel
authors: Susi
authors: S
authors: Krämer
authors: Elena
authors: E
authors: Bank
authors: Stefan
authors: S
authors: Tenzer
authors: Paul
authors: P
authors: Walther
authors: Max
authors: M
authors: Bastian
authors: Ger
authors: G
authors: van Zandbergen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D006801:Humans; D007891:Leishmania / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D010586:Phagocytes / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
keywords: ANXA5, annexin V; CFSE, carboxyfluorescein succinimidyl ester; CM, complete medium; IF, immunofluorescence; IL, interleukin; LAP; LAP, LC3-associated phagocytosis; Lm, Leishmania; MACS, magnetic-associated cell sorting; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; MOI, multiplicity of infection; PBMCs, peripheral blood mononuclear cells; PS, phosphatidylserine; T-cell proliferation; TGFB, transforming growth factor; anti-inflammatory; apoptotic-like Leishmania; autophagy; hMDM, human monocyte derived macrophage; human primary macrophages; immune evasion; log.ph, logarithmic phase; stat.ph, stationary phase; β; TT, tetanus toxoid