コンテンツへスキップ
Merck
  • Apoptotic-like Leishmania exploit the host's autophagy machinery to reduce T-cell-mediated parasite elimination.

Apoptotic-like Leishmania exploit the host's autophagy machinery to reduce T-cell-mediated parasite elimination.

Autophagy (2015-03-25)
Peter Crauwels, Rebecca Bohn, Meike Thomas, Stefan Gottwalt, Florian Jäckel, Susi Krämer, Elena Bank, Stefan Tenzer, Paul Walther, Max Bastian, Ger van Zandbergen
要旨

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.

材料
製品番号
ブランド
製品内容

Sigma-Aldrich
ウシ胎児血清, sterile-filtered, non-USA origin, suitable for cell culture
Roche
In Situ細胞死検出キット、フルオレセイン, sufficient for ≤50 tests, suitable for detection
Sigma-Aldrich
バフィロマイシンA1 Streptomyces griseus由来, ≥90% (HPLC)
Sigma-Aldrich
スタウロスポリン 放線菌由来, ≥98% (HPLC), film
Sigma-Aldrich
TWEEN® 20, viscosity 250-450 mPa.s (25 °C)
Sigma-Aldrich
Anti-Phosphatidylserine, clone 1H6, Upstate®, from mouse
Sigma-Aldrich
スパウチン-1, ≥98% (HPLC)
Sigma-Aldrich
Miltefosine, An ether lipid analog that acts as an inhibitor of CTP:phosphocholine cytidyltransferase and displays remarkable antiproliferative effect both in vitro and in vivo.