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Interaction of Yersinia enterocolitica with macrophages leads to macrophage cell death through apoptosis
K Ruckdeschel1, A Roggenkamp, V Lafont
1INSERM U431, Université Montpellier II, France.
Abstract:
Suppression of the host defense is one of the hallmarks of Yersinia enterocolitica infection. This enteric pathogen resists phagocytosis and interferes with macrophage functions from an extracellular localization (oxidative-burst generation and tumor necrosis factor alpha production). In this study, we investigated the fate of the Y. enterocolitica-infected macrophage. We found that murine J774A.1 macrophages and macrophages derived from human monocytes were killed by infection with Y. enterocolitica. Analysis of cellular morphology and DNA fragmentation revealed that macrophage cell death occurs through the induction of apoptosis. A total of 92% +/- 5% (mean +/- standard deviation) of murine J774A.1 macrophages and 74% +/- 6% of human monocyte-derived macrophages underwent apoptosis upon Yersinia infection after 4 and 20 h, respectively. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone blocked completion of the Yersinia-induced apoptotic program but not the surface exposure of phosphatidylserine as an early-stage apoptotic event. Analysis of different Yersinia mutants showed that macrophage apoptosis depends on a functional Y. enterocolitica type III protein secretion system. Apoptotic cell death of macrophages was not related to the YopE-mediated cytotoxic effect of Yersinia, since disruption of actin microfilaments by a Y. enterocolitica strain expressing a restricted repertoire of yop genes, including YopE, did not result in macrophage apoptosis. Furthermore, Yersinia-induced cytotoxic alterations in epithelial HeLa cells, which are conferred by YopE, did not lead to apoptosis. Our data demonstrate for the first time that Y. enterocolitica promotes the apoptosis of macrophages, an effect which is clearly distinct from the morphological alterations mediated by Yersinia on epithelial HeLa cells.
Insights
Yersinia enterocolitica infection triggers macrophage apoptosis, a programmed cell death distinct from its effects on epithelial cells. This process relies on the bacteria's type III secretion system, highlighting a key mechanism in host defense suppression.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Yersinia enterocolitica infection suppresses host defenses, including macrophage functions like phagocytosis and cytokine production.
- The pathogen interferes with macrophage oxidative burst and tumor necrosis factor alpha generation extracellularly.
Purpose of the Study:
- To investigate the fate of macrophages infected with Yersinia enterocolitica.
- To determine the mechanism and bacterial factors involved in Yersinia-induced macrophage cell death.
Main Methods:
- Infection of murine J774A.1 macrophages and human monocyte-derived macrophages with Y. enterocolitica.
- Analysis of cellular morphology, DNA fragmentation, and phosphatidylserine exposure.
- Utilized caspase inhibitors and Y. enterocolitica mutants lacking functional type III secretion systems or specific Yops.
Main Results:
- Y. enterocolitica infection induced apoptosis in 92% of murine and 74% of human macrophages.
- Macrophage apoptosis was dependent on a functional Y. enterocolitica type III protein secretion system.
- The YopE-mediated cytotoxic effect on epithelial cells was distinct from the apoptosis induced in macrophages.
Conclusions:
- Yersinia enterocolitica actively promotes macrophage apoptosis, a novel finding in host-pathogen interactions.
- This apoptotic pathway is mediated by the type III secretion system and is independent of YopE's cytotoxic effects.
- Understanding this mechanism is crucial for comprehending Yersinia's immune evasion strategies.