Lysozyme activates Enterococcus faecium to induce necrotic cell death in macrophages |
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Authors: | Sabine Gröbner Evelyn Fritz Friederike Schoch Martin Schaller Alexander C Berger Michael Bitzer Ingo B Autenrieth |
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Institution: | 1. Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Str. 6, 72076, Tübingen, Germany 2. Department of Dermatology, University of Tübingen, Tübingen, Germany 3. Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
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Abstract: | Enterococci are commensal organisms in the alimentary tract. However, they can cause a variety of life-threatening infections,
especially in nosocomial settings. We hypothesized that induction of cell death might enable these facultative pathogenic
bacteria to evade the innate immune response and to cause infections of their host. We demonstrate that E. faecium when exposed to lysozyme induces cell death in macrophages in vitro and in vivo. Flow cytometric analyses of J774A.1 macrophages
infected with E. faecium revealed loss of cell membrane integrity indicated by uptake of propidium iodide and decrease of the inner mitochondrial
transmembrane potential ΔΨm. Inhibition of caspases, treatment of macrophages with cytochalasin D, or rifampicin did not prevent cells from dying, suggesting
cell death mechanisms that are independent of caspase activation, bacterial uptake, and intracellular bacterial replication.
Characteristics of necrotic cell death were demonstrated by both lack of procaspase 3 activation and cell shrinkage, electron
microscopy, and release of lactate dehydrogenase. Pretreatment of E. faecium with lysozyme and subsequently with broad spectrum protease considerably reduced cell death, suggesting that a bacterial
surface protein is causative for cell death induction. Moreover, in a mouse peritonitis model we demonstrated that E. faecium induces cell death of peritoneal macrophages in vivo. Altogether, our results show that enterococci, under specific conditions
such as exposure to lysozyme, induce necrotic cell death in macrophages, which might contribute to disseminated infections
by these facultative pathogenic bacteria. |
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