Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA)
Abstract Regulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated stra...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04286-3 |
| _version_ | 1798035184049717248 |
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| author | Lioba Klaas Juliane Vier Ian E. Gentle Georg Häcker Susanne Kirschnek |
| author_facet | Lioba Klaas Juliane Vier Ian E. Gentle Georg Häcker Susanne Kirschnek |
| author_sort | Lioba Klaas |
| collection | DOAJ |
| description | Abstract Regulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated strain of vaccinia virus used in vaccination. While most target cells seem to be protected by antiapoptotic proteins encoded in the MVA genome, macrophages die when infected with MVA. We targeted key signaling components of specific cell death-pathways and pattern recognition-pathways using genome editing and small molecule inhibitors in an in vitro murine macrophage differentiation model. Upon infection with MVA, we observed activation of mitochondrial and death-receptor-induced apoptosis-pathways as well as the necroptosis-pathway. Inhibition of individual pathways had a little protective effect but led to compensatory death through the other pathways. In the absence of mitochondrial apoptosis, autocrine/paracrine TNF-mediated apoptosis and, in the absence of caspase-activity, necroptosis occurred. TNF-induction depended on the signaling molecule STING, and MAVS and ZBP1 contributed to MVA-induced apoptosis. The mode of cell death had a substantial impact on the cytokine response of infected cells, indicating that the immunogenicity of a virus may depend not only on its PAMPs but also on its ability to modulate individual modalities of cell death. These findings provide insights into the diversity of cell death-pathways that an infection can trigger in professional immune cells and advance our understanding of the intracellular mechanisms that govern the immune response to a virus. |
| first_indexed | 2024-04-11T20:54:42Z |
| format | Article |
| id | doaj.art-60e2a85296fe4c9a9862e99e0ddca3a6 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T20:54:42Z |
| publishDate | 2021-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-60e2a85296fe4c9a9862e99e0ddca3a62022-12-22T04:03:44ZengNature Publishing GroupCell Death and Disease2041-48892021-10-01121111310.1038/s41419-021-04286-3Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA)Lioba Klaas0Juliane Vier1Ian E. Gentle2Georg Häcker3Susanne Kirschnek4Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center – University of FreiburgFaculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center – University of FreiburgFaculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center – University of FreiburgFaculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center – University of FreiburgFaculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center – University of FreiburgAbstract Regulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated strain of vaccinia virus used in vaccination. While most target cells seem to be protected by antiapoptotic proteins encoded in the MVA genome, macrophages die when infected with MVA. We targeted key signaling components of specific cell death-pathways and pattern recognition-pathways using genome editing and small molecule inhibitors in an in vitro murine macrophage differentiation model. Upon infection with MVA, we observed activation of mitochondrial and death-receptor-induced apoptosis-pathways as well as the necroptosis-pathway. Inhibition of individual pathways had a little protective effect but led to compensatory death through the other pathways. In the absence of mitochondrial apoptosis, autocrine/paracrine TNF-mediated apoptosis and, in the absence of caspase-activity, necroptosis occurred. TNF-induction depended on the signaling molecule STING, and MAVS and ZBP1 contributed to MVA-induced apoptosis. The mode of cell death had a substantial impact on the cytokine response of infected cells, indicating that the immunogenicity of a virus may depend not only on its PAMPs but also on its ability to modulate individual modalities of cell death. These findings provide insights into the diversity of cell death-pathways that an infection can trigger in professional immune cells and advance our understanding of the intracellular mechanisms that govern the immune response to a virus.https://doi.org/10.1038/s41419-021-04286-3 |
| spellingShingle | Lioba Klaas Juliane Vier Ian E. Gentle Georg Häcker Susanne Kirschnek Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) Cell Death and Disease |
| title | Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) |
| title_full | Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) |
| title_fullStr | Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) |
| title_full_unstemmed | Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) |
| title_short | Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA) |
| title_sort | diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus ankara mva |
| url | https://doi.org/10.1038/s41419-021-04286-3 |
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