Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization
Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 6 vom: 01. Juni, Seite 3021-3037 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shibata, Takehiko [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.02.2021 Date Revised 07.12.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI125505 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM309481236 |
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| 100 | 1 | |a Shibata, Takehiko |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cytokines | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a Infectious disease | |
| 650 | 4 | |a Innate immunity | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a growth arrest-specific protein 6 |2 NLM | |
| 650 | 7 | |a Receptor Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Axl Receptor Tyrosine Kinase |2 NLM | |
| 700 | 1 | |a Makino, Airi |e verfasserin |4 aut | |
| 700 | 1 | |a Ogata, Ruiko |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Shigeki |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Toshihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Nagata, Kisaburo |e verfasserin |4 aut | |
| 700 | 1 | |a Terauchi, Yoshihiko |e verfasserin |4 aut | |
| 700 | 1 | |a Oishi, Taku |e verfasserin |4 aut | |
| 700 | 1 | |a Fujieda, Mikiya |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Yoshimasa |e verfasserin |4 aut | |
| 700 | 1 | |a Ato, Manabu |e verfasserin |4 aut | |
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