TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade
ABSTRACTThe iron-regulated surface determinant protein B (IsdB) of Staphylococcus aureus is involved in the acquisition of iron from hemoglobin. Moreover, IsdB elicits an adaptive immune response in mice and humans. Here, we show that IsdB also has impact on innate immunity. IsdB induces the release...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-01-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00225-23 |
| _version_ | 1797353871148843008 |
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| author | Juan José Izquierdo Gonzalez Md Faruq Hossain Jolanda Neef Erin E. Zwack Chih-Ming Tsai Dina Raafat Kevin Fechtner Luise Herzog Thomas P. Kohler Rabea Schlüter Alexander Reder Silva Holtfreter George Y. Liu Sven Hammerschmidt Uwe Völker Victor J. Torres Jan Maarten van Dijl Christopher H. Lillig Barbara M. Bröker Murty N. Darisipudi |
| author_facet | Juan José Izquierdo Gonzalez Md Faruq Hossain Jolanda Neef Erin E. Zwack Chih-Ming Tsai Dina Raafat Kevin Fechtner Luise Herzog Thomas P. Kohler Rabea Schlüter Alexander Reder Silva Holtfreter George Y. Liu Sven Hammerschmidt Uwe Völker Victor J. Torres Jan Maarten van Dijl Christopher H. Lillig Barbara M. Bröker Murty N. Darisipudi |
| author_sort | Juan José Izquierdo Gonzalez |
| collection | DOAJ |
| description | ABSTRACTThe iron-regulated surface determinant protein B (IsdB) of Staphylococcus aureus is involved in the acquisition of iron from hemoglobin. Moreover, IsdB elicits an adaptive immune response in mice and humans. Here, we show that IsdB also has impact on innate immunity. IsdB induces the release of proinflammatory cytokines, including IL-6 and IL-1β, in innate immune cells of humans and mice. In silico analysis and thermophoresis show that IsdB directly binds to TLR4 with high affinity. TLR4 sensing was essential for the IsdB-mediated production of IL-6, IL-1β, and other cytokines as it was abolished by blocking of TLR4-MyD88-IRAK1/4-NF-κB signaling. The release of IL-1β additionally required activation of the NLRP3 inflammasome. In human monocytes infected with live S. aureus, IsdB was necessary for maximal IL-1β release. Our studies identify S. aureus IsdB as a novel pathogen-associated molecular pattern that triggers innate immune defense mechanisms.IMPORTANCEThe prevalence of multidrug-resistant Staphylococcus aureus is of global concern, and vaccines are urgently needed. The iron-regulated surface determinant protein B (IsdB) of S. aureus was investigated as a vaccine candidate because of its essential role in bacterial iron acquisition but failed in clinical trials despite strong immunogenicity. Here, we reveal an unexpected second function for IsdB in pathogen-host interaction: the bacterial fitness factor IsdB triggers a strong inflammatory response in innate immune cells via Toll-like receptor 4 and the inflammasome, thus acting as a novel pathogen-associated molecular pattern of S. aureus. Our discovery contributes to a better understanding of how S. aureus modulates the immune response, which is necessary for vaccine development against the sophisticated pathogen. |
| first_indexed | 2024-03-08T13:37:15Z |
| format | Article |
| id | doaj.art-40712ab5c48b4f21a5ca40becd530a7c |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-08T13:37:15Z |
| publishDate | 2024-01-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-40712ab5c48b4f21a5ca40becd530a7c2024-01-16T15:40:00ZengAmerican Society for MicrobiologymBio2150-75112024-01-0115110.1128/mbio.00225-23TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascadeJuan José Izquierdo Gonzalez0Md Faruq Hossain1Jolanda Neef2Erin E. Zwack3Chih-Ming Tsai4Dina Raafat5Kevin Fechtner6Luise Herzog7Thomas P. Kohler8Rabea Schlüter9Alexander Reder10Silva Holtfreter11George Y. Liu12Sven Hammerschmidt13Uwe Völker14Victor J. Torres15Jan Maarten van Dijl16Christopher H. Lillig17Barbara M. Bröker18Murty N. Darisipudi19Institute of Immunology, University Medicine Greifswald, Greifswald, GermanyInstitute for Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, GermanyDepartment of Medical Microbiology, University of Groningen, University Medical Center, Groningen, the NetherlandsDepartment of Microbiology, New York University Grossman School of Medicine, New York, USADepartment of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California, USAInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyDepartment of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyImaging Center of the Department of Biology, University of Greifswald, Greifswald, GermanyDepartment of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyDepartment of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California, USADepartment of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyDepartment of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyDepartment of Microbiology, New York University Grossman School of Medicine, New York, USADepartment of Medical Microbiology, University of Groningen, University Medical Center, Groningen, the NetherlandsInstitute for Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, GermanyInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyInstitute of Immunology, University Medicine Greifswald, Greifswald, GermanyABSTRACTThe iron-regulated surface determinant protein B (IsdB) of Staphylococcus aureus is involved in the acquisition of iron from hemoglobin. Moreover, IsdB elicits an adaptive immune response in mice and humans. Here, we show that IsdB also has impact on innate immunity. IsdB induces the release of proinflammatory cytokines, including IL-6 and IL-1β, in innate immune cells of humans and mice. In silico analysis and thermophoresis show that IsdB directly binds to TLR4 with high affinity. TLR4 sensing was essential for the IsdB-mediated production of IL-6, IL-1β, and other cytokines as it was abolished by blocking of TLR4-MyD88-IRAK1/4-NF-κB signaling. The release of IL-1β additionally required activation of the NLRP3 inflammasome. In human monocytes infected with live S. aureus, IsdB was necessary for maximal IL-1β release. Our studies identify S. aureus IsdB as a novel pathogen-associated molecular pattern that triggers innate immune defense mechanisms.IMPORTANCEThe prevalence of multidrug-resistant Staphylococcus aureus is of global concern, and vaccines are urgently needed. The iron-regulated surface determinant protein B (IsdB) of S. aureus was investigated as a vaccine candidate because of its essential role in bacterial iron acquisition but failed in clinical trials despite strong immunogenicity. Here, we reveal an unexpected second function for IsdB in pathogen-host interaction: the bacterial fitness factor IsdB triggers a strong inflammatory response in innate immune cells via Toll-like receptor 4 and the inflammasome, thus acting as a novel pathogen-associated molecular pattern of S. aureus. Our discovery contributes to a better understanding of how S. aureus modulates the immune response, which is necessary for vaccine development against the sophisticated pathogen.https://journals.asm.org/doi/10.1128/mbio.00225-23cytokinesinnate immunityIsdBStaphylococcus aureusTLR4NLRP3 inflammasome |
| spellingShingle | Juan José Izquierdo Gonzalez Md Faruq Hossain Jolanda Neef Erin E. Zwack Chih-Ming Tsai Dina Raafat Kevin Fechtner Luise Herzog Thomas P. Kohler Rabea Schlüter Alexander Reder Silva Holtfreter George Y. Liu Sven Hammerschmidt Uwe Völker Victor J. Torres Jan Maarten van Dijl Christopher H. Lillig Barbara M. Bröker Murty N. Darisipudi TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade mBio cytokines innate immunity IsdB Staphylococcus aureus TLR4 NLRP3 inflammasome |
| title | TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade |
| title_full | TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade |
| title_fullStr | TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade |
| title_full_unstemmed | TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade |
| title_short | TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade |
| title_sort | tlr4 sensing of isdb of staphylococcus aureus induces a proinflammatory cytokine response via the nlrp3 caspase 1 inflammasome cascade |
| topic | cytokines innate immunity IsdB Staphylococcus aureus TLR4 NLRP3 inflammasome |
| url | https://journals.asm.org/doi/10.1128/mbio.00225-23 |
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