TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade
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
Affiliations
Juan José Izquierdo Gonzalez
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
Md Faruq Hossain
Institute for Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
Jolanda Neef
Department of Medical Microbiology, University of Groningen, University Medical Center, Groningen, the Netherlands
Erin E. Zwack
Department of Microbiology, New York University Grossman School of Medicine, New York, USA
Chih-Ming Tsai
Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California, USA
Dina Raafat
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
Kevin Fechtner
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
Luise Herzog
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
Thomas P. Kohler
Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany
Rabea Schlüter
Imaging Center of the Department of Biology, University of Greifswald, Greifswald, Germany
Alexander Reder
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany
Silva Holtfreter
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
George Y. Liu
Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California, USA
Sven Hammerschmidt
Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany
Uwe Völker
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany
Victor J. Torres
Department of Microbiology, New York University Grossman School of Medicine, New York, USA
Jan Maarten van Dijl
Department of Medical Microbiology, University of Groningen, University Medical Center, Groningen, the Netherlands
Christopher H. Lillig
Institute for Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
Barbara M. Bröker
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
Murty N. Darisipudi
Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
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.
