Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes
Abstract Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations wit...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-024-01014-9 |
| _version_ | 1827326589504847872 |
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| author | Lea A. Tölken Antje D. Paulikat Lana H. Jachmann Alexander Reder Manuela Gesell Salazar Laura M. Palma Medina Stephan Michalik Uwe Völker Mattias Svensson Anna Norrby-Teglund Katharina J. Hoff Michael Lammers Nikolai Siemens |
| author_facet | Lea A. Tölken Antje D. Paulikat Lana H. Jachmann Alexander Reder Manuela Gesell Salazar Laura M. Palma Medina Stephan Michalik Uwe Völker Mattias Svensson Anna Norrby-Teglund Katharina J. Hoff Michael Lammers Nikolai Siemens |
| author_sort | Lea A. Tölken |
| collection | DOAJ |
| description | Abstract Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. Methods Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. Results In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. Conclusions Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients. |
| first_indexed | 2024-03-07T14:47:47Z |
| format | Article |
| id | doaj.art-8cfa48c1af2241b6be605e7677b877f0 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-03-07T14:47:47Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-8cfa48c1af2241b6be605e7677b877f02024-03-05T19:52:24ZengBMCJournal of Biomedical Science1423-01272024-02-0131111710.1186/s12929-024-01014-9Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenesLea A. Tölken0Antje D. Paulikat1Lana H. Jachmann2Alexander Reder3Manuela Gesell Salazar4Laura M. Palma Medina5Stephan Michalik6Uwe Völker7Mattias Svensson8Anna Norrby-Teglund9Katharina J. Hoff10Michael Lammers11Nikolai Siemens12Department of Molecular Genetics and Infection Biology, University of GreifswaldDepartment of Molecular Genetics and Infection Biology, University of GreifswaldDepartment of Molecular Genetics and Infection Biology, University of GreifswaldDepartment of Functional Genomics, University Medicine GreifswaldDepartment of Functional Genomics, University Medicine GreifswaldCenter for Infectious Medicine, Karolinska Institutet, Karolinska University HospitalDepartment of Functional Genomics, University Medicine GreifswaldDepartment of Functional Genomics, University Medicine GreifswaldCenter for Infectious Medicine, Karolinska Institutet, Karolinska University HospitalCenter for Infectious Medicine, Karolinska Institutet, Karolinska University HospitalInstitute of Mathematics and Computer Science, University of GreifswaldDepartment of Synthetic and Structural Biochemistry, Institute of Biochemistry, University of GreifswaldDepartment of Molecular Genetics and Infection Biology, University of GreifswaldAbstract Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. Methods Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. Results In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. Conclusions Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.https://doi.org/10.1186/s12929-024-01014-9Streptococcus pyogenesDendritic cellsInterleukin-18CovR/SNecrotizing soft tissue infection |
| spellingShingle | Lea A. Tölken Antje D. Paulikat Lana H. Jachmann Alexander Reder Manuela Gesell Salazar Laura M. Palma Medina Stephan Michalik Uwe Völker Mattias Svensson Anna Norrby-Teglund Katharina J. Hoff Michael Lammers Nikolai Siemens Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes Journal of Biomedical Science Streptococcus pyogenes Dendritic cells Interleukin-18 CovR/S Necrotizing soft tissue infection |
| title | Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes |
| title_full | Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes |
| title_fullStr | Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes |
| title_full_unstemmed | Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes |
| title_short | Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes |
| title_sort | reduced interleukin 18 secretion by human monocytic cells in response to infections with hyper virulent streptococcus pyogenes |
| topic | Streptococcus pyogenes Dendritic cells Interleukin-18 CovR/S Necrotizing soft tissue infection |
| url | https://doi.org/10.1186/s12929-024-01014-9 |
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