Academic Journal
Intracellular Staphylococcus aureus triggers isolate-specific host transcriptional responses alongside TNF-R1 regulated cell fate decisions.
| Τίτλος: | Intracellular Staphylococcus aureus triggers isolate-specific host transcriptional responses alongside TNF-R1 regulated cell fate decisions. |
|---|---|
| Συγγραφείς: | Walter A; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany., Bischler T; Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany., Jungblut M; Rudolf-Virchow-Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Breitsprecher LF; Center of Cellular Nanoanalytics Osnabrück, Integrated Bioimaging Facility, University of Osnabrück, Osnabrück, Germany., Vilotic F; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany., Beck J; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany., Hofmann L; Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany., Schäfer N; Department of Orthopedic Surgery, Experimental Orthopedics, Center for Medical Biotechnology (ZMB), University of Regensburg, Regensburg, Germany., Ziesmann T; Institute for Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany., Franzkoch R; Center of Cellular Nanoanalytics Osnabrück, Integrated Bioimaging Facility, University of Osnabrück, Osnabrück, Germany., Härteis S; Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany., Gadjalova I; Institute for Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.; TranslaTUM, Center for Translational Cancer Research, Technical University Munich, Munich, Germany., Distler U; Institute for Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany., Beliu G; Rudolf-Virchow-Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.; Regensburg Center for Ultrafast Nanoscopy, University of Regensburg, Regensburg, Germany., Psathaki OE; Center of Cellular Nanoanalytics Osnabrück, Integrated Bioimaging Facility, University of Osnabrück, Osnabrück, Germany., Hensel M; Center of Cellular Nanoanalytics Osnabrück, Integrated Bioimaging Facility, University of Osnabrück, Osnabrück, Germany.; Division of Microbiology, University of Osnabrück, Osnabrück, Germany., Schneider-Brachert W; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany., Gräfenhan T; Core Unit Systems Medicine, University of Würzburg, Würzburg, Germany., Stempfl T; Center of Excellence for Fluorescent Bioanalytics (KFB), University of Regensburg, Regensburg, Germany., Kieninger B; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany., Mühlen S; Department of Molecular Immunology, Ruhr-University Bochum, Bochum, Germany., Alt V; Department of Trauma Surgery, University Hospital Regensburg, Regensburg, Germany., Mannala GK; Department of Trauma Surgery, University Hospital Regensburg, Regensburg, Germany., Fritsch J; Department of Infection Prevention and Infectious Diseases, University Hospital of Regensburg, University of Regensburg, Regensburg, 93053, Germany. Juergen.Fritsch@ukr.de. |
| Πηγή: | Cell communication and signaling : CCS [Cell Commun Signal] 2026 Sep 28; Vol. 24 (1). Date of Electronic Publication: 2026 Sep 28. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central, c2003- |
| Ιατρικοί όροι (MeSH): | Staphylococcus aureus*/isolation & purification , Staphylococcus aureus*/physiology , Receptors, Tumor Necrosis Factor, Type I*/metabolism , Receptors, Tumor Necrosis Factor, Type I*/genetics , Host-Pathogen Interactions*/genetics , Intracellular Space*/microbiology , Transcription, Genetic*, Monocytes/microbiology ; Monocytes/metabolism ; Humans ; U937 Cells ; Signal Transduction ; Apoptosis |
| Περίληψη: | Background: Staphylococcus aureus (S. aureus) is an increasingly recognized intracellular pathogen, yet infection outcomes vary with bacterial isolate and host cell type. Many mechanisms underlying these differences remain poorly understood. This study investigated how distinct intracellular S. aureus isolates influence host signaling programs and infection outcomes by modulating cell death pathways and TNF-R1 dependent regulation of host cell fates across different human cell lines. Methods: The intracellular localization of four S. aureus isolates was analyzed via transmission electron microscopy (TEM), structured illumination microscopy (SIM), serial block-face scanning electron microscopy (SBF-SEM), and imaging flow cytometry. The transcriptional reprogramming of infected U937 monocytes was examined via mRNA sequencing. Infection outcomes and early TNF-R1 surface expression were characterized and compared with those of A549 and SaOS-2 cell lines employing flow cytometry and Western blot analysis, characterizing host cell death mechanisms in both wild-type and TNF-R1‒deficient backgrounds. Results: All S. aureus isolates localized to the endo-lysosomal and cytosolic compartments but were also frequently detected in nucleo-proximal regions. In U937 monocytes, infection induced a conserved stress signature alongside isolate‑specific transcriptional programs divergently affecting inflammation, metabolism, and cell fate, which was markedly attenuated in response to the chronic‑infection isolate EDCC 5464. Similarly, cell death outcomes were isolate‑ and cell type-dependent, involved caspase activation consistent with intrinsic and extrinsic apoptosis signaling, and caspase-1 activation at distinct temporal dynamics. TNF‑R1 loss initially delayed but later increased later isolate-independent cytotoxicity. Higher TNF-R1 surface expression was triggered in U937 monocytes by all viable isolates, but only by EDCC 5464 in SaOS-2 and A549 cells. Viability of the latter was only marginally influenced by isolate or TNF-R1 loss. Conclusions: These results highlight the multilayered determinants governing intracellular S. aureus survival, host cell susceptibility, and noncanonical intracellular localization that warrants further investigation. The TNF/TNF-R1 axis appears to critically influence regulated host defenses during early infection stages in a tissue-specific manner, though its mechanistic contribution remains to be fully elucidated. Together with distinct isolate-driven gene expression profiles of U937 monocytes, infection risks under TNF-targeted therapies and the contribution of S. aureus heterogeneity should be considered in the design of future host-directed treatment strategies. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Competing interests: The authors declare no competing interests. |
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| Grant Information: | 318346496, 446605368 Deutsche Forschungsgemeinschaft; 422048538, 467522186 Deutsche Forschungsgemeinschaft; 547933897 Deutsche Forschungsgemeinschaft |
| Contributed Indexing: | Keywords: Staphylococcus aureus; Apoptosis; Host cell death; Host response; Host‒pathogen interactions; Intracellular infection; Perinuclear; TNF receptor 1; TNF-α; Transcriptomics Local Abstract: [plain-language-summary] The bacterium Staphylococcus aureus (S. aureus) often lives harmlessly in humans but can cause severe or recurrent infections when the skin barrier is broken or when the immune system is weakened. A major reason for its persistence is its ability to hide inside human cells, where it is shielded from immune attacks and antibiotics. To effectively target such bacteria, it is crucial to understand that infections vary depending on both the bacterial strain and the infected tissue type. Many reasons behind these differences are still puzzling. We explored how different types of S. aureus (collected from different disease types) change how different human cells respond to infection. We focused on how each strain influences the way immune cells adjust their gene activity during infection, and how a receptor called TNF‑R1 is involved in managing cell death responses.Bacteria are found in compartments meant to destroy them but frequently also in close association to the cell nucleus, an unexpected location that requires further investigation. All strains triggered a similar stress response but also distinct patterns differentially influencing inflammation, metabolism, and cell survival. A strain linked to chronic infection caused weaker responses, suggesting greater ability to remain undetected. The immune cells had greater presence of TNF-R1 on their surface when infected, and when they lacked this receptor entirely, they initially survived longer but later showed greater damage, indicating its key role in infection control. In lung and bone cells, these effects were less pronounced.In conclusion, S. aureus uses various survival strategies that have heterogeneous impact on different host tissues. Some bacteria localized to unexpected compartments close to the cell’s control center inside all analyzed human cell types. Importantly, while the exact mechanisms are not yet clear, TNF-R1 influences host infection responses in the studied immune cells, highlighting that the interaction of bacterial programs and critical host factors must be carefully considered when developing targeted treatments. |
| Substance Nomenclature: | 0 (Receptors, Tumor Necrosis Factor, Type I) |
| Entry Date(s): | Date Created: 20260929 Date Completed: 20260930 Latest Revision: 20261001 |
| Update Code: | 20261001 |
| PubMed Central ID: | PMC13621601 |
| DOI: | 10.1186/s12964-026-03246-8 |
| PMID: | 42811321 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1478-811X |
|---|---|
| DOI: | 10.1186/s12964-026-03246-8 |