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From innate immune activation to DNA damage repair: Mechanistic insights into cellular defense pathways
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Innate immunity, the body’s first line of defense against pathogens, and DNA repair, a vital mechanism for maintaining genome stability, are essential for cellular homeostasis, damage repair, and protection against disease development. Despite ongoing research, the precise mechanisms that regulate these responses, and how they influence each other, remain largely unknown. This study seeks to explore factors that modulate innate immune responses and DNA damage repair and provide a deeper understanding of how these pathways interact to coordinate cellular defenses.

Through four different projects, this research provides insights into mechanisms underlying the regulation of innate immunity and DNA damage response.

In Project I we show that HUWE1, a protein previously described to be involved in DNA damage repair is also a negative regulator of the endolysosomal system. By regulating viral degradation within the endosome, HUWE1 contributes to antiviral innate defense.

In Project II we reveal how AIM2-like receptors, known to alarm the immune system in response to cytosolic DNA, also bind nuclear DNA and impede DNA damage repair by interfering with chromatin decompaction. This study shows that AIM2-like receptor deficiency protects against radiation-induced tissue injury and uncovers AIM2-like receptors as potential targets against genotoxic tissue damage.

In Project III we describe a novel role of aspirin, a commonly used anti-inflammatory drug, in facilitating DNA repair. Through acetylation of histones and chromatin remodeling aspirin promotes recruitment of DNA repair machinery to DNA damage sites.

In Project IV we show that membrane vesicles secreted by gut microbiota prime the innate immune system, which in turn protects the host against viral infections.

Research presented in this thesis provides a deeper understanding of how host genetic traits and environmental factors such as gut microbiota regulate the host’s defense systems. Moreover, the projects described herein demonstrate how molecules, traditionally associated with either innate immunity or DNA repair, have dual functions that bridge these two fundamental biological processes. By identifying mechanisms bridging these responses, the findings described in this thesis shed light on how an imbalance in these defense systems contributes to the development of pathology and provides the basis for identifying new therapeutic strategies for treatments of diseases associated with inflammation and DNA damage.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2025. , p. 42
Keywords [en]
innate immunity, DNA repair, inflammation, viral clearance, cellular defense mechanisms
National Category
Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-237115ISBN: 978-91-8107-058-3 (print)ISBN: 978-91-8107-059-0 (electronic)OAI: oai:DiVA.org:su-237115DiVA, id: diva2:1920318
Public defence
2025-02-14, Vivi Täckholmsalen, NPQ-huset, Svante Arrhenius väg 20, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2025-01-22 Created: 2024-12-11 Last updated: 2025-01-15Bibliographically approved
List of papers
1. The endolysosomal system drives type I IFN independent antiviral innate defense
Open this publication in new window or tab >>The endolysosomal system drives type I IFN independent antiviral innate defense
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-237114 (URN)
Available from: 2024-12-11 Created: 2024-12-11 Last updated: 2024-12-11
2. Nuclear AIM2-Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair
Open this publication in new window or tab >>Nuclear AIM2-Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair
2021 (English)In: Advanced Science, E-ISSN 2198-3844, Vol. 8, no 22, article id 2102534Article in journal (Refereed) Published
Abstract [en]

Radiation is an essential preparative procedure for bone marrow (BM) transplantation and cancer treatment. The therapeutic efficacy of radiation and associated toxicity varies from patient to patient, making it difficult to prescribe an optimal patient-specific irradiation dose. The molecular determinants of radiation response remain unclear. AIM2-like receptors (ALRs) are key players in innate immunity and determine the course of infections, inflammatory diseases, senescence, and cancer. Here it is reported that mice lacking ALRs are resistant to irradiation-induced BM injury. It is shown that nuclear ALRs are inhibitors of DNA repair, thereby accelerate genome destabilization, micronuclei generation, and cell death, and that this novel function is uncoupled from their role in innate immunity. Mechanistically, ALRs bind to and interfere with chromatin decompaction vital for DNA repair. The finding uncovers ALRs as targets for new interventions against genotoxic tissue injury and as possible biomarkers for predicting the outcome of radio/chemotherapy. 

Keywords
AIM2-like receptors, cancer, chemotherapy, chromatin compaction, DNA repair, inflammasome, radiotherapy
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-215761 (URN)10.1002/advs.202102534 (DOI)000707933000001 ()34658166 (PubMedID)2-s2.0-85117129274 (Scopus ID)
Available from: 2023-03-27 Created: 2023-03-27 Last updated: 2024-12-11Bibliographically approved
3. Aspirin protects against genotoxicity by promoting genome repair
Open this publication in new window or tab >>Aspirin protects against genotoxicity by promoting genome repair
2023 (English)In: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 33, no 4, p. 325-327Article in journal, Letter (Refereed) Published
Abstract [en]

Radiation sickness is a major health concern.1 The quest for radiation countermeasures started in the wake of the devastation witnessed following the nuclear detonations during the Second World War and has continued through the subsequent radiological accidents around the world. A radioprotector is also required for prophylactic use by staff working at radiation sources, pilots, and astronauts at high risk of space radiation, or patients undertaking lengthy radiological procedures. Despite decades of research, a safe, efficient, and cost-effective radioprotector is yet to be unveiled.

National Category
Genetics and Genomics
Identifiers
urn:nbn:se:su:diva-234711 (URN)10.1038/s41422-023-00783-6 (DOI)000942212900001 ()36859712 (PubMedID)2-s2.0-85149003056 (Scopus ID)
Available from: 2024-10-22 Created: 2024-10-22 Last updated: 2025-02-07Bibliographically approved
4. The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis
Open this publication in new window or tab >>The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis
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2022 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 55, no 5, p. 847-861, e1-e10Article in journal (Refereed) Published
Abstract [en]

The microbiota are vital for immune homeostasis and provide a competitive barrier to bacterial and fungal pathogens. Here, we investigated how gut commensals modulate systemic immunity and response to viral infection. Antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming. The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions. Instead, membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells. DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner. In summary, this study establishes an important role for the microbiota in peripheral cGAS-STING activation, which promotes host resistance to systemic viral infections. Moreover, it uncovers an underappreciated risk of antibiotic use during viral infections.

Keywords
innate immunity, pattern recognition receptors, microbiota, bacterial membrane vesicles, interferons, cGAS, STING, virus, infections
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-204891 (URN)10.1016/j.immuni.2022.04.006 (DOI)000802171100010 ()35545033 (PubMedID)2-s2.0-85129773156 (Scopus ID)
Available from: 2022-05-30 Created: 2022-05-30 Last updated: 2024-12-11Bibliographically approved

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Swacha, Patrycja

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