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.