Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length-dependent manner. This is observed over a wide length-span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length-dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections.

Coronavirus disease 2019 (COVID-19) is a disease characterized by a profound dysregulation of the innate immune system. This knowledge has emerged from the large body of single-cell omics studies of patients with COVID-19, which have provided one of the most detailed cellular atlases of a human disease ever. However, we are only beginning to understand the innate immunological pathways that govern host defense and immunopathology in COVID-19. In this review, we discuss the emerging understanding of how SARS-CoV-2 and host-derived molecules activate specific pattern recognition receptors to elicit protective interferon responses and pathological cytokine responses, with particular focus on acute infection of the lung and lung pathophysiology in critical COVID-19. In addition, we discuss how these pathways are modulated by virus-host interactions and host stress-sensing pathways. In-depth understanding of the disease mechanisms will likely uncover specific molecular targets for the treatment of COVID-19 and other emerging viral infections. In addition, it will reveal the fine balance between beneficial protective versus pathological disease causing immune responses.

The immune system detects disturbances in homeostasis that occur during infection, sterile tissue damage and cancer. This initiates immune responses that seek to eliminate the trigger of immune activation and to reestablish homeostasis. At the same time, these mechanisms can also play a crucial role in the progression of disease. The occurrence of DNA in the cytosol constitutes a potent trigger for the innate immune system, governing the production of key inflammatory cytokines such as type I interferons and IL-1β. More recently, it has become clear that cytosolic DNA also triggers other biological responses, including various forms of programmed cell death. In this article we review the emerging literature on the pathways governing DNA-stimulated cell death and the current knowledge on how these processes shape immune responses to exogenous and endogenous challenges.

The two cytokines interleukin (IL)-4 and interferon (IFN)-gamma play major roles in the generation and regulation of immune responses. Central in this respect is their mutually antagonistic functions. First, IL-4 promotes T helper cell type 2 (Th2) differentiation and stability and inhibits Th1-cell differentiation. A direct role of IFN-gamma in Th1-cell differentiation is debatable, whereas inhibition of Th2-cell differentiation and roles in Th1-cell stabilization are well established functions of IFN-gamma. Secondly, IL-4 and IFN-gamma also affect antibody class switch and expression of Fc receptors differentially, which strongly affect the effector mechanisms following antibody production. Thirdly, macrophage activities induced or enhanced by IFN-gamma, such as expression of certain cytokines, surface molecules and enzymes, are antagonized by IL-4. Together, these functions of IL-4 and IFN-gamma place the two cytokines at cardinal positions in the regulation of immune reactions. In this review the known molecular mechanisms underlying the observed functions of IL-4 and IFN-gamma are presented and discussed.