Biological DNA Sensor defines the meaning of DNA sensing pathways and demonstrates the importance of the innate immune responses induced by double stranded DNA (dsDNA) through its influencing functions in disease pathology and immune activity of adjuvants for vaccines. Though discussed in specific subsections of existing books, dsDNA and its immunogenic properties has never received the complete treatment given in this book. Biological DNA Sensor approaches the impact of dsDNA's immunogenicity on disease and vaccinology holistically. It paints a complete and concise picture on the topic so you can understand this area of study and make more informed choices for your respective research needs. Chapters are authored by researchers who are renowned for their research focus, ensuring that this book provides the most complete views on the topics. - Multi-authored by a distinguished panel of world-class experts - Ideal source of information for those wanting to learn about DNA sensing - Provides in-depth explanations of DNA sensing pathways and the innate immune system, bridging the gap between them

In this chapter, we reflect on our early understanding of the immunogenic properties of dsDNA and give a chronological account of the journey we have taken to discover the individual cellular DNA sensors which have played important roles in mediating DNA induced inflammation.

Invading microbes are detected by cellular sensors, the consequences of which result in the production of potent anti-pathogen proteins such as type I interferon (IFN) as well as other cytokines capable of stimulating the adaptive immune response. Examples comprise the RIG-I-like helicase (RLH) and the Toll-like receptor (TLR) families which recognize non-self-pathogen derived molecules (PAMPs) including bacterial lipopolysaccharides as well as nucleic acids. In addition, an endoplasmic reticulum (ER) associated transmembrane protein referred to as STING (for stimulator of interferon genes) was established as being essential for triggering the production of innate immune proteins in response to the sensing of cytosolic DNA. Such DNA can be ‘self’-DNA produced from necrotic or apoptotic cells, or the actual genomes of DNA pathogens that become exposed following infection. Moreover, while STING appears essential for controlling innate signaling events triggered by DNA microbes, chronic STING activation also appears to be responsible for certain inflammatory diseases manifested by ‘self’-DNA. Thus, understanding STING function may lead to the design of new compounds that may facilitate vaccine development or conversely that may provide new therapies for the treatment of inflammatory disease.

Cyclic dinucleotides (c-di-NMPs), such as c-di-GMP and c-di-AMP were first discovered in bacteria, where they play important roles as second messenger molecules that regulate bacterial cellular functions. In addition, these and other c-di-NMPs exert potent biological effects on mammalian cells, such as the inhibition of cancer cell proliferation, immune cell activation, and the triggering of type I interferon production. Here, we introduce the biology of c-di-NMPs in bacterial systems and review the current state of the literature on their biological effects in mammalian cells. Emphasis is placed on evaluating the evidence that c-di-NMPs have potent immune stimulatory effects on cultured mouse and human cells and can act as adjuvants and immune stimulants in animal models. In addition, we highlight areas where further experimentation could hasten the development of c-di-NMPs as adjuvants in potent and safe systemic and mucosal vaccines.

Toll-like receptors, NOD-like receptors and numerous intracellular sensors that detect nucleotides in the cytosol help to initiate immune responses to viral infections. Many of the cytosolic nucleotide sensors and their downstream mediators also play a role in RNA metabolism, DNA repair and cancer. Here we review the evidence that links cytosolic DNA sensors to processes that are activated in cancer cells.

Aluminum-based adjuvants (alum) are among the oldest and most widely used vaccine adjuvants. After decades of largely empirical use, the last years have witnessed a flurry of studies aiming to decipher the immunological mechanisms of action of alum. Along with other hypotheses, recent reports support that alum induces the release by host cells of their own DNA at sites of injection. Extracellular self-DNA would in turn activate the innate immune system through known and yet to be identified innate immune pathways and in this way boost the adaptive response to vaccine antigens. This chapter discusses the evidence supporting the view of self-DNA as a damage-associated molecular pattern implicated in the adjuvant activity of alum, its possible links with other proposed mechanisms, as well as future directions in the area of the sensing of self-nucleic acids in the modulation of immunological responses to vaccines.

Ideal vaccines are expected to give lifetime protection from infectious diseases, and if possible, from allergic diseases, autoimmune diseases and cancer. DNA vaccination was introduced two decades ago as a simple plasmid inoculation method with a capability of inducing both cellular and humoral immune responses. Recent studies have provided insights into the molecular mechanisms by which the double-stranded structure of DNA vaccine induces the activation of type-I interferon (IFN)-mediated innate immune responses via STING/TBK1 complex, similar to cytosolic double stranded DNA (dsDNA) recognition of immune cells. In this chapter, DNA vaccines and the current knowledge on their mechanism of action will be introduced. The possibilities of using this knowledge for improving immunogenicity of DNA vaccines in humans will then be discussed.