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

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.

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.

Microbial and host DNA are potent stimulators of innate immune responses and have been implicated in both host defense and autoimmune diseases. To date more than 10 immunological sensors of DNA have been proposed, and we are now beginning to understand the functions and mechanism of action of these proposed DNA sensors in host defense and diseases. Much of the current knowledge on DNA sensing has been obtained through studies with herpesviruses. Hence, in this chapter, we review and critically assess the literature on innate DNA recognition from the perspective of herpesviruses sensing. Finally, we extend the discussion beyond herpesviruses, and propose important questions that need to be addressed in the emerging field of innate immune activation by DNA.

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.

The innate immune response serves as the first line of defense against microbial infections by detecting pathogen-associated molecular patterns through germline-encoded pattern recognition receptors. Proteins of the PYHIN family have gained substantial research focus in recent years as central mediators of innate immune responses induced by cytosolic microbial DNA. Sensing of DNA by PYHINs typically leads to activation of inflammasomes and/or type I interferon responses that are crucial for host defense against invading pathogens. Certain members of the family are also involved in the development of autoimmune diseases as well as transcriptional regulation. Although the generation of knockout mice strains has unraveled the essential role of PYHIN proteins such as AIM2 in the development of antimicrobial innate immune responses, the exact biological role of several other PYHIN family members remains to be understood. This chapter reviews the important discoveries on PYHIN proteins and their role in microbial defense, autoimmunity and transcriptional regulation.

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.

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.

Nanopores are nanometer scale holes formed naturally by proteins or cells, and can be used for a variety of applications, including sequencing DNA and detecting anthrax. They can be integrated into artificially constructed encapsulated cells of silicon wafers while allowing small molecules like oxygen, glucose and insulin to pass, while keeping out large system molecules. "Nanopores: Sensing and Fundamental Biological Interactions" examines the emerging research directions surrounding nanopores such as genome sequencing and early disease detection using biomarker identification. Covering the applications of nanopores in genetics, proteomics, drug discovery, early disease detection and detection of emerging environmental threats, it is a must-have book for biomedicalengineers and research scientists.

The detection of bacterial pathogens by the innate immune system is mediated by various pattern recognition receptors that sense microbial molecules such as cell wall components, virulence factors or nucleic acids. Bacterial DNA is recognized by Toll-like receptor 9 (TLR9) at endosomal compartments and by cyclic GMP-AMP synthase, polymerase III/RIG-I, AIM2-like receptors (ALRs), DNA helicases as well as other incompletely characterized proteins in the host cell cytosol. Depending on the receptor and specific engagement of the adapter molecules MyD88, STING, MAVS or ASC, sensing of bacterial DNA triggers expression of NF-κB-dependent proinflammatory genes, type I IFN responses, and/or inflammasome activation. Whereas inflammatory gene expression and inflammasome activation are required for an effective host defense to most bacterial infections, type I IFNs appear to play a regulatory role and can be beneficial or detrimental for the host. This chapter summarizes the current knowledge about the mechanisms of DNA sensing and its function in bacterial infections.