Deoxyribonucleic acid (DNA), the fundamental molecule that packsgenetic instructions for the development of living organisms, has been dis-covered to hold yet another vital function for our biology — inflammation.The fact that DNA is an abundant commodity in our body and causes itsimmunogenic property is one that cannot be taken lightly. Now, we knowthat DNA induced inflammation is responsible for the pathogenicity ofautoimmune and infectious diseases and metabolic disorders. Furthermore,we have evidence that DNA induced inflammation is involved in thedevelopment of cancer. Therefore the awareness of the immunogenicnature of dsDNA has provided us with the opportunity to gain furtherinsights into the workings of human diseases. DNA seemed to be anironic choice as a trigger molecule for inflammation. After all, who wouldexpect that self-products containing our genetic blueprint could turnagainst us and induce adverse inflammatory reactions upon detection bythe immune system? However, on deeper reflection, it does make practi-cal sense to have nucleic acids as signaling entities that sound off the alarmto indicate impending danger to the body. Pathogens including viruses,bacteria and parasites, like human beings, have their genetic informationstored in nucleic acids. Their invasion into the host system is likely to beassociated with the introduction of their genetic materials and thereforeit would be the most appropriate indication of pathogenic invasion. Onthe other hand, the release of our own DNA into the surrounding physi-ological environment could also indicate cell death as a result of trauma,which may invite infection to occur and require immune defenses to beput in place. Therefore in more ways than one, DNA is an aptly chosenalarm molecule for the immune system to react to danger. Regarding thepotential impact it has on various aspects of our health, we have seen anexplosion of research on DNA sensing in the past eight years. This surgein publication was due in part to the discovery that DNA could be sensednot only by TLR9 in the endosomes, but also by sensors present in thecytosol. More importantly, DNA from pathogens as well as from mamma-lian derived sources is equally potent in inducing inflammation.
It is the purpose of this book to bring together the research on thesignaling mechanism of DNA induced inflammation as well as its impacton diseases and vaccinology. The book has three sections: In Section I,Ishii, Fitzgerald, Barber and Saitoh discuss the signaling pathway leadingto DNA induced inflammation, in Section II, Kawai, Marshak—Rothstein,Opitz, Bowie, Gasser and Arditi discuss the impact of DNA inflamma-tion on human diseases and lastly, in Section Ill, Coban, Desmet and Lenzcomment on how the inflammatory response of DNA could influence theoutcome of vaccination in DNA vaccination strategies and adjuvants tar-geting the DNA sensing pathway.
We are greatly indebted to the contributors whose participation andcooperation made this book possible. We thank them for their patiencewith our persistent requests for completion of their manuscript. We areappreciative for the editorial and technical assistance provided by ElizabethGibson and Mary Preap. To the publisher we are grateful for this timelyopportunity to consolidate the wealth of knowledge we have acquired onDNA sensing which could facilitate future investigations. Lastly, we wouldlike to pay tribute to Alick Issacs and his colleagues who were way aheadof their time in that they had the audacity to identify a molecule thatis so fundamental to our existence, namely, DNA, as a danger signalingmolecule.

List of Contributors xi

Preface xv

Section A The Discovery of dsDNA Immunogenicity and the Definition of DNA Sensing Pathways 1

1.Route to Discovering the Immunogenic Properties of DNA from TLR9 to Cytosolic DNA Sensors Choon Kit Tang, Cevayir Coban, Shizuo Akira and Ken J. Ishii 3

      Introduction 3

      The Importance of the Innate Immune System 4

      Endosomal-Membrane Bound DNA Sensor —TLR9 7

      Cytosolic DNA Sensors 11

      Conclusion 35

      Acknowledgment 35

      References 35

2.The PYHIN Family of Molecules and their Functions Sensing dsDNA Sivapriya Kailasan Vanaja, Vijay A. K. Rathinam and Katherine A. Fitzgerald 43

      Introduction 43

      Members of the PYHIN Family 44

      Structural Basis of DNA Recognition by PYHIN Proteins 46

      Microbial DNA Sensing and Signaling by PYHIN Proteins 47

      Transcriptional Regulation by PYHIN Proteins 55

      Role of PYHIN Proteins in the Development of Autoimmunity 56

      Regulation of PYHIN Proteins 57

      Conclusions 59

      References 59

3.Cytosolic DNA-Sensing and the STING Pathway Glen N. Barber 67

      Introduction 67

      The Toll-Like Pathway: TLR9 and CpG DNA 68

      The STING Pathway and Intracellular DNA Signaling 70

      STING and Inflammatory Disease 75

      Other Sensors of Intracellular DNA 76

      Conclusion 77

      References 78

4.Regulation of Intracellular dsDNA-Induced Innate Immune Responses by Autophagy-Related Proteins Tatsuya Saitoh 83

      Part I. Autophagy-Related Proteins and STING-Dependent IFN Responses 83

      Part II. Autophagy and STING-Dependent Bactericidal Responses 88

      Part III. Autophagy and AIM2-Dependent Inflammatory Responses 90

      Conclusion 95

      References 96

Section B dsDNA and Its Part in Modulating Human Diseases 101

5.Host DNA Induced Inflammation and Autoimmune

Diseases Surya Pandey and Taro Kawai 103

      Introduction 103

      The Type I IFN System as the Crux of Autoimmunity 104

      Self and Non-Self-DNA Recognition 105

      Heterogeneity in Innate Receptors for DNA 107

      Mechanisms Underlying Host DNA Induced Inflammation and Autoimmunity 113

      Conclusions and Future Perspectives 124

      References 125

6.Toll-Like Receptor 9 and Toll-Like Receptor 7 in the Development and Regulation of Systemic Autoimmune Disease Ann Marshak-Rothstein and Michael P. Cancro 133

      Introduction 133

      Nucleic Acid Sensing TLRs 134

      Immune Complex Activation of pDCs and Type I IFN 134

      Activation of Autoreactive B Cells Depends on BCR/TLR Co-Engagement 136

      Autoantigens and TLR Activation 137

      Aberrant Self-Antigen Clearance and Detection 138

      Paradoxical Roles ofTLR9 and TLR7 in Murine Models of SLE 140

      Critical Role for B Cells in TLR-Mediated Regulation of Autoimmune

      Disease and TLR9-Dependent Suppression of Autoimmune Disease 142

      Cell Intrinsic Regulation ofTLR9 and TLR7 in B Cells 143

      Compartmental Restriction of TLR Responses 145

      Summary and Unanswered Questions 146

      References 147

7.Bacterial Infections and the DNA Sensing Pathway Jan Naujoks and Bastian Opitz 153

      Introduction 153

      The Role of TLR9 in Bacterial Infections 154

      The AIM2 Inflammasome as a Sensor of Bacterial DNA 156

      STING-Dependent Cytosolic DNA Sensors and Type I IFN Responses

      During Bacterial Infections 158

      Conclusion 163

      Acknowledgments 163

      References 164

8.Viral Infections and the DNA Sensing Pathway: Lessons from Herpesviruses and Beyond Soren R. Paludan and Andrew G. Bowie 171

      Introduction 171

      Innate Immunological Recognition of Herpesvirus DNA 173

      DNA Sensors Involved in Recognition of Herpesvirus DNA 175

      Role for STING in the Response to Intracellular DNA Sensing 183

      Roles of Known DNA Sensors in Herpesvirus Infection Independent of their Role as PRRs 185

      Viral Evasion of DNA-Driven Innate Immune Responses 187

      DNA Sensing Beyond Herpesviruses 190

      Concluding Remarks 193

      Acknowledgments 194

      References 194

9.Cancer Pathogenesis and DNA Sensing Y.J. Shen, A.R. Lam, S.S.W. Ho, C.X. Koo, N. Le Bert and S. Gasser 205

      IFN-Inducing Cytosolic DNA Sensors 205

      Mediators of IFN-Inducing Cytosolic DNA Sensors 211

      STING and TRIF Pathways 211

      NF-xB 213

      Proinflammatory Cytokines 214

      Inflammasome-Inducing Cytosolic DNA Sensors 215

      Conclusion 217

      References 217

10.DNA Damage Responses in Atherosclerosis Kenichi Shimada, Timothy R. Crother and Moshe Arditi 231

Background 231

Evidence of DNA Damage in Atherosclerosis 232

Types of DNA Damage 234

Mitochondrial DNA Damage 236

DNA Damage Responses in Atherosclerosis 237

DNA Damage Sensing and Inflammation in Atherosclerosis 243

Conclusion 246

Acknowledgment 247

References 247

Section C The DNA Sensing Pathway and Its Impact on Vaccinology 255

11.DNA Vaccine: Does it Target the Double Stranded-DNA Sensing

Pathway? Cevayir Coban, Miyuki Tozuka, Nao Jounai, Kouji Kobiyama,Fumihiko Takeshita, Choon Kit Tang and Ken J. Ishii 257

      Introduction 257

      DNA Vaccines: Proof of Concept 258

      DNA Vaccines: Mouse vs. Man 258

      What Immunological Responses are Triggered after DNA Vaccination? 259

      Cytosolic Double Stranded (ds)-DNA Sensing by Immune System 261

      Does Plasmid DNA act in a Common Immunological way of DNA Sensing? 263

      DNA Sensing Machinery: Is there a Hope to Improve DNA Vaccine

      Immunogenicity in Humans? 265

      Can DNA Plasmid Metabolites Be Adjuvant? 266

      Conclusions 267

      Acknowledgments 268

      References 268

12.Adjuvants Targeting the DNA Sensing Pathways — Alum Based Adjuvants Christophe J. Desmet 271

      Understanding the Mechanisms of Action of Alum Through Vaccine

      Immunology 271

      Recent Immunological Insights Into the Mechanisms of Action of Alum 273

      Triggering of Innate Immune Signaling Following Alum-Adjuvanted Immunization 278

      DNA Release and Signaling in the Adjuvant Activity of Alum 284

      A Model for Self-DNA Induced Responses in Alum Immunization 298

      Conclusions and Perspectives on the Role of Self-DNA Sensing in Vaccination 304

      References 305

13. Adjuvants Targeting the DNA Sensing Pathways — Cyclic-di-GMP and other Cyclic-Dinucleotides Rebecca Schmidt and Laurel L. Lenz 313

      Introduction 313

      Production and Functions of Cyclic-Dinucleotides in Bacteria 314

      Production and Measurement of c-di-NMPS 319

      Effects of c-di-NMPS on Cancer Cells 320

      Effects of c-di-NMPS on Mammalian Innate Immune Responses 322

      c-di-NMPS as Vaccine Adjuvants 328

      Conclusions 335

      References 336

Index 341

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