Biological DNA Sensor

List of Contributors

Preface

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

Chapter 1. Route to Discovering the Immunogenic Properties of DNA from TLR9 to Cytosolic DNA Sensors

Introduction

The Importance of the Innate Immune System

Endosomal-Membrane Bound DNA Sensor – TLR9

Cytosolic DNA Sensors

Conclusion

Acknowledgment

References

Chapter 2. The PYHIN Family of Molecules and their Functions Sensing dsDNA

Introduction

Members of the Pyhin Family

Structural Basis of DNA Recognition by PYHIN Proteins

Microbial DNA Sensing and Signaling by PYHIN Proteins

Transcriptional Regulation by PYHIN Proteins

Role of PYHIN Proteins in the Development of Autoimmunity

Regulation of PYHIN Proteins

Conclusions

References

Chapter 3. Cytosolic DNA-Sensing and the STING Pathway

Introduction

The Toll-Like Pathway: TLR9 and CpG DNA

The STING Pathway and Intracellular DNA Signaling

STING and Inflammatory Disease

Other Sensors of Intracellular DNA

Conclusion

References

Chapter 4. Regulation of Intracellular dsDNA-Induced Innate Immune Responses by Autophagy-Related Proteins

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

Part II. Autophagy and STING-Dependent Bactericidal Responses

Part III. Autophagy and AIM2-Dependent Inflammatory Responses

Conclusion

References

Section B: dsDNA and Its Part in Modulating Human Diseases

Chapter 5. Host DNA Induced Inflammation and Autoimmune Diseases

Introduction

The Type I IFN System as the Crux of Autoimmunity

Self and Non-Self-DNA Recognition

Heterogeneity in Innate Receptors for DNA

Mechanisms Underlying Host DNA Induced Inflammation and Autoimmunity

Conclusions and Future Perspectives

References

Chapter 6. Toll-Like Receptor 9 and Toll-Like Receptor 7 in the Development and Regulation of Systemic Autoimmune Disease

Introduction

Nucleic Acid Sensing TLRs

Immune Complex Activation of pDCs and Type I IFN

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

Autoantigens and TLR Activation

Aberrant Self-Antigen Clearance and Detection

Paradoxical Roles of TLR9 and TLR7 in Murine Models of SLE

Critical Role for B Cells in TLR-Mediated Regulation of Autoimmune Disease and TLR9-Dependent Suppression of Autoimmune Disease

Cell Intrinsic Regulation of TLR9 and TLR7 in B Cells

Compartmental Restriction of TLR Responses

Summary and Unanswered Questions

References

Chapter 7. Bacterial Infections and the DNA Sensing Pathway

Introduction

The Role of TLR9 in Bacterial Infections

The AIM2 Inflammasome as a Sensor of Bacterial DNA

Sting-Dependent Cytosolic DNA Sensors and Type I IFN Responses During Bacterial Infections

Conclusion

Acknowledgments

References

Chapter 8. Viral Infections and the DNA Sensing Pathway: Lessons from Herpesviruses and Beyond

Introduction

Innate Immunological Recognition of Herpesvirus DNA

DNA Sensors Involved in Recognition of Herpesvirus DNA

Role for Sting in the Response to Intracellular DNA Sensing

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

Viral Evasion of DNA-Driven Innate Immune Responses

DNA Sensing Beyond Herpesviruses

Concluding Remarks

Acknowledgments

References

Chapter 9. Cancer Pathogenesis and DNA Sensing

IFN-Inducing Cytosolic DNA Sensors

Mediators of IFN-Inducing Cytosolic DNA Sensors

STING and TRIF Pathways

NF-κB

ProInflammatory Cytokines

Inflammasome-Inducing Cytosolic DNA Sensors

Conclusion

References

Chapter 10. DNA Damage Responses in Atherosclerosis

Background

Evidence of DNA Damage in Atherosclerosis

Types of DNA Damage

Mitochondrial DNA Damage

DNA Damage Responses in Atherosclerosis

DNA Damage Sensing and Inflammation in Atherosclerosis

Conclusion

Acknowledgment

References

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

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

Introduction

DNA Vaccines: Proof of Concept

DNA Vaccines: Mouse vs. Man

What Immunological Responses are Triggered after DNA Vaccination?

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

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

DNA Sensing Machinery: Is there a Hope to Improve DNA Vaccine Immunogenicity in Humans?

Can DNA Plasmid Metabolites Be Adjuvant?

Conclusions

Acknowledgments

References

Chapter 12. Adjuvants Targeting the DNA Sensing Pathways – Alum Based Adjuvants

Understanding the Mechanisms of Action of Alum Through Vaccine Immunology

Recent Immunological Insights Into the Mechanisms of Action of Alum

Triggering of Innate Immune Signaling Following Alum-Adjuvanted Immunization

DNA Release and Signaling in the Adjuvant Activity of Alum

A Model for Self-DNA Induced Responses in Alum Immunization

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

References

Chapter 13. Adjuvants Targeting the DNA Sensing Pathways – Cyclic-di-GMP and other Cyclic-Dinucleotides

Introduction

Production and Functions of Cyclic-Dinucleotides in Bacteria

Production and Measurement of c-di-NMPS

Effects of c-di-NMPS on Cancer Cells

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

c-di-NMPS as Vaccine Adjuvants

Conclusions

References

Index