William T. Jackson is Assistant Professor of Microbiology at the Medical College of Wisconsin in Milwaukee, Wisconsin, USA

Michele S. Swanson is Professor of Microbiology and Immunology at the University of Michigan Medical School, Ann Arbor, Michigan, USA

Contributors xiii

Preface xvii

Acknowledgments xix

1 Autophagy and Immunity 1
Xu Liu and Daniel J. Klionsky

1.1 Introduction 1

1.2 Autophagy 2

1.2.1 Types of autophagy 2

1.2.2 Morphology 3

1.2.3 Molecular machinery 3

1.2.4 Physiological roles 5

1.3 Autophagy and immunity 6

1.3.1 Xenophagy: autophagic clearance of intracellular microorganisms 6

1.3.2 Autophagy and cryptides 9

1.3.3 Autophagy and pattern recognition receptors (PRRs) 9

1.3.4 Autophagy and MHC antigen presentation 10

1.3.5 Autophagy regulation by immune signaling molecules 11

1.3.6 Autophagy, inflammation, and autoimmunity 11

1.4 Conclusion 12

References 12

2 Techniques for Studying Autophagy 19
Isei Tanida and Masato Koike

2.1 Introduction 19

2.2 Reagents and tools for studying autophagy 21

2.2.1 Reagents to monitor the lysosomal flux of LC3-II 21

2.2.2 Reagents that induce autophagy 21

2.2.3 Reagents and recombinant tools that inhibit autophagy 22

2.3 Detection of LC3-I and LC3-II by immunoblotting 22

2.4 Immunofluorescent analyses of endogenous LC3 23

2.5 Monitoring autophagy using fluorescent protein-tagged LC3 23

2.6 Morphological analyses of autophagosomes and autolysosomes by TEM 24

2.6.1 Reagents or stock solutions 26

2.6.2 Resin embedding of cell pellets or microbes 26

2.6.3 Resin flat embedding of cells grown on glass or plastic coverslips 27

2.7 Techniques for immunoelectron microscopy 28

References 29

3 Role of Autophagy In DNA Virus Infections in Vivo 33
Xiaonan Dong and Beth Levine

3.1 Introduction 33

3.2 In vivo interplay between autophagy and DNA viruses in plants and invertebrates 34

3.3 In vivo interplay between autophagy and DNA viruses in vertebrates 35

3.3.1 Autophagy is an essential antiviral mechanism that protects against HSV-1 in vivo 35

3.3.2 The autophagy-HBV interplay in vivo: a balance between viral exploitation and tumor suppression 40

3.3.3 Autophagy may suppress γ-herpesvirus persistent infection 42

3.4 Conclusion 43

Acknowledgments 44

References 44

4 Studying RNA Viruses and Autophagy in Vivo 49
Mehrdad Alirezaei and J. Lindsay Whitton

4.1 Introduction 49

4.2 In vivo interactions between autophagy and RNA viruses in plants and invertebrates 50

4.2.1 Plants 50

4.2.2 Invertebrates 50

4.3 In vivo Interactions between autophagy and RNA viruses in vertebrates 51

4.3.1 Togaviridae 51

4.3.2 Caliciviridae 51

4.3.3 Orthomyxoviridae 53

4.3.4 Flaviviridae 53

4.3.5 Picornaviridae 54

4.4 Conclusion 62

Acknowledgments 63

References 63

5 Autophagy and Picornavirus Infection 67
Tom Wileman, Zhigang Zhou, Matthew Whelband, Eleanor Cottam, Stephen Berryman, Terry Jackson and Rebecca Roberts

5.1 Introduction 67

5.2 Selective autophagy involves autophagy receptors with LC3-interacting domains 69

5.3 Autophagy is activated during virus infection 69

5.4 Picornaviruses and autophagy 69

5.4.1 Poliovirus 70

5.4.2 Coxsackievirus 72

5.4.3 Human enterovirus 71 73

5.4.4 Encephalomyocarditis virus 73

5.4.5 Foot-and-mouth disease virus 74

5.4.6 Human rhinoviruses 75

5.5 Caution in interpretation of induction of LC3 puncta and double-membraned vesicles in the context of autophagy 75

5.5.1 LC3 puncta 75

5.6 Conclusions and future research 77

References 78

6 Flaviviruses and Autophagy 81
Tristan X. Jordan and Glenn Randall

6.1 Introduction 81

6.1.1 Autophagy 81

6.2 Flaviviruses 83

6.3 Dengue virus 83

6.3.1 Autophagosomes as a platform for replication? 85

6.3.2 Modulation of lipid metabolism 86

6.3.3 Potential role for the autophagy-related proteins USP10 and USP13 in DENV virion maturation 87

6.3.4 Cytoprotective autophagy 88

6.3.5 The role of autophagy in an ADE model of monocyte infection 89

6.3.6 Autophagy in DENV infections in mice 89

6.4 Other Flaviviruses 90

6.4.1 Japanese encephalitis virus 90

6.4.2 Modoc virus 90

6.4.3 West Nile virus 90

6.5 Concluding remarks 92

Acknowlegments 92

References 93

7 Autophagy: A Home Remodeler for Hepatitis C Virus 101
Marine L.B. Hillaire, Elodie Décembre, and Marlène Dreux

7.1 Introduction 101

7.1.1 Autophagy 101

7.1.2 Hepatitis C virus (HCV) disease, genome and replication 103

7.2 HCV induces a proviral autophagy 111

7.3 How does HCV trigger autophagy vesicle accumulation? 111

7.4 Dynamic membrane remodeling by autophagy 113

7.5 Interlinkage of autophagy with the innate immune response 114

7.6 Autophagy and cell death 115

7.7 Removal of aberrant deposits and organelles by autophagy: implications for liver injury associated with chronic hepatitis C 116

7.7.1 Autophagy and lipid metabolism 116

7.7.2 Mitophagy and HCV persistence 117

7.8 Conclusions and future directions 118

Acknowledgments 119

References 119

8 Modulating Autophagy to Cure Human Immunodeficiency Virus Type-1 127
Stephen A. Spector and Grant R. Campbell

8.1 Introduction 127

8.2 HIV subverts autophagy to promote its own replication 129

8.3 HIV infection inhibits autophagy during permissive infection while induction of autophagy leads to inhibition of HIV 130

8.4 HIV-induced autophagy in bystander CD4⁺ T cells results in cell death 130

8.5 Modulation of autophagy as a mechanism for HIV-associated neurocognitive impairment 132

8.6 How can autophagy be exploited to control and eradicate HIV? 134

Acknowledgments 137

References 138

9 Autophagy in the Infected Cell: Insights from Pathogenic Bacteria 143
Andrea Sirianni and Serge Mostowy

9.1 Introduction 143

9.2 Autophagy–bacteria interactions 143

9.2.1 Salmonella typhimurium 144

9.2.2 Mycobacterium tuberculosis 145

9.2.3 Legionella pneumophila 146

9.2.4 Listeria monocytogenes 147

9.2.5 Shigella flexneri 149

9.2.6 Mycobacterium marinum 150

9.3 Conclusions 151

Acknowledgments 151

References 152

10 Rab Proteins in Autophagy: Streptococcus Model 159
Takashi Nozawa and Ichiro Nakagawa

10.1 Introduction 159

10.2 Rab GTPase 160

10.3 Rab GTPases in starvation-induced autophagy 160

10.4 Rab localization in autophagy during Streptococcus infection 161

10.5 Involvement of Rab7 in the initial formation of GcAV 163

10.6 Requirement of Rab23 for GcAV formation 163

10.7 Facilitation by Rab9A of GcAV enlargement and lysosomal fusion 164

10.8 Conclusion and perspective 165

References 167

11 Helicobacter Pylori Infection Control by Autophagy 171
Laura K. Greenfield, Frances Dang, and Nicola L. Jones

11.1 Helicobacter pylori 171

11.2 H. pylori and evasion of host immune responses 176

11.3 Autophagy 178

11.4 Acute H. pylori infection: induction of autophagy in gastric epithelial cells 180

11.5 Chronic H. pylori infection: suppression of autophagy in gastric epithelial cells 184

11.6 H. pylori induction of autophagy in immune cells 185

11.7 Host genetics affecting autophagic clearance of H. pylori 185

11.8 H. pylori disrupted autophagy and gastric cancer 186

11.9 H. pylori therapy: is autophagy a contender? 187

11.10 Concluding remarks 188

Acknowledgments 189

References 189

12 Interactions Between Salmonella and The Autophagy System 201
Teresa L.M. Thurston and David W. Holden

12.1 Introduction 201

12.2 Salmonella’s life within the host 201

12.3 Salmonella’s survival in a harsh intracellular habitat 202

12.4 Models for studying Salmonella infection 203

12.5 Mechanisms of Salmonella autophagy 204

12.5.1 Salmonella is targeted for antibacterial autophagy 204

12.5.2 Antibacterial autophagy induction 205

12.5.3 Eat-me signals for antibacterial autophagy 206

12.5.4 Autophagy receptors provide cargo specificity 208

12.6 Autophagy of Salmonella in vivo 209

12.7 Bacterial countermeasures 210

12.7.1 Could Salmonella counteract autophagy? 210

12.7.2 Potential autophagy avoidance mechanisms 210

12.7.3 SseL deubiquitinates autophagy-targeted protein aggregates 210

12.7.4 Does Salmonella inhibit selective antibacterial autophagy? 211

12.8 Perspectives 211

References 213

13 Host Factors That Recruit Autophagy as Defense Against Toxoplasma Gondii 219
Carlos S. Subauste

13.1 Introduction 219

13.2 CD40, autophagy and lysosomal degradation of T. gondii 220

13.3 Events downstream of CD40 involved in the stimulation of autophagy 222

13.4 Relevance of autophagy during in vivo infection with T. gondii 224

13.5 IFN-γ and ATG5 in T. gondii infection 224

13.6 T. gondii manipulates host cell signaling to inhibit targeting by LC3⁺ structures and to maintain the nonfusogenic nature of the parasitophorous vacuole 227

13.7 Autophagy machinery within T. gondii 228

13.8 Conclusion 229

Acknowledgments 229

References 229

14 Mycobacterium Tuberculosis and The Autophagic Pathway 233
Gabriela María Recalde and María Isabel Colombo

14.1 Mycobacterium tuberculosis, a pathogen that resides in a self-tailored compartment to avoid killing by the host cell 233

14.2 The ESX-1 secretion system 235

14.3 Mycobacterium marinum, a close relative that escapes and forms actin tails in the cytoplasm 235

14.4 Mycobacterium actively modulates autophagy 236

14.5 Mycobacterium tuberculosis, a pathogen also able to escape toward the cytoplasm 239

14.6 Concluding remarks 240

References 241

15 Autophagy Enhances yhe Efficacy of BCG Vaccine 245
Arshad Khan, Christopher R. Singh, Emily Soudani, Pearl Bakhru, Sankaralingam Saikolappan, Jeffrey D. Cirillo, N. Tony Eissa, Subramanian Dhandayuthapani and Chinnaswamy Jagannath

15.1 Introduction 246

15.2 Induction of autophagy through mTOR enhances antigen presentation via the MHC-II pathway in macrophages and dendritic cells 247

15.2.1 Rapamycin-induced autophagy enhances antigen presentation in APCs 248

15.2.2 Rapamycin and Torin1-induced autophagy enhances both antigen presentation and IL-1β secretion from BCG infected APCs 248

15.3 Intracellular mechanisms of autophagic routing of particulate BCG vaccine and secreted Ag85B into autophagosomes and enhanced MHC-II mediated antigen presentation 251

15.3.1 Overexpression of secreted Ag85B in BCG vaccine leads to aggresome formation in the cytosol of APCs 251

15.3.2 Overexpressed Ag85B from BCG vaccine forms aggresomes, which enhance antigen presentation through autophagy 251

15.3.3 Discussion: in vitro studies on autophagy and antigen presentation 253

15.4 Rapamycin activation of dendritic cells enhances efficacy of DC-BCG vaccine 255

15.4.1 Discussion 256

15.5 Rapamycin coadministration with BCG vaccine in mice enhances CD4 and CD8 T cell mediated protection against tuberculosis 256

15.5.1 Discussion 262

15.6 Conclusions 262

Acknowledgments 263

References 263

16 Autophagy’s Contribution to Innate and Adaptive Immunity: An Overview 267
Christina Bell, Michel Desjardins, Pierre Thibault and Kerstin Radtke

16.1 Autophagy: different routes to the same goal? 267

16.2 Xenophagy: it is a dog-eat-dog world 269

16.3 Autophagy and Toll-like receptors: a mutual turn-on 269

16.4 Autophagy and antigen presentation: a cry for help to clear pathogenic invaders 270

16.5 Autophagy and inflammasomes: Mutual regulation for an effective immune response 273

16.6 Cross-talk between autophagy and cytokines 273

Acknowledgments 275

References 275

17 Autophagy in Immune Responses to Viruses 279
Christophe Viret and Mathias Faure

17.1 Innate immunity against viruses 279

17.2 Autophagy in antiviral innate immunity 281

17.2.1 Virus sensing for autophagy induction 281

17.2.2 Role of autophagy in xenophagy of viruses 282

17.2.3 Role of autophagy in antiviral innate immunity signaling 283

17.3 Autophagy manipulation by viruses to resist innate immunity 285

17.3.1 Autophagy manipulation by viruses to prevent IFN-I synthesis 285

17.3.2 Viruses subvert autophagy to interfere with inflammatory responses 286

17.3.3 Autophagy and cell death during virus infection 287

17.4 Autophagy in antiviral adaptive immunity 287

17.4.1 Promotion of adaptive immune responses to viral infection by autophagy 287

17.4.2 MHC class II-restricted presentation of viral epitopes 288

17.4.3 MHC class I-restricted presentation of viral epitopes 290

17.4.4 Autophagy and cross-presentation 292

17.5 Autophagy manipulation by viruses to escape adaptive immunity 294

17.5.1 MHC class II antigen presentation pathway 294

17.5.2 MHC class I antigen presentation pathway 295

17.5.3 Autophagy and antigen-presenting cell function 295

17.6 Concluding remarks 296

Acknowledgments 296

References 297

18 Processing and MHC Presentation Of Antigens After Autophagy-Assisted Endocytosis, Exocytosis, and Cytoplasm Degradation 303
Christian Münz

18.1 Introduction 303

18.2 Substrate recognition by macroautophagy 305

18.3 Antigen processing for MHC class II presentation by macroautophagy 307

18.4 A role of macroautophagy in MHC class I antigen presentation 308

18.5 Antigen release by autophagy-assisted exocytosis 309

18.6 Autophagy-assisted phagocytosis 310

18.7 Conclusions and outlook 312

Acknowledgments 312

References 312

Index 317

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