William T. Jackson & Michele S. Swanson 
Autophagy, Infection, and the Immune Response [PDF ebook] 

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 gamma-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 Gc AV 163
10.6 Requirement of Rab23 for Gc AV formation 163
10.7 Facilitation by Rab9A of Gc AV 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 Sse L 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-gamma 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 THE 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 m TOR 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-1ß 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

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