Moonlighting Proteins Novel Virulence Factors in Bacterial Infections

by Henderson, Brian

• ISBN13: 9781118951118
• ISBN10: 1118951115
• Edition: 1st
• Format: Hardcover
• Copyright: 2017-04-17
• Publisher: Wiley-Blackwell

Summary

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections is a complete examination of the ways in which proteins with more than one unique biological action are able to serve as virulence factors in different bacteria.

The book explores the pathogenicity of bacterial moonlighting proteins, demonstrating the plasticity of protein evolution as it relates to protein function and to bacterial communication. Highlighting the latest discoveries in the field, it details the approximately 70 known bacterial proteins with a moonlighting function related to a virulence phenomenon. Chapters describe the ways in which each moonlighting protein can function as such for a variety of bacterial pathogens and how individual bacteria can use more than one moonlighting protein as a virulence factor. The cutting-edge research contained here offers important insights into many topics, from bacterial colonization, virulence, and antibiotic resistance, to protein structure and the therapeutic potential of moonlighting proteins.

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections will be of interest to researchers and graduate students in microbiology (specifically bacteriology), immunology, cell and molecular biology, biochemistry, pathology, and protein science.

Author Biography

Brian Henderson is Professor of Biochemistry in the Department of Microbial Diseases at the UCL-Eastman Dental Institute, University College London. He has worked in academia, both in the UK and North America, and also in the pharmaceutical and biopharmaceutical industry. He has been a cell biologist, immunologist and pharmacologist and over the past twenty years has focused on bacteria-host interactions in relation to human infection and the maintenance of the human microbiota. This is the discipline of Cellular Microbiology and Henderson published the first book on this subject in 1999. At the inception of his career as a cellular microbiologist he discovered a potent bone-destroying protein generated by a pathogenic bacterium. This protein, surprisingly, was the cell stress protein, heat shock protein (Hsp)60. This was one of the earliest bacterial moonlighting proteins discovered and is the reason that the editor has spent the last 20 years exploring the role of protein moonlighting in the life of the bacterium and its interactions with its human host. Henderson has written or edited 17 books and monographs and was the senior editor of the Cambridge University Press Monograph series: Advances in Molecular and Cellular Microbiology.

Table of Contents

List of Contributors xv

Preface xix

About the Editor xxiii

Part I Overview of Protein Moonlighting 1

1 What is Protein Moonlighting and Why is it Important? 3
Constance J. Jeffery

1.1 What is Protein Moonlighting? 3

1.2 Why is Moonlighting Important? 5

1.2.1 Many More Proteins Might Moonlight 5

1.2.2 Protein Structure/Evolution 5

1.2.3 Roles in Health and Disease 8

1.2.3.1 Humans 8

1.2.3.2 Bacteria 10

1.3 Current questions 11

1.3.1 How Many More Proteins Moonlight? 11

1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 11

1.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein? 12

1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 12

1.3.5 What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function? 12

1.4 Conclusions 13

References 13

2 Exploring Structure–Function Relationships in Moonlighting Proteins 21
Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo

2.1 Introduction 21

2.2 Multiple Facets of Protein Function 22

2.3 The Protein Structure–Function Paradigm 23

2.4 Computational Approaches for Identifying Moonlighting Proteins 25

2.5 Classification of Moonlighting Proteins 26

2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 27

2.5.1.1 α‐Enolase, Streptococcus pneumonia 27

2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 29

2.5.1.3 MAPK1/ERK2, Homo sapiens 30

2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 30

2.5.2.1 Malate synthase, Mycobacterium tuberculosis 31

2.5.2.2 BirA, Escherichia coli 31

2.5.2.3 MRDI, Homo sapiens 33

2.5.3 Proteins Using the Same Residues for Different Functions 33

2.5.3.1 GAPDH E. coli 33

2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 33

2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 34

2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 34

2.5.4.2 Aldolase, Plasmodium falciparum 36

2.5.5 Proteins with Different Structural Conformations for Different Functions 36

2.5.5.1 RfaH, E. coli 36

2.6 Conclusions 37

References 39

Part II Proteins Moonlighting in Prokarya 45

3 Overview of Protein Moonlighting in Bacterial Virulence 47
Brian Henderson

3.1 Introduction 47

3.2 The Meaning of Bacterial Virulence and Virulence Factors 47

3.3 Affinity as a Measure of the Biological Importance of Proteins 49

3.4 Moonlighting Bacterial Virulence Proteins 50

3.4.1 Bacterial Proteins Moonlighting as Adhesins 52

3.4.2 Bacterial Moonlighting Proteins That Act as Invasins 59

3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 59

3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 60

3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 63

3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 64

3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 66

3.7 Conclusions 67

References 68

4 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81
Willem van Eden

4.1 Autoimmunity and Conservation 81

4.2 Immunogenicity of Conserved Proteins 82

4.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 84

4.3.1 HSP as Targets for T‐Cell Regulation 85

4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87

References 88

Part III Proteins Moonlighting in Bacterial Virulence 93

Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 95

5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97
Brian Henderson

5.1 Introduction 97

5.2 Tuberculosis and the Tuberculoid Granuloma 97

5.3 Mycobacterial Factors Responsible for Granuloma Formation 98

5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 100

5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 100

5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 101

5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 102

5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 105

5.5 Conclusions 106

References 106

6 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111
Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduno

6.1 Background 111

6.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 112

6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 112

6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 113

6.3.2 Yeast Two‐Hybrid Screens 118

6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 120

6.4.1 Ability of GroEL and HtpB to Associate with Membranes 121

6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 122

6.5 Identifying Functionally Important Amino Acid Positions in HtpB 124

6.5.1 Site‐Directed Mutagenesis 125

6.6 Functional Evolution of HtpB 126

6.7 Concluding Remarks 127

References 129

Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 135

7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137
Brian Henderson

7.1 Introduction 137

7.2 Proline and PPIs 137

7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 138

7.4 Bacterial PPIs as Virulence Factors 138

7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 140

7.5 Other Bacterial PPIs Involved in Virulence 140

7.6 Conclusions 142

References 142

Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 147

8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149
Michael A. Sirover

8.1 Introduction 149

8.2 GAPDH Membrane Function and Bacterial Virulence 150

8.2.1 Bacterial GAPDH Virulence 151

8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 153

8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 153

8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 154

8.3.2 Formation of GAPDH^cys‐NO by Bacterial NO Synthases 155

8.3.3 GAPDH^cys‐NO in Bacterial Virulence: Induction of Macrophage Apoptosis 155

8.3.4 GAPDH^cys‐NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity 156

8.3.5 GAPDH^cys‐NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins 157

8.4 GAPDH Control of Gene Expression and Bacterial Virulence 158

8.4.1 Bacterial GAPDH Virulence 159

8.5 Discussion 160

Acknowledgements 162

References 162

9 Streptococcus pyogenes GAPDH: A Cell‐Surface Major Virulence Determinant 169
Vijay Pancholi

9.1 Introduction and Early Discovery 169

9.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities 170

9.3 AutoADP‐Ribosylation of SDH and Other Post‐Translational Modifications 172

9.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms 173

9.5 Surface Export of SDH/GAPDH: A Cause or Effect? 178

9.6 SDH: The GAS Virulence Factor‐Regulating Virulence Factor 180

9.7 Concluding Remarks and Future Perspectives 183

References 183

10 Group B Streptococcus GAPDH and Immune Evasion 195
Paula Ferreira and Patrick Trieu‐Cuot

10.1 The Bacterium GBS 195

10.2 Neonates are More Susceptible to GBS Infection than Adults 195

10.3 IL‐10 Production Facilitates Bacterial Infection 196

10.4 GBS Glyceraldehyde‐3‐Phosphate Dehydrogenase Induces IL‐10 Production 197

10.5 Summary 199

References 200

11 Mycobacterium tuberculosis Cell‐Surface GAPDH Functions as a Transferrin Receptor 205
Vishant M. Boradia, Manoj Raje, and Chaaya Iyengar Raje

11.1 Introduction 205

11.2 Iron Acquisition by Bacteria 206

11.2.1 Heme Uptake 206

11.2.2 Siderophore‐Mediated Uptake 207

11.2.3 Transferrin Iron Acquisition 207

11.3 Iron Acquisition by Intracellular Pathogens 207

11.4 Iron Acquisition by M. tb 208

11.4.1 Heme Uptake 208

11.4.2 Siderophore‐Mediated Iron Acquisition 209

11.4.3 Transferrin‐Mediated Iron Acquisition 209

11.5 Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 210

11.6 Macrophage GAPDH and Iron Uptake 210

11.6.1 Regulation 210

11.6.2 Mechanism of Iron Uptake and Efflux 211

11.6.3 Role of Post‐Translational Modifications 211

11.7 Mycobacterial GAPDH and Iron Uptake 212

11.7.1 Regulation 212

11.7.2 Mechanism of Iron Uptake 215

11.7.3 Uptake by Intraphagosomal M. tb 216

11.8 Conclusions and Future Perspectives 216

Acknowledgements 218

References 219

12 GAPDH and Probiotic Organisms 225
Hideki Kinoshita

12.1 Introduction 225

12.2 Probiotics and Safety 225

12.3 Potential Risk of Probiotics 227

12.4 Plasminogen Binding and Enhancement of its Activation 228

12.5 GAPDH as an Adhesin 229

12.6 Binding Regions 232

12.7 Mechanisms of Secretion and Surface Localization 234

12.8 Other Functions 235

12.9 Conclusion 236

References 237

Part 3.4 Cell‐Surface Enolase: A Complex Virulence Factor 245

13 Impact of Streptococcal Enolase in Virulence 247
Marcus Fulde and Simone Bergmann

13.1 Introduction 247

13.2 General Characteristics 248

13.3 Expression and Surface Exposition of Enolase 249

13.4 Streptococcal Enolase as Adhesion Cofactor 252

13.4.1 Enolase as Plasminogen‐Binding Protein 252

13.4.1.1 Plasminogen‐Binding Sites of Streptococcal Enolases 253

13.4.2 Role of Enolase in Plasminogen‐Mediated Bacterial‐Host Cell Adhesion and Internalization 254

13.4.3 Enolase as Plasminogen‐Binding Protein in Non‐Pathogenic Bacteria 255

13.5 Enolase as Pro‐Fibrinolytic Cofactor 256

13.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix 257

13.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease 258

13.7 Conclusion 258

Acknowledgement 259

References 259

14 Streptococcal Enolase and Immune Evasion 269
Masaya Yamaguchi and Shigetada Kawabata

14.1 Introduction 269

14.2 Localization and Crystal Structure 271

14.3 Multiple Binding Activities of α‐Enolase 273

14.4 Involvement of α‐Enolase in Gene Expression Regulation 276

14.5 Role of Anti‐α‐Enolase Antibodies in Host Immunity 277

14.6 α‐Enolase as Potential Therapeutic Target 279

14.7 Questions Concerning α‐Enolase 281

References 281

15 Borrelia burgdorferi Enolase and Plasminogen Binding 291
Catherine A. Brissette

15.1 Introduction to Lyme Disease 291

15.2 Life Cycle 292

15.3 Borrelia Virulence Factors 292

15.4 Plasminogen Binding by Bacteria 293

15.5 B. burgdorferi and Plasminogen Binding 294

15.6 Enolase 295

15.7 B. burgdorferi Enolase and Plasminogen Binding 297

15.8 Concluding Thoughts 301

Acknowledgements 301

References 301

Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors 309

16 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens 311
Reiko Ikeda and Tomoe Ichikawa

16.1 Introduction 311

16.2 Identification of Triosephosphate Isomerase on S. aureus

as a Molecule that Binds to the Pathogenic Yeast C. neoformans 312

16.2.1 Co‐Cultivation of S. aureus and C. neoformans 312

16.2.2 Identification of Adhesins on S. aureus and C. neoformans 312

16.2.3 Mechanisms of C. neoformans Cell Death 313

16.3 Binding of Triosephosphate Isomerase with Human Plasminogen 314

16.4 Plasminogen‐Binding Proteins on Trichosporon asahii 314

16.5 Plasminogen Receptors on C. neoformans 316

16.6 Conclusions 316

References 317

17 Moonlighting Functions of Bacterial Fructose 1,6‐Bisphosphate Aldolases 321
Neil J. Oldfield, Fariza Shams, Karl G. Wooldridge, and David P.J. Turner

17.1 Introduction 321

17.2 Fructose 1,6‐bisphosphate Aldolase in Metabolism 321

17.3 Surface Localization of Streptococcal Fructose 1,6‐bisphosphate Aldolases 322

17.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor 323

17.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells 324

17.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen 325

17.7 Other Examples of FBAs with Possible Roles in Pathogenesis 326

17.8 Conclusions 327

References 327

Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence 333

18 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma 335
Anne Gründel, Kathleen Friedrich, Melanie Pfeiffer, Enno Jacobs, and Roger Dumke

18.1 Introduction 335

18.2 Binding of Human Plasminogen to M. pneumoniae 337

18.3 Localization of PDHB on the Surface of M. pneumoniae Cells 340

18.4 Conclusions 343

References 344

Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins 349

19 Unexpected Interactions of Leptospiral Ef‐Tu and Enolase 351
Natália Salazar and Angela Barbosa

19.1 Leptospira –Host Interactions 351

19.2 Leptospira Ef‐Tu 352

19.3 Leptospira Enolase 353

19.4 Conclusions 354

References 354

20 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix‐Binding Adhesins 357
Christopher P. Ptak, Chih‐Jung Kuo, and Yung‐Fu Chang

20.1 Introduction 357

20.2 Identification of Antigen 85 358

20.3 Antigen 85 Family Proteins: Mycolyl Transferases 359

20.3.1 Role of the Mycomembrane 359

20.3.2 Ag85 Family of Homologous Proteins 359

20.3.3 Inhibition and Knockouts of Ag85 360

20.4 Antigen 85 Family Proteins: Matrix‐Binding Adhesins 361

20.4.1 Abundance and Location 361

20.4.2 Ag85 a Fibronectin‐Binding Adhesin 362

20.4.3 Ag85 an Elastin‐Binding Adhesin 363

20.4.4 Implication in Disease 364

20.5 Conclusion 365

Acknowledgement 365

References 365

Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors 371

21 Miscellaneous IL‐1β‐Binding Proteins of Aggregatibacter actinomycetemcomitans 373
Riikka Ihalin

21.1 Introduction 373

21.2 A. actinomycetemcomitans Biofilms Sequester IL‐1β 374

21.3 A. actinomycetemcomitans Cells Take in IL‐1β 375

21.3.1 Novel Outer Membrane Lipoprotein of A. actinomycetemcomitans Binds IL‐1β 375

21.3.2 IL‐1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of A. actinomycetemcomitans 377

21.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL‐1β 377

21.3.4 DNA‐Binding Histone‐Like Protein HU Interacts with IL‐1β 378

21.4 The Potential Effects of IL‐1β on A. actinomycetemcomitans 379

21.4.1 Biofilm Amount Increases and Metabolic Activity Decreases 379

21.4.2 Potential Changes in Gene Expression 380

21.5 Conclusions 381

References 382

Part 3.9 Moonlighting Outside of the Box 387

22 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity 389
Janine Z. Bowring, Alberto Marina, José R. Penadés, and Nuria Quiles‐Puchalt

22.1 Introduction 389

22.2 Bacteriophage T4 I‐TevI Homing Endonuclease Functions as a Transcriptional Autorepressor 391

22.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator 394

22.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins 398

22.5 Moonlighting Bacteriophage Proteins De‐Repressing Phage‐Inducible Chromosomal Islands 398

22.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role 401

22.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication 404

22.8 Discussion 404

References 406

23 Viral Entry Glycoproteins and Viral Immune Evasion 413
Jonathan D. Cook and Jeffrey E. Lee

23.1 Introduction 413

23.2 Enveloped Viral Entry 414

23.3 Moonlighting Activities of Viral Entry Glycoproteins 415

23.3.1 Viral Entry Glycoproteins Moonlighting as Evasins 416

23.3.2 Evading the Complement System 417

23.3.3 Evading Antibody Surveillance 419

23.3.3.1 The Viral Glycan Shield 419

23.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy 421

23.3.3.3 Antigenic Variations in Viral Glycoproteins 421

23.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation 423

23.3.4 Evading Host Restriction Factors 423

23.3.5 Modulation of Other Immune Pathways 424

23.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways 427

23.4.1 Sabotaging Signal Transduction Cascades 427

23.4.2 Host Surface Protein Sabotage 428

23.5 Conclusions 429

References 429

Index 439