Staphylococcus aureus (eBook)

Fabio BagnoliGSK Vaccines, Siena, Italye-mail: fabio.x.bagnoli@gsk.comRino RappuoliGSK Vaccines, Siena, Italye-mail: rino.r.rappuoli@gsk.comGuido GrandiUniversity of Trento, Povo, Italye-mail: guido.grandi@unitn.it

Declaration of Interest 6
Authorship 6
Preface 7
Contents 10
5 Carriage, Clinical Microbiology and Transmission of Staphylococcus aureus 12
Abstract 12
1 Clinical Microbiology 13
1.1 Introduction of Rapid Molecular Detection Methodologies 15
1.2 Enhancing Culture-based Techniques 15
1.3 Replacing Culture-based Techniques 16
1.4 Point-of-Care Technologies 18
2 S. aureus Carriage 18
3 S. aureus Transmission 20
3.1 MRSA Transmission in the Hospital 21
3.2 Preventing MRSA Transmission 22
3.3 MRSA Transmission in the Community 23
4 Summary 25
References 25
3 Worldwide Epidemiology and Antibiotic Resistance of Staphylococcus aureus 31
Abstract 31
1 Introduction 33
2 General Epidemiology of S. aureus 34
3 Molecular Epidemiology 35
3.1 Molecular Typing Methods 35
3.1.1 Pulsed-Field Gel Electrophoresis (PFGE) 35
3.1.2 Multilocus Sequence Typing (MLST) 36
3.1.3 Staphylococcal Protein A (spa) Typing 36
3.1.4 SCCmec Typing 36
3.1.5 Whole Genome Sequencing (WGS) 37
3.2 Worldwide Distribution of the Principal Clones and Lineages 38
3.2.1 Healthcare-Associated MRSA 38
3.2.2 CA-MRSA 42
3.2.3 LA-MRSA 45
3.2.4 Molecular Epidemiology of MSSA 46
4 S. aureus and Antibiotic Resistance 47
4.1 Vancomycin 48
4.2 Linezolid 51
4.3 Daptomycin 52
5 Conclusions 53
Acknowledgments 53
References 54
5018 Structure and Function of Surface Polysaccharides of Staphylococcus aureus 67
Abstract 67
1 Introduction 69
2 Capsular Polysaccharides (CPs) 69
2.1 Structures of CP5 and CP8 70
2.2 Biosynthesis of CP 70
2.3 Nontypeable S. aureus Isolates 73
2.4 Regulation of CP Biosynthesis 74
2.5 Role of S. aureus CPs in Virulence 76
2.6 CP5 and CP8 as Vaccine Components 77
3 Wall Teichoic Acid (WTA) 78
3.1 Structure of WTA 78
3.2 Biosynthesis of WTA 79
3.3 Regulation of WTA Biosynthesis 81
3.4 Role of WTA in S. aureus Physiology 82
3.5 Role of WTA as Phage Receptor and Glycocode for Horizontal Gene Transfer 83
3.6 Role of WTA in Antibiotic Resistance and WTA Inhibitory Compounds 84
3.7 Role of WTA in Colonization and Virulence 85
3.8 WTA as a Vaccine Candidate 87
4 Polysaccharide Intercellular Adhesin (PIA)/Poly-N-Acetyl Glucosamine (PNAG) 87
4.1 Structure of PIA/PNAG 88
4.2 Biosynthesis of PIA/PNAG 89
4.3 Regulation of PIA/PNAG Biosynthesis 89
4.4 Role of PIA/PNAG in Virulence 90
4.5 PIA/PNAG as a Vaccine Candidate 90
5 Conclusions 91
References 92
5002 Cell Wall-Anchored Surface Proteins of Staphylococcus aureus: Many Proteins, Multiple Functions 104
Abstract 104
1 Introduction 105
2 CWA Surface Protein Secretion and Surface Display 106
2.1 Secretion 106
2.2 Sorting 106
3 Cell Wall-Anchored Protein Structure and Function 108
3.1 The MSCRAMM Family 108
3.1.1 Structure 108
3.1.2 Ligand Binding: Dock, Lock, and Latch 108
3.1.3 Ligand Binding: The Collagen Hug 112
3.1.4 Post-Translational Modification 113
3.2 G5-E Repeat Domains 115
3.3 Three-Helical Bundles 116
3.4 The NEAT Motif Family 116
3.5 The Legume Lectin Domain 117
3.6 Fibronectin Binding by Tandem ?-Zipper 117
3.7 Nucleotidase Motif 118
4 CWA Proteins as Colonization and Virulence Factors 119
4.1 Approaches to Elucidating the Contribution of CWA Proteins to the Virulence of S. aureus 119
4.2 CWA Proteins Promote Colonization of the Host 121
4.3 CWA Protein Interactions with Fibrinogen/Fibrin 122
5 Discussion and Future Prospects 123
References 124
16 Staphylococcus aureus Pore-Forming Toxins 130
Abstract 130
1 Identification of S. aureus Toxins: An Overview 131
1.1 Alpha-Toxin: The Prototypical Beta-Barrel Pore-Forming Toxin 133
2 Beta-Barrel Bicomponent Pore-Forming Leukocidins 134
2.1 Panton–Valentine Leukocidin (LukSF-PV/PVL) 134
2.2 Gamma-Hemolysin HlgACB 135
2.3 Leukocidin ED (LukED) 135
2.4 Leukocidin AB (LukAB) 136
3 Mode of Action of S. aureus Beta-Barrel Pore-Forming Leukocidins 137
4 Identification of Proteinaceous Cellular Receptors for the Leukocidins 139
4.1 Alpha-Toxin and ADAM10 140
4.2 LukED: CCR5, CXCR1, CXCR2, and DARC 141
4.3 LukSF-PV/PVL: C5aR and C5L2 143
4.4 HlgAB: CXCR1, CXCR2, CCR2, and DARC 143
4.5 HlgCB: C5aR and C5L2 144
4.6 LukAB: CD11b 144
5 Toxin Redundancy 146
6 Conclusions 147
Acknowledgments and/or funding sources: 147
References 147
5019 The Role of Two-Component Signal Transduction Systems in Staphylococcus aureus Virulence Regulation 154
Abstract 154
1 Introduction 155
2 Global Regulators of Virulence Expression 158
2.1 AgrCA 158
2.1.1 Molecular Basis of Agr Regulation 158
2.1.2 Agr and Virulence Regulation 162
2.2 SaeRS 164
2.2.1 Molecular Basis of SaeRS 164
2.2.2 SaeRS and Virulence Regulation 166
3 Response to AMPs and Cell Wall Damage 168
3.1 VraSR 168
3.2 GraXSR 172
3.3 BraRS 174
4 Cell Wall Metabolism, Autolysis and Cell Death 175
4.1 WalRK 176
4.2 ArlRS 179
4.3 LytSR 180
5 Respiration, Fermentation and Nitrate Metabolism 182
5.1 SrrAB 182
5.2 NreCBA 185
5.3 AirRS 186
6 Nutrient Sensing and Metabolism 188
6.1 HssSR 188
6.2 KdpDE 189
6.3 PhoRP 191
7 Conclusions 192
References 192
32 Staphylococcus aureus-Associated Skin and Soft Tissue Infections: Anatomical Localization, Epidemiology, Therapy and Potential Prophylaxis 208
Abstract 208
1 Introduction 210
2 Human Skin Anatomy 211
3 Overview of SSTIs 213
3.1 Superficial Skin Infections—Impetigo and Ecthyma 213
3.2 Follicular Infections—Folliculitis, Furunculosis, Carbunculosis 216
3.3 Intradermal Infections—Erysipelas, Cellulitis, Necrotizing Fasciitis 217
4 Epidemiology of Staphylococcus aureus SSTIs 217
4.1 Community-Acquired SSTIs 217
4.2 Surgical Site Infections (SSIs) 218
4.3 Affected Populations and Medical Cost of Hospitalizations Associated with SA-SSTIs 221
4.4 Paediatric SA-SSTIs 222
5 Virulence Factors and Pathogenesis of S. aureus-Associated Skin Infections 223
6 Therapy for SA-SSTIs 225
7 Prevention of SA-SSTIs 225
8 Discussion 228
Acknowledgments 228
References 229
19 Staphylococcus aureus-Associated Musculoskeletal Infections 237
Abstract 237
1 Introduction 238
2 Staphylococcus aureus Osteomyelitis 238
2.1 Epidemiology 238
2.2 Pathogenesis 239
2.2.1 General Pathogenesis and Classification 239
2.2.2 Molecular and Cellular Pathogenesis 241
2.3 Clinical Manifestations and Diagnosis 245
2.4 Special Forms of Osteomyelitis 248
2.4.1 Vertebral Osteomyelitis 248
2.4.2 Postoperative Sternum Osteomyelitis 249
2.5 Management 250
3 Staphylococcus aureus Infections of Native Joints 256
4 Staphylococcus aureus Pyomyositis 259
5 Conclusions 260
References 261
5001 Bacteremia, Sepsis, and Infective Endocarditis Associated with Staphylococcus aureus 270
Abstract 270
1 Introduction 271
2 Staphylococcus aureus Bacteremia 271
2.1 Epidemiology 271
2.2 Clinical Manifestations and Outcomes 274
2.3 Management 277
3 Staphylococcus aureus Infective Endocarditis 284
3.1 Epidemiology 284
3.2 Prosthetic Valve Endocarditis 285
3.3 Pathophysiology 285
3.4 Clinical Manifestations and Outcomes 286
3.5 Management 287
4 Conclusions 290
Acknowledgements 290
References 290
2 Amphixenosic Aspects of Staphylococcus aureus Infection in Man and Animals 304
Abstract 304
1 Introduction 305
2 Factors Influencing Prevalence of Staphylococcal Amphixenoses and Related Risks 307
3 The Role of Companion Animals in the Amphixenosic Transmission of S. aureus 311
4 The Amphixenosic Transmission of S. aureus: Human Versus Pet Animals and Vice Versa 316
5 The Epidemiology of Livestock-Associated S. aureus: The Role of Bovine Milk and Dairy Cattle 318
6 Livestock-Associated S. aureus: The Role of Swine and Chickens 319
7 Conclusions 321
8 Future Directions 322
References 322
42 Treatment of Staphylococcus aureus Infections 331
Abstract 331
1 Introduction 333
2 Guidelines for Therapy of S. aureus Infections 339
3 General Considerations for Therapy of S. aureus Infections 340
3.1 Noninvasive Skin and Soft Tissue Infections 340
3.2 Invasive Infections 347
4 Considerations in the Therapy of Specific Clinical Syndromes 349
4.1 Bacteremia 349
4.2 Endocarditis and Intravascular Infection 353
4.3 Pneumonia 354
4.4 Osteomyelitis, Including Discitis 356
4.5 Epidural Abscess 358
4.6 Septic Arthritis 359
4.7 Pyomyositis 360
4.8 Necrotizing Fasciitis 362
4.9 Impetigo 363
4.10 Mastitis and Breast Abscess 363
4.11 Conjunctivitis 364
4.12 Orbital Infections 364
4.13 Endophthalmitis and Panophthalmitis 365
4.14 Parotitis 366
4.15 Toxinoses 366
4.15.1 Staphylococcal Toxic Shock Syndrome (TSS) 366
4.15.2 Staphylococcal Scalded Skin Syndrome (SSSS) 367
4.16 Urogenital Infections 368
4.17 Lemierre’s Syndrome 369
4.18 Meningitis and Other CNS Infections 369
5 Conclusions 371
References 372
5004 The Innate Immune Response Against Staphylococcus aureus 390
Abstract 390
1 Introduction 391
2 The Encounter at the Epithelial Barrier 393
2.1 The Sentinel Function of Toll-like Receptor-2: Permitting Colonization and Preventing Invasion 394
2.2 Bacterial Invasion: Immune Defense Relies on Intracellular Sensors and Inflammasome Activation 396
2.3 Linking Inflammasomes to Protective T Cell Responses: The Role of NLRP3 in Th17 Differentiation 397
3 Professional Phagocytes and Their Effector Functions 398
3.1 Phagocytosis: Linking Intracellular Lysis to Antigen Presentation 398
3.2 Tissue-resident Phagocytes 400
3.2.1 Mast Cells: Well-prepared Guardians of Skin and Mucosa 400
3.2.2 Macrophages: Tissue-Specific Vigilants Balancing the Local Immune Response 400
3.3 Blood-Derived Phagocytes 401
3.3.1 Neutrophils: Recruited to Resolve Uncontrolled Spread of Infection 402
3.4 Dendritic Cells: Orchestrating the Adaptive Immune Response in Tissue and Lymph Nodes 403
3.4.1 Myeloid Dendritic Cells: Expert Control of T Cell Responses 403
3.4.2 Plasmacytoid Dendritic Cells and Type I Interferons: Fine-Tuning of Innate and Adaptive Immune Responses 404
4 The Last Frontiers Before Adaptive Immunity 405
4.1 Innate Immune B Cells: Rapid Supply of Antibacterial Antibodies 405
4.2 Natural Killer Cells: Neglected Sensors for Intracellular Persisting S. aureus? 406
4.3 Innate Lymphoid Cells: Confinement of S. aureus to Its Niche? 407
5 Conclusion 407
References 410
1 Adaptive Immunity Against Staphylococcus aureus 424
Abstract 424
1 Introduction 425
2 Immunological Overview 425
3 Role of B Cells and Antibodies 426
3.1 Preexisting Antibodies as Immunologic Correlates for Protection 427
3.2 Role of Antibodies in Vaccine-Mediated Protection 427
3.3 Evasion Mechanisms from the Humoral Immune Response 429
4 Role of T Cells 430
4.1 Th1 Cells 431
4.2 Th2 Cells 432
4.3 Th17 Cells 433
4.4 Regulatory T Cells 435
5 Conclusion 435
Acknowledgements 436
References 436
5017 Staphylococcal Immune Evasion Proteins: Structure, Function, and Host Adaptation 445
Abstract 445
1 Introduction 447
2 The Mechanisms of Immune Evasion 448
3 Conserved Structural Properties of Evasion Molecules: A Structure–Function Analysis 451
3.1 Proteins Consisting of an OB-Fold and/or ?-Grasp Domain 453
3.1.1 The Superantigens 454
3.1.2 Superantigen-like Proteins 455
3.1.3 The EAP Domain Proteins 457
3.1.4 Chemotaxis Inhibitory Protein of S. aureus 457
3.1.5 FPR2 Inhibitory Proteins 458
3.1.6 Staphylokinase 458
3.1.7 Staphylococcal Nuclease 459
3.2 Proteins Consisting of a Triple Alpha Helix 459
3.2.1 The Immunoglobulin-Binding Proteins 459
3.2.2 The Staphylococcal Complement Inhibitor Family 460
3.2.3 The Extracellular Fibrinogen-Binding Protein Family 461
3.2.4 Staphylococcal Coagulases 461
3.3 The Staphylococcal Toxins: ?-Barrel Pore-Formers and ?-Helices 462
3.3.1 The ?-Barrel Pore-Forming Toxins 462
3.3.2 The Phenol-Soluble Modulins 464
3.4 Additional Secreted Enzymes 465
3.4.1 Staphylococcal Proteases 465
3.4.2 ?-Hemolysin 465
3.5 The Structure–Function Relationship 466
4 Genomic Location and Host Specificity 467
4.1 Core Variable Genome 468
4.1.1 Genomic Islands 468
4.1.2 Immune Evasion Cluster 2 (IEC2) 471
4.1.3 Other Clustered Immune Evasion Genes 472
4.2 Mobile Genetic Elements 473
4.2.1 SaPIs 473
4.2.2 Prophages 474
4.3 Host Adaptation of Immune Evasion Molecules 476
5 Future Perspectives 477
5.1 Therapeutic Strategies Based on Evasion Molecules for S. aureus Infections 477
5.2 Therapeutic Strategies for Other Inflammatory Conditions and Cancer 479
6 Conclusions 480
Acknowledgements 480
References 481
54 Vaccines for Staphylococcus aureus and Target Populations 494
Abstract 494
1 Introduction 496
2 Rationale Behind the Need of a S. Aureus Vaccine 498
3 Target Populations Suitable for S. Aureus Vaccine Efficacy Trials 500
3.1 End-Stage Renal Disease (ESRD) Patients 500
3.2 Intensive Care Unit (ICU) Patients 508
3.3 Surgery Patients 508
3.4 Community-Acquired Skin and Soft Tissue Infections (CA-SSTIs) Patients 509
4 Preclinical Research on Antigens Selected for Clinical Development 511
4.1 Antigens that Reached Phase III Trials 511
4.2 Antigens Currently Being Tested in Phase II Trials 512
4.3 Antigen Combinations that Reached Phase I Trials 513
4.4 Recently Proposed Antigens that Are Still in Preclinical Phase 514
5 Clinical Data on Vaccine Candidates that Reached Phase III 516
5.1 Summary of Phase I–III Trial Data on V710 516
5.2 Summary of Phase I–III Trial Data on StaphVax 517
6 Lack of Established Correlates of Protection 519
7 Discussion 521
Acknowledgments 522
References 523
5005 Lysin Therapy for Staphylococcus aureus and Other Bacterial Pathogens 532
Abstract 532
1 Introduction 533
2 Mechanism of Action 534
3 Lysin Efficacy 536
4 Staphylococcus aureus-Specific Lysins 536
5 Synergy 537
6 Biofilms 538
7 Effects of Antibodies 538
8 Bacterial Resistance to Lysins 539
9 Conclusion 540
Acknowledgments 541
Literature Cited 541