Staphylococcus aureus - Microbiology, Pathology, Immunology, Therapy and Prophylaxis

Declaration of Interest

Authorship

Preface

Contents

5 Carriage, Clinical Microbiology and Transmission of Staphylococcus aureus

Abstract

1 Clinical Microbiology

1.1 Introduction of Rapid Molecular Detection Methodologies

1.2 Enhancing Culture-based Techniques

1.3 Replacing Culture-based Techniques

1.4 Point-of-Care Technologies

2 S. aureus Carriage

3 S. aureus Transmission

3.1 MRSA Transmission in the Hospital

3.2 Preventing MRSA Transmission

3.3 MRSA Transmission in the Community

4 Summary

References

3 Worldwide Epidemiology and Antibiotic Resistance of Staphylococcus aureus

Abstract

1 Introduction

2 General Epidemiology of S. aureus

3 Molecular Epidemiology

3.1 Molecular Typing Methods

3.1.1 Pulsed-Field Gel Electrophoresis (PFGE)

3.1.2 Multilocus Sequence Typing (MLST)

3.1.3 Staphylococcal Protein A (spa) Typing

3.1.4 SCCmec Typing

3.1.5 Whole Genome Sequencing (WGS)

3.2 Worldwide Distribution of the Principal Clones and Lineages

3.2.1 Healthcare-Associated MRSA

3.2.2 CA-MRSA

3.2.3 LA-MRSA

3.2.4 Molecular Epidemiology of MSSA

4 S. aureus and Antibiotic Resistance

4.1 Vancomycin

4.2 Linezolid

4.3 Daptomycin

5 Conclusions

Acknowledgments

References

5018 Structure and Function of Surface Polysaccharides of Staphylococcus aureus

Abstract

1 Introduction

2 Capsular Polysaccharides (CPs)

2.1 Structures of CP5 and CP8

2.2 Biosynthesis of CP

2.3 Nontypeable S. aureus Isolates

2.4 Regulation of CP Biosynthesis

2.5 Role of S. aureus CPs in Virulence

2.6 CP5 and CP8 as Vaccine Components

3 Wall Teichoic Acid (WTA)

3.1 Structure of WTA

3.2 Biosynthesis of WTA

3.3 Regulation of WTA Biosynthesis

3.4 Role of WTA in S. aureus Physiology

3.5 Role of WTA as Phage Receptor and Glycocode for Horizontal Gene Transfer

3.6 Role of WTA in Antibiotic Resistance and WTA Inhibitory Compounds

3.7 Role of WTA in Colonization and Virulence

3.8 WTA as a Vaccine Candidate

4 Polysaccharide Intercellular Adhesin (PIA)/Poly-N-Acetyl Glucosamine (PNAG)

4.1 Structure of PIA/PNAG

4.2 Biosynthesis of PIA/PNAG

4.3 Regulation of PIA/PNAG Biosynthesis

4.4 Role of PIA/PNAG in Virulence

4.5 PIA/PNAG as a Vaccine Candidate

5 Conclusions

References

5002 Cell Wall-Anchored Surface Proteins of Staphylococcus aureus: Many Proteins, Multiple Functions

Abstract

1 Introduction

2 CWA Surface Protein Secretion and Surface Display

2.1 Secretion

2.2 Sorting

3 Cell Wall-Anchored Protein Structure and Function

3.1 The MSCRAMM Family

3.1.1 Structure

3.1.2 Ligand Binding: Dock, Lock, and Latch

3.1.3 Ligand Binding: The Collagen Hug

3.1.4 Post-Translational Modification

3.2 G5-E Repeat Domains

3.3 Three-Helical Bundles

3.4 The NEAT Motif Family

3.5 The Legume Lectin Domain

3.6 Fibronectin Binding by Tandem ?-Zipper

3.7 Nucleotidase Motif

4 CWA Proteins as Colonization and Virulence Factors

4.1 Approaches to Elucidating the Contribution of CWA Proteins to the Virulence of S. aureus

4.2 CWA Proteins Promote Colonization of the Host

4.3 CWA Protein Interactions with Fibrinogen/Fibrin

5 Discussion and Future Prospects

References

16 Staphylococcus aureus Pore-Forming Toxins

Abstract

1 Identification of S. aureus Toxins: An Overview

1.1 Alpha-Toxin: The Prototypical Beta-Barrel Pore-Forming Toxin

2 Beta-Barrel Bicomponent Pore-Forming Leukocidins

2.1 Panton–Valentine Leukocidin (LukSF-PV/PVL)

2.2 Gamma-Hemolysin HlgACB

2.3 Leukocidin ED (LukED)

2.4 Leukocidin AB (LukAB)

3 Mode of Action of S. aureus Beta-Barrel Pore-Forming Leukocidins

4 Identification of Proteinaceous Cellular Receptors for the Leukocidins

4.1 Alpha-Toxin and ADAM10

4.2 LukED: CCR5, CXCR1, CXCR2, and DARC

4.3 LukSF-PV/PVL: C5aR and C5L2

4.4 HlgAB: CXCR1, CXCR2, CCR2, and DARC

4.5 HlgCB: C5aR and C5L2

4.6 LukAB: CD11b

5 Toxin Redundancy

6 Conclusions

Acknowledgments and/or funding sources:

References

5019 The Role of Two-Component Signal Transduction Systems in Staphylococcus aureus Virulence Regulation

Abstract

1 Introduction

2 Global Regulators of Virulence Expression

2.1 AgrCA

2.1.1 Molecular Basis of Agr Regulation

2.1.2 Agr and Virulence Regulation

2.2 SaeRS

2.2.1 Molecular Basis of SaeRS

2.2.2 SaeRS and Virulence Regulation

3 Response to AMPs and Cell Wall Damage

3.1 VraSR

3.2 GraXSR

3.3 BraRS

4 Cell Wall Metabolism, Autolysis and Cell Death

4.1 WalRK

4.2 ArlRS

4.3 LytSR

5 Respiration, Fermentation and Nitrate Metabolism

5.1 SrrAB

5.2 NreCBA

5.3 AirRS

6 Nutrient Sensing and Metabolism

6.1 HssSR

6.2 KdpDE

6.3 PhoRP

7 Conclusions

References

32 Staphylococcus aureus-Associated Skin and Soft Tissue Infections: Anatomical Localization, Epidemiology, Therapy and Potential Prophylaxis

Abstract

1 Introduction

2 Human Skin Anatomy

3 Overview of SSTIs

3.1 Superficial Skin Infections—Impetigo and Ecthyma

3.2 Follicular Infections—Folliculitis, Furunculosis, Carbunculosis

3.3 Intradermal Infections—Erysipelas, Cellulitis, Necrotizing Fasciitis

4 Epidemiology of Staphylococcus aureus SSTIs

4.1 Community-Acquired SSTIs

4.2 Surgical Site Infections (SSIs)

4.3 Affected Populations and Medical Cost of Hospitalizations Associated with SA-SSTIs

4.4 Paediatric SA-SSTIs

5 Virulence Factors and Pathogenesis of S. aureus-Associated Skin Infections

6 Therapy for SA-SSTIs

7 Prevention of SA-SSTIs

8 Discussion

Acknowledgments

References

19 Staphylococcus aureus-Associated Musculoskeletal Infections

Abstract

1 Introduction

2 Staphylococcus aureus Osteomyelitis

2.1 Epidemiology

2.2 Pathogenesis

2.2.1 General Pathogenesis and Classification

2.2.2 Molecular and Cellular Pathogenesis

2.3 Clinical Manifestations and Diagnosis

2.4 Special Forms of Osteomyelitis

2.4.1 Vertebral Osteomyelitis

2.4.2 Postoperative Sternum Osteomyelitis

2.5 Management

3 Staphylococcus aureus Infections of Native Joints

4 Staphylococcus aureus Pyomyositis

5 Conclusions

References

5001 Bacteremia, Sepsis, and Infective Endocarditis Associated with Staphylococcus aureus

Abstract

1 Introduction

2 Staphylococcus aureus Bacteremia

2.1 Epidemiology

2.2 Clinical Manifestations and Outcomes

2.3 Management

3 Staphylococcus aureus Infective Endocarditis

3.1 Epidemiology

3.2 Prosthetic Valve Endocarditis

3.3 Pathophysiology

3.4 Clinical Manifestations and Outcomes

3.5 Management

4 Conclusions

Acknowledgements

References

2 Amphixenosic Aspects of Staphylococcus aureus Infection in Man and Animals

Abstract

1 Introduction

2 Factors Influencing Prevalence of Staphylococcal Amphixenoses and Related Risks

3 The Role of Companion Animals in the Amphixenosic Transmission of S. aureus

4 The Amphixenosic Transmission of S. aureus: Human Versus Pet Animals and Vice Versa

5 The Epidemiology of Livestock-Associated S. aureus: The Role of Bovine Milk and Dairy Cattle

6 Livestock-Associated S. aureus: The Role of Swine and Chickens

7 Conclusions

8 Future Directions

References

42 Treatment of Staphylococcus aureus Infections

Abstract

1 Introduction

2 Guidelines for Therapy of S. aureus Infections

3 General Considerations for Therapy of S. aureus Infections

3.1 Noninvasive Skin and Soft Tissue Infections

3.2 Invasive Infections

4 Considerations in the Therapy of Specific Clinical Syndromes

4.1 Bacteremia

4.2 Endocarditis and Intravascular Infection

4.3 Pneumonia

4.4 Osteomyelitis, Including Discitis

4.5 Epidural Abscess

4.6 Septic Arthritis

4.7 Pyomyositis

4.8 Necrotizing Fasciitis

4.9 Impetigo

4.10 Mastitis and Breast Abscess

4.11 Conjunctivitis

4.12 Orbital Infections

4.13 Endophthalmitis and Panophthalmitis

4.14 Parotitis

4.15 Toxinoses

4.15.1 Staphylococcal Toxic Shock Syndrome (TSS)

4.15.2 Staphylococcal Scalded Skin Syndrome (SSSS)

4.16 Urogenital Infections

4.17 Lemierre’s Syndrome

4.18 Meningitis and Other CNS Infections

5 Conclusions

References

5004 The Innate Immune Response Against Staphylococcus aureus

Abstract

1 Introduction

2 The Encounter at the Epithelial Barrier

2.1 The Sentinel Function of Toll-like Receptor-2: Permitting Colonization and Preventing Invasion

2.2 Bacterial Invasion: Immune Defense Relies on Intracellular Sensors and Inflammasome Activation

2.3 Linking Inflammasomes to Protective T Cell Responses: The Role of NLRP3 in Th17 Differentiation

3 Professional Phagocytes and Their Effector Functions

3.1 Phagocytosis: Linking Intracellular Lysis to Antigen Presentation

3.2 Tissue-resident Phagocytes

3.2.1 Mast Cells: Well-prepared Guardians of Skin and Mucosa

3.2.2 Macrophages: Tissue-Specific Vigilants Balancing the Local Immune Response

3.3 Blood-Derived Phagocytes

3.3.1 Neutrophils: Recruited to Resolve Uncontrolled Spread of Infection

3.4 Dendritic Cells: Orchestrating the Adaptive Immune Response in Tissue and Lymph Nodes

3.4.1 Myeloid Dendritic Cells: Expert Control of T Cell Responses

3.4.2 Plasmacytoid Dendritic Cells and Type I Interferons: Fine-Tuning of Innate and Adaptive Immune Responses

4 The Last Frontiers Before Adaptive Immunity

4.1 Innate Immune B Cells: Rapid Supply of Antibacterial Antibodies

4.2 Natural Killer Cells: Neglected Sensors for Intracellular Persisting S. aureus?

4.3 Innate Lymphoid Cells: Confinement of S. aureus to Its Niche?

5 Conclusion

References

1 Adaptive Immunity Against Staphylococcus aureus

Abstract

1 Introduction

2 Immunological Overview

3 Role of B Cells and Antibodies

3.1 Preexisting Antibodies as Immunologic Correlates for Protection

3.2 Role of Antibodies in Vaccine-Mediated Protection

3.3 Evasion Mechanisms from the Humoral Immune Response

4 Role of T Cells

4.1 Th1 Cells

4.2 Th2 Cells

4.3 Th17 Cells

4.4 Regulatory T Cells

5 Conclusion

Acknowledgements

References

5017 Staphylococcal Immune Evasion Proteins: Structure, Function, and Host Adaptation

Abstract

1 Introduction

2 The Mechanisms of Immune Evasion

3 Conserved Structural Properties of Evasion Molecules: A Structure–Function Analysis

3.1 Proteins Consisting of an OB-Fold and/or ?-Grasp Domain

3.1.1 The Superantigens

3.1.2 Superantigen-like Proteins

3.1.3 The EAP Domain Proteins

3.1.4 Chemotaxis Inhibitory Protein of S. aureus

3.1.5 FPR2 Inhibitory Proteins

3.1.6 Staphylokinase

3.1.7 Staphylococcal Nuclease

3.2 Proteins Consisting of a Triple Alpha Helix

3.2.1 The Immunoglobulin-Binding Proteins

3.2.2 The Staphylococcal Complement Inhibitor Family

3.2.3 The Extracellular Fibrinogen-Binding Protein Family

3.2.4 Staphylococcal Coagulases

3.3 The Staphylococcal Toxins: ?-Barrel Pore-Formers and ?-Helices

3.3.1 The ?-Barrel Pore-Forming Toxins

3.3.2 The Phenol-Soluble Modulins

3.4 Additional Secreted Enzymes

3.4.1 Staphylococcal Proteases

3.4.2 ?-Hemolysin

3.5 The Structure–Function Relationship

4 Genomic Location and Host Specificity

4.1 Core Variable Genome

4.1.1 Genomic Islands

4.1.2 Immune Evasion Cluster 2 (IEC2)

4.1.3 Other Clustered Immune Evasion Genes

4.2 Mobile Genetic Elements

4.2.1 SaPIs

4.2.2 Prophages

4.3 Host Adaptation of Immune Evasion Molecules

5 Future Perspectives

5.1 Therapeutic Strategies Based on Evasion Molecules for S. aureus Infections

5.2 Therapeutic Strategies for Other Inflammatory Conditions and Cancer

6 Conclusions

Acknowledgements

References

54 Vaccines for Staphylococcus aureus and Target Populations

Abstract

1 Introduction

2 Rationale Behind the Need of a S. Aureus Vaccine

3 Target Populations Suitable for S. Aureus Vaccine Efficacy Trials

3.1 End-Stage Renal Disease (ESRD) Patients

3.2 Intensive Care Unit (ICU) Patients

3.3 Surgery Patients

3.4 Community-Acquired Skin and Soft Tissue Infections (CA-SSTIs) Patients

4 Preclinical Research on Antigens Selected for Clinical Development

4.1 Antigens that Reached Phase III Trials

4.2 Antigens Currently Being Tested in Phase II Trials

4.3 Antigen Combinations that Reached Phase I Trials

4.4 Recently Proposed Antigens that Are Still in Preclinical Phase

5 Clinical Data on Vaccine Candidates that Reached Phase III

5.1 Summary of Phase I–III Trial Data on V710

5.2 Summary of Phase I–III Trial Data on StaphVax

6 Lack of Established Correlates of Protection

7 Discussion

Acknowledgments

References

5005 Lysin Therapy for Staphylococcus aureus and Other Bacterial Pathogens

Abstract

1 Introduction

2 Mechanism of Action

3 Lysin Efficacy

4 Staphylococcus aureus-Specific Lysins

5 Synergy

6 Biofilms

7 Effects of Antibodies

8 Bacterial Resistance to Lysins

9 Conclusion

Acknowledgments

Literature Cited