Unifying Microbial Mechanisms Shared Strategies of Pathogenesis

Microbial pathogenesis is the study of the mechanisms by which microbes (bacteria, viruses, protozoa, and multicellular parasites) cause infectious disease and make their hosts (humans) ill. Bacterial infections we thought were easily treatable are again a huge cause for concern with the well-publicized rise of antibiotic resistance. There are very few effective antiviral drugs and we live with the threat of epidemics such as bird flu and the outbreaks of viruses such the recent (and ongoing) Ebola crisis. Parasitic diseases such as malaria continue to pose a heavy burden in the developing world and with climate change could spread into the developed world. There is therefore an urgent need to understand microbial mechanisms, with research programmes and university courses dedicated to the subject.

Contents

Preface xv

Acknowledgement xvii

Chapter 1: Introduction to Pathogenesis 1

Introduction

Henle-Koch postulates and evolving

views of infectious disease causation

Experimental models of pathogenicity

The ethics of using humans, animals and cell lines in

pathogenics research 6

Advantages and disadvantages of human experimentation

in the study of the pathogenesis of infectious diseases 8

Animal models in the study of the pathogenesis of

infectious diseases 8

Other considerations in experimental models of the

pathogenesis of infectious diseases 10

Human cell lines as a surrogate for microbe–host interactions 12

Bibliography

Chapter 2: Normal Microbiotas of the Human Body 17

Introduction

Microbiota of the skin 20

Microbiota of the vagina 22

Microbiota of the urinary tract 25

Microbiota of the conjunctiva 31

Respiratory tract microbiota 31

Microbiota of the alimentary canal

Mouth 34

Oesophagus 40

Stomach 40

Small intestine 40

Large intestine 44

Key concepts

Bibliography

Chapter 3: Biofilms 59

Introduction

Biofilms structure and properties

Mucosae versus skin 60

Initial steps in biofilm formation 61

Biofilm development and the climax community 63

Quorum sensing in biofilms 65

Biofilm dispersal 67

Biofilms in human infections

Peripheral and central i.v. catheters 67

Urinary catheters 68

Bladder biofilms 69

Endotracheal tubes 69

Peritoneal cavity dialysis catheters 70

Prosthetic joints 71

Heart valves 71

Chronic wounds 71

Otitis media 73

Cystic fibrosis 74

Biofilm formation by filamentous fungi

Biofilm formation by viruses

How biofilms are studied

Key concepts

Bibliography

Chapter 4: Adhesion to Host Surfaces 87

Introduction

Barrier epithelia

Skin 88

Mucous membranes (mucosae) 89

Blood and lymphatic vessels 91

Blood-brain barrier 92

Foeto-placental interface 93

The extracellular matrix and intercellular adhesion molecules

Abiotic surfaces 94

Initial adhesion events 95

Adhesin–receptor interactions

Protein–carbohydrate (lectin) interactions 97

Bacteria 98

Fungi 102

Viruses 103

Parasites 106

Protein–protein interactions

Microbial surface components recognising adhesive matrix

molecules 107

Fibrinogen-binding MSCRAMMs 115

Vitronectin-binding MSCRAMMs 116

Proteoglycan-binding adhesives 117

Bacteria 117

Viruses 117

Parasites 118

Anchorless adhesins (Moonlighting proteins) 119

Bacteria 119

Fungi 120

Protozoa and multicellular parasites 120

Cell wall glycopolymers 121

Capsules 121

Galectins as bridging molecules in microbial adhesions

Adhesion to other barriers

Endothelium of blood vessels and lymphatics 124

Key concepts

References

Chapter 5: Facilitated Cell Entry 129

Introduction

Crossing intact skin

Enzymatic degradation 131

Crossing intact mucosal epithelium

Entry via microfold (M) cells 132

Enzymatic degradation 133

Polar tube formation 134

Moving junction 134

Paracytosis 135

Endocytosis 138

Reorganisation of the actin cytoskeleton and endosomal

trafficking 141

Exploitation of endocytosis pathways by pathogens

Bacteria 145

Zipper mechanism

Trigger mechanism 148

Viruses 156

Fungi 156

Microtubule reorganisation

Transcytosis

Key concepts

Bibliography

Chapter 6: Exotoxins and Endotoxins 167

Bacterial exotoxins

Introduction 167

Membrane-acting toxins 168

Superantigens (SAs) 168

Heat-stable exotoxins (STs) 170

Membrane-damaging exotoxins

α-helical pore-forming exotoxins 172

β-barrel pore-forming exotoxins 173

RTX exotoxins 175

MARTX exotoxins 176

Intracellular exotoxins

AB exotoxins 177

AB5 exotoxins 179

AB exotoxins 182

Fungal toxins

Parasite exotoxins

Endotoxins

Key concepts

Bibliography

Chapter 7: Extracellular Degradative Enzymes 187

Introduction

Proteases

Potential roles of microbial proteases in pathogenesis

Tissue destruction and cell internalisation 188

Inactivation of plasma protease inhibitors 189

Activation of bradykinin-generating and blood-clotting

cascades 190

Protease-activated receptor 190

Chemoattractant molecules 191

Immunoglobulins 191

Microbe and parasite glycosidases

Deglycosylation of immunoglobulins 194

Adhesion 194

Microbe and parasite phospholipases

Bacterial phospholipases 196

Fungal phospholipases 198

Parasite phospholipases 198

Key concepts

Bibliography

Chapter 8: Evasion of the Human Innate Immune System 201

Introduction

Antimicrobial peptides

Overview 201

Bacterial evasion of AMPSs 204

Fungal evasion of AMPs 205

Virus evasion of AMPs 205

Parasite evasion of AMPs 205

The complement system

Recruiting and mimicking RCAs 210

Destroying complement components 213

Microbial envelope/wall components that inhibit

complement 214

Evasion resulting from cell wall structure 214

Consuming complement in the fluid phase 214

Circumvention of phagocytosis

Chemoattraction 216

Regulation of chemokines 218

Circumventing pattern recognition receptors

Subversion of PRR crosstalk 223

Targeting cytosolic PRRs, IPS-1, RIG-I and MDA5 224

Masking microbe-associated molecular patterns 225

Manipulating host inhibitory signaling

Pathogen survival inside host cells

Bacteria 228

Arresting the phagosome/endosome 229

Diverting the endosomal/phagosomal pathways 232

Survival in the endolysosome/phagolysosome 233

Fungi 235

Parasites 237

Escape to the cytosol

Virus interactions with intracellular vacuoles

Cytosolic motility of intracellular pathogens

Escape of intracellular pathogens from host cells

Cytolysis 245

Actin-mediated cell-to-cell spread 245

Protrusion into the extracellular environment (extrusion) 247

Induction of programmed cell death 247

Preventing programmed cell death 248

Interference with the host cell cycle 248

Reprogramming the host cell 249

Evading autophagy

Preventing the induction of autophagy 250

Preventing the maturation of the autophagosome into an

autolysosome 251

Avoiding pathogen capture by the autophagosome 251

Utilising the autophagosome as a habitat for survival,

replication, or escape from the host cell 253

The role of autophagy in eukaryotic pathogens 253

Evading natural killer cells

Evasion of the natural killer group 2D receptor 257

Evasion of natural cytotoxicity receptors 258

Key concepts

Bibliography

Chapter 9: Evasion of the Human Adaptive Immune System 263

Introduction

Antigen presentation

Linking sensing of MAMPs by pattern-recognition

receptors with antigen processing 264

Activating naïve T cells by licenced dendritic cells 265

Follicular helper CD4+ T cells help B cells make

high-affinity, class-switched antibodies 267

Inhibition of antigen presentation by

MHC class I and class II pathways

Viral subversion of the MHC class I antigen-processing

pathway 270

Bacterial subversion of the MHC class I antigen-processing

pathway 270

Viral subversion of the MHC class II pathway

antigen-presenting pathway 271

Bacterial subversion of the MHC class II antigen-processing

pathway 273

Parasite evasion of the MHC class II antigen-processing

pathway 273

Manipulation of co-stimulatory molecules 275

Manipulation of regulatory receptors and ligands 276

Up-regulation of IL-10 276

Evasion of antibody

Antigen modulation

Antigenic and phase variation

Subverting B lymphocytes (B Cells)

Subverting T lymphocytes (T Cells)

Key concepts

Bibliography

Chapter 10: Persistent and Latent Infections 295

Introduction

Persistent bacterial infections

Introduction 296

Helicobacter pylori 296

Treponema pallidum subspecies pallidum 301

Mycobacterium tuberculosis 302

Salmonella typhi serovar Typhi 307

Persistent virus infections

Introduction 308

Herpesviruses 309

Hepatitis B, C and D viruses 313

Measles virus 316

Adenoviruses 317

Human papilloma viruses 317

Human polyomaviruses 319

Human immunodeficiency virus 320

Human T-cell lymphotropic virus type 1 321

Persistent parasite infections

Introduction 322

Helminths 322

Plasmodium 323

Leishmania 325

Trypanosoma cruzi 327

Toxoplasma gondii 329

Myeloid-derived suppressor cells in chronic infections 330

Key concepts

Bibliography

Index 337