Handbook of Tuberculosis

fmatter1
Half-Title Page
Series Page
Title Page
Copyright Page
Contents
List of Contributors
Foreword
Timeline
Introduction: On the Shoulders of Giants
Preface
ch1
1 Biochemistry of the Cell Envelope of Mycobacterium tuberculosis
1.1 Overview of the Cell Envelope of M. tuberculosis
1.2 Free Lipids and Lipoglycans Associated with the Outer Layer of the Cell Wall of M. tuberculosis
1.3 The mAGP Complex
1.3.1 Mycolic Acids
1.3.2 AG
1.3.3 PG
References
ch2
2 Polyketides and Polyketide-Containing Glycolipids of Mycobacterium tuberculosis: Structure, Biosynthesis and Biological Activities
2.1 Introduction
2.1.1 Organization and Composition of the Envelope of M. tuberculosis
2.1.2 Biosynthesis of Lipids from the Cell Envelope: Role of Polyketide Synthases
2.2 Biosynthesis of Polyketides in M. tuberculosis
2.2.1 The Mas-Like Family: Formation of Methyl-Branched Fatty Acids
2.2.2 The Pps Cluster: Synthesis of Phthiocerol and Phenolphthiocerol
2.2.3 Mycolic Condensation: Role of Pks13
2.2.4 MbtC and MbtD: Synthesis of the ß-Hydroxybutyrate Block of Mycobactins
2.2.5 Pks12: Formation of Mycoketide
2.2.6 Orphan Pks
2.3 Biosynthesis and Translocation of the Polyketide-Derived Lipids in M. tuberculosis
2.3.1 PGLs and DIMs
2.3.1.1 Activation of the Pks Substrates
2.3.1.2 Modification of the Phthiocerol and Phenolphthiocerol Chains
2.3.1.3 Release of the Polyketides and Transfer onto their Acceptors
2.3.1.4 Formation of the Saccharidic Appendage of PGL
2.3.1.5 Translocation
2.3.2 Trehalose-Containing Lipids
2.3.2.1 Trehalose Monomycolate and TDM
2.3.2.2 SLs
2.3.2.3 PAT and DAT
2.3.2.4 LOS
2.3.3 Mannosyl-ß-1-Phosphomycoketides
2.4 Role of Polyketide-Derived Lipids in M. tuberculosis Biology
2.4.1 Contribution to the Functions of the Cell Envelope
2.4.2 Contribution to M. tuberculosis Pathogenicity
2.4.2.1 Early Interaction with Host Cells
2.4.2.2 Intracellular Fate of M. tuberculosis
2.4.2.3 Multiplication and Persistence within the Host
2.4.2.4 Modulation of the Host Immune Responses
2.5 Conclusions
References
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3 Physiology of Mycobacterium tuberculosis
3.1 Introduction
3.2 Physiology and Virulence
3.3 Key Features of Tuberculosis
3.4 Physiology of M. tuberculosis
3.4.1 Structure and Composition of the Cell Wall
3.4.2 Cellular Metabolism in M. tuberculosis
3.4.3 Regulated Physiological Adaptability
3.4.4 Tolerance of Damage Caused by Host Immune Effectors
3.4.5 Slow Growth and States of Low Metabolic Activity
3.5 Determinants of Virulence in M. tuberculosis
3.6 Physiology and Drug Discovery
3.6.1 Essential and Conditionally Essential Genes in M. tuberculosis
3.6.2 Dependence of M. tuberculosis Gene Function on the Infection Model
3.6.3 Current Trends
3.7 Conclusions
References
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4 Nutrient Uptake by Mycobacteria
4.1 Introduction
4.2 Cell Envelope of Mycobacteria
4.2.1 Permeability Barriers in Mycobacterial Cell Envelopes
4.2.2 Principle Pathways of Nutrients Across the Mycobacterial Cell Envelope
4.3 Transport Across Mycobacterial Outer Membranes
4.3.1 Porin-Mediated Diffusion of Hydrophilic Solutes
4.3.2 Direct Diffusion of Hydrophobic Solutes Through the Cell Membranes
4.4 Transport Across the Inner Membrane
4.4.1 Transporters of Carbon-Containing Compounds
4.4.1.1 Transporters of Carbohydrates
4.4.1.2 Transporters of Lipids
4.4.2 Transporters of Phosphorus-Containing Solutes
4.4.3 Transporters of Sulfur-Containing Solutes
4.4.4 Transporters of Nitrogen-Containing Solutes
4.4.5 Transporters of Inorganic Cations
4.4.6 Transporters of Other Solutes
References
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5 Iron Uptake by Mycobacterium tuberculosis
5.1 The Battle for Iron between M. tuberculosis and its Host
5.2 Structures of MBTs and CMBTs from M. tuberculosis
5.3 Chromosomal Loci Involved in MBT and CMBT Biosynthesis and Transport
5.4 Regulation of Genes Involved in MBT/CMBT-Mediated Iron Acquisition
5.5 Phenotype of M. tuberculosis Strains with Mutations in Genes of the MBT/CMBT System
5.6 Enzymological Studies of Proteins Involved in MBT and CMBT Biosynthesis
5.7 Current Working Model for the Biosynthesis of MBTs and CMBTs
5.8 MBT and CMBT Trafficking and Sequestration of Iron in the Host
5.9 Release of Iron from the Fe3+-MBT/CMBT Complexes
5.10 Inhibition of Iron Uptake in M. tuberculosis: A Novel Avenue for Exploration of Potential Anti-Tuberculosis Drugs
References
ch6
6 Protein Transport in Mycobacterium tuberculosis
6.1 Introduction
6.2 Sec Pathway
6.3 Sec Pathway in M. tuberculosis
6.4 Lipoprotein Processing and Export in M. tuberculosis
6.5 A Connection between Sec Export and Protein Glycosylation in M. tuberculosis
6.6 SecA1 and SecA2 in M. tuberculosis
6.7 Tat Pathway
6.8 Tat Pathway in M. tuberculosis
6.9 ESX-1 Pathway in M. tuberculosis
6.10 PE and PPE Protein Export in M. tuberculosis
6.11 Conclusions
References
ch7
7 The PE and PPE Protein Families of Mycobacterium tuberculosis
7.1 Introduction
7.2 The PE Protein Family
7.2.1 The PE_PGRS Subfamily
7.2.2 Gene Expression in the PE_PGRS Subfamily
7.2.3 Cellular Localization of PE_PGRS Proteins
7.2.4 Immunology and Host Response to PE_PGRS Proteins
7.2.5 Genetic Variation in the PE_PGRS Subfamily
7.3 The PPE Protein Family
7.4 PE/PPE Proteins and the ESAT-6 Family
7.4.1 PE/PPE Genes and ESX-1
7.4.2 PE/PPE Genes and ESX-5
7.5 Evolution of PE/PPE Genes
References
ch8
8 Virulence and Persistence Mechanisms of Mycobacterium
8.1 Introduction
8.2 Approaches to Defining Virulence/Persistence Factors of M. tuberculosis
8.2.1 Use of Targeted Genetic Mutants in Animal Models
8.2.2 Whole-Genome Scanning Approaches
8.2.3 Epidemiology-Driven Approaches
8.3 Classification of Strain-Independent Virulence/Persistence Factors
8.3.1 Intermediate Metabolism and Nutrient Uptake
8.3.2 Respiratory Pathways
8.3.3 Lipids
8.3.4 Cell Wall-Associated Proteins
8.3.5 Repair and Detoxification Systems
8.3.6 Signal Transduction and Transcription
8.4 Strain-Dependent Virulence/Persistence Factors
8.5 Persistence Mechanisms in Latent Disease
8.6 Conclusions
References
ch9
9 Genomics of the Mycobacterium tuberculosis Complex
9.1 Introduction
9.2 Genome Structure
9.3 Repetitive DNA
9.4 The PE and PPE Proteins
9.5 Gene Expression
9.6 Physiology
9.7 Drug Targets
9.8 Antigen Mining
9.9 Evolution
9.10 Conclusions
References
ch10
10 Transcriptomics and Transcriptional Regulation
10.1 Introduction
10.2 Transcription of Housekeeping Genes
10.3 Alternative Factors
10.4 Regulation by Accessory Transcription Factors
10.4.1 Two-Component Systems
10.4.2 Metal-Dependent Transcriptional Regulators
10.4.3 Regulation by Cyclic AMP (cAMP)
10.5 Regulation of the M. tuberculosis Transcriptome During Infections
References
ch11
11 Proteomics of Mycobacterium tuberculosis
11.1 History of Proteomics
11.2 The M. tuberculosis Proteome in the Pre-Genome Era
11.3 The M. tuberculosis Proteome in the Post-Genome Era
11.4 Conclusions
References
ch12
12 The Proteome of Mycobacterium tuberculosis in Three Dimensions
12.1 From Structural Biology to Structural Genomics
12.2 The 3D Structures of Mycobacterium tuberculosis Proteins
12.3 The 3D Structures of Protein–Ligand Interactions Involving M. tuberculosis Targets
12.4 The 3D Structures of M. tuberculosis Host Protein–Ligand Interactions
12.5 Structure-Based Discovery of Functions of M. tuberculosis Proteins
12.6 Structure-Based Discovery of Inhibitors Against M. tuberculosis Proteins
12.7 Future Perspectives in M. tuberculosis Structural Biology
References
ch13
13 Molecular Mechanisms of Dormancy and Resuscitation
13.1 Role of Latency in the Global Tuberculosis Epidemic
13.2 Important Questions of Latency and Resuscitation
13.2.1 Catching the Dormant Bacillus at Home
13.2.2 The Metabolic and Replicative State of in vivo M. tuberculosis from Latent Infections
13.3 Models of Latency
13.3.1 in vivo Latency Models: A Catalog of Mycobacterial Abuse
13.3.2 The Hypoxic Model of Latency
13.3.2.1 Rationale
13.3.2.2 Models of Hypoxia-Induced Latency
13.3.2.3 The DosR-Regulated Initial Response to Hypoxia
13.3.3 in vivo Models of Latency
13.4 Resuscitation of Tuberculosis
13.4.1 Prevalence and Predisposing Factors
13.4.1.1 The Apices: A Favorable Location
13.4.2 Models of Reactivation
13.5 Conclusions and Forward Directions
References
ch14
14 Mycobacterium tuberculosis: Life and Death in the Phagosome
14.1 Introduction
14.2 The Two Faces of the Macrophage
14.3 The Intraphagosomal Environment in Resting Macrophages
14.4 How s the Bug Do It?
14.5 Okay, So That s the Resting Macrophage, What Happens When You Activate It?
14.6 The Killing Phagosome
14.7 The Immune Interface
14.8 Inside-Out Manipulation of the Host
14.9 Conclusions
References
ch15
15 Mechanisms of Drug Action, Drug Resistance and Drug Tolerance in Mycobacterium tuberculosis: Expected Phenotypes from Evolutionary Pressures from a Highly Successful Pathogen
15.1 Introduction
15.1.1 Gene Transfer Enabled the Discovery of Mycobacterial-Specific Drug Resistances
15.1.2 Intrinsic Resistance to Antibiotics
15.1.3 Acquired Drug Resistance versus Drug Tolerance
15.1.4 General Drug Resistance Mechanisms
15.1.5 General Features of Drug Resistance in M. tuberculosis
15.1.6 Drug Combination and Prevention of Drug Resistance
15.2 Mechanisms of Drug Action and Resistance
15.2.1 INH and ETH
15.2.1.1 Mechanism of INH and ETH Action
15.2.1.2 Mechanisms of INH and ETH Resistance
15.2.1.3 Inactivation of the Genes Encoding the Activators KatG and EtaA/EthA
15.2.1.4 Overexpression or Alteration of the Gene Encoding the Target InhA
15.2.1.5 Inactivation of Redox Regulators, ndh and mshA
15.2.1.6 Mutated Alleles Associated, but Not Causative of INH Resistance, ahpC and kasA
15.2.1.7 Other Genes that may be Involved in INH Resistance
15.2.2 RIF
15.2.2.1 Mechanism of Action
15.2.2.2 Mechanism of Resistance
15.2.3 PZA
15.2.3.1 Mechanism of Action
15.2.3.2 Mechanism of Resistance
15.2.4 EMB
15.2.4.1 Mechanism of Action
15.2.4.2 Mechanism of Resistance
15.2.5 SM
15.2.5.1 Mechanism of Action
15.2.5.2 Mechanism of Resistance
15.2.6 FQs
15.2.7 Kanamycin, Amikacin, Capreomycin and Viomycin
15.2.8 Cycloserine (CS)
15.2.9 PAS
15.3 Virulence and Transmissibility of Drug-Resistant Organisms
References
ch16
16 Experimental Genetics of Mycobacterium tuberculosis
16.1 Introduction
16.2 Early Genetic Studies with M. tuberculosis and Other Mycobacteria
16.3 Indirect Approaches
16.3.1 Subtractive Hybridization
16.3.2 Promoter Fusion
16.3.3 DNA Transfer
16.4 Current Methods of Gene Inactivation in M. tuberculosis
16.5 Analysis of Mutant Pools
16.6 Virulence and the Choice of Screening System
References
ch17
17 Molecular Evolution of Mycobacteria
17.1 Introduction
17.2 Bacterial Population Structures
17.3 Evolutionary Forces and the Bacterial Species Concept
17.4 Mycobacterial Species and the M. tuberculosis Complex
17.5 The Phylogeny of M. tuberculosis and M. africanum
17.6 The Global Phylogeography of M. tuberculosis
17.7 Evolutionary History of Human Tuberculosis
17.8 Relevance for Tuberculosis Control
17.9 Conclusions
References
index1
Index
fmatter2
Half-Title Page
Series Page
Title Page
Copyright Page
Contents
List of Contributors
Foreword
Timeline
Introduction: On the Shoulders of Giants
Preface
ch18
1 Determinants of Phagocytosis, Phagosome Biogenesis and Autophagy for Mycobacterium tuberculosis
1.1 Introduction
1.2 Mycobacterial Determinants in Host Recognition: Example of Host Adaptation
1.3 Hierarchy of Host Receptors: Importance of the Lung Environment
1.4 Other Macrophage Receptors for M. tuberculosis
1.5 Relationship Between Route of Entry and Survival for M. tuberculosis
1.6 Host Intracellular Trafficking Regulators and Phago-Lysosome Biogenesis
1.7 Rabs and Rab Effectors Affected by M. tuberculosis
1.8 Host Lipids Affected by M. tuberculosis
1.9 Mycobacterial Products Affecting Phago-Lysosome Biogenesis
1.10
Induction of Autophagy Overcomes M. tuberculosis Phagosome Maturation Block
and Kills Intracellular Mycobacteria
References
ch19
2 Dendritic Cells Inflammatory Signature Induced by Microbial Pathogens
2.1 Introduction
2.2 DC Biology and Function
2.3 Microbial Infections and DC Responses
2.4 DCs in Anti-Mycobacterial Responses
2.5 Inflammation and its Regulation
2.6 Bacterial Signaling via TLRs
2.7 Bacteria–Host and Mycobacteria–Host Interactions: A Genome-Wide Approach
2.8 Genome-Wide Studies to Dissect DC Inflammatory Signatures
2.9 Conclusions
References
ch20
3
Mycobacterium tuberculosis Interactions with Dendritic
Cells and Macrophages
3.1 Introduction
3.2 Interactions of M. tuberculosis with Innate Receptors on APCs
3.3
Transport of M. tuberculosis to DLNs for Priming
3.4 Cytokine Secretion, Costimulation and Antigen Presentation
3.5 TLR Ligands Expressed by M. tuberculosis, Particularly TLR2
3.6 TLR2-Mediated Exploitation of APC Function by M. tuberculosis
3.7 Conclusions
References
ch21
4 Killing Mechanisms of the Host Against Mycobacterium
tuberculosis
4.1 Introduction
4.2 Macrophages: An Important Component of the Cellular Immune Response in Host Defense Against M. tuberculosis
4.3 Macrophages Require Activation for Optimal Microbial Killing
4.4 Reactive Nitrogen and Oxygen Intermediates in Host Defense Against Tuberculosis
4.5 Phago-Lysosome Biogenesis in M. tuberculosis Killing
4.6 The IFNγ–LRG-47 Pathway and the Role of Autophagy in Defense Against M. tuberculosis
4.7 Sunlight and Anti-microbial Peptides: Key Components for Innate Immunity Against M. tuberculosis
4.8 Apoptosis as a Killing Mechanism of M. tuberculosis
4.9 Infection Equilibrium and the Relativity of M. tuberculosis Killing
4.10 Conclusions
References
ch22
5 Manipulation of the Macrophage Response by Pathogenic Mycobacteria
5.1 Introduction
5.2 The Macrophage
5.3
Internalization of M. tuberculosis in Macrophages
5.3.1 Complement Receptors
5.3.2 Mannose Receptor
5.3.3 Cholesterol
5.3.4 Surfactants
5.3.5 Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Non-Integrin
5.4 The Mycobacterial Phagosome
5.4.1 Modulation of the Mycobacterial Phagosome – Host Factors
5.4.1.1 Coronin 1
5.4.1.2 Immunity-Related GTPases
5.4.2 Modulation of the Mycobacterial Phagosome – Mycobacterial Factors
5.4.2.1 Mycobacterial Glycolipids
5.4.2.2 Exported Repetitive Protein (Erp)
5.4.2.3 Isocitrate Lyase
5.4.2.4 Mycobacterial Phosphatase SapM
5.4.2.5 Mycobacterial Protein Kinase G
5.5 Interference with Antigen Processing and Presentation Functions
5.6 Subversion of Macrophage Activation and Signal Transduction
5.6.1 Reactive Oxygen and Nitrogen Intermediates and the Mycobacterial Proteasome
5.6.2 IFN-γ, TNF-α and Phagosome–Lysosome Fusion
5.6.3 Macrophage Activation and Mycobacterial LAM
5.6.4 TLRs and Macrophage Activation
5.6.5 Mammalian Cell Entry Proteins
5.6.6 Intracellular Pathogen Resistance Gene
5.7 Conclusions
References
ch23
6
Human CD4 and CD8 T Cell Responses to Mycobacterium
tuberculosis: Antigen Specificity, Function, Implications
and Applications
6.1 Introduction
6.2 Human CD4+ T Cells, Cytokines and Resistance to Mycobacterial Infections, Including Tuberculosis
6.3 CD4+ T Cell Subsets in Human Tuberculosis
6.3.1 Th1 Cells
6.3.2 Th2 Cells
6.3.3 Tr Cells, Including Th3 Cells
6.4 The M. tuberculosis Antigen Repertoire Recognized by CD4+ T Cells in Humans
6.4.1 Mycobacterial Heat Shock Proteins Conservation Breeds Immunodominance
6.4.2
The M. tuberculosis Secretome – A Rich Source of Immunodominant Antigens
for Human T Cells
6.4.3 Antigen Discovery: Genome and Proteome Based Approaches Lead to the Identification of New Families of Antigenic Targets
6.4.3.1 ESAT-6, PE and PPE Superfamilies
6.4.3.2 Additional Antigen Discovery Strategies
6.4.3.3 Towards a Comprehensive and Integrated M. tuberculosis Antigenomics
Database
6.4.3.4 Post-Translational Modification of M. tuberculosis Proteins Can Create New Antigenic Determinants for CD4+ T Cells
6.4.3.5 New Classes of 'Post-Genomic Antigens': Towards the Discovery of Phase/Stage-Specific M. tuberculosis Antigens and Phase/Stage-Specific Vaccines?
6.4.3.6 Phase-Specific Antigen Profiles of M. tuberculosis: Do Starvation
and Reactivation Antigens Exist?
6.5 The Contribution of CD8+ T Cells to Protective TB Immunity: The Mouse Model
6.6 CD8+ T Cells in Human TB
6.7 Redundant Functions of CD8+ and CD4+ T Cells in TB Protection
6.8 Unique Role for CD8+ T Cells in TB Protection
6.9 Model of TB Reactivation Based upon T Cell Function
6.10 CD8 Antigen Processing and Presentation
6.11 The CD8 Antigenic Repertoire and Immunodominance
6.11.1
CD8 Epitopes Processed and Presented by M. tuberculosis-Infected Cells
6.11.2 Identification of Immunodominant CD8 Antigens and Epitopes
6.11.3 CD8 Antigenic Repertoire Summary
6.11.3.1 The Vast Majority of Defined CD8 Epitopes are Restricted by HLA-B Alleles
6.11.3.2 Many Immunodominant Epitopes are Longer than 9 Amino Acids and May Not Have Been Identified Using Current Bioinformatic Tools
6.11.3.3 CFP-10 is an Immundominant CD8 Antigen
6.12 Compartmentalization of M. tuberculosis-Specific T Cell Responses in Human TB
6.13 Immunodominance and Chronic Infection with M. tuberculosis
6.14
Future Outlook: What do we Know, What do we Need to Know, and How
can Immunology Translate into Better Diagnostics, Vaccines and Biomarkers?
6.14.1 Improved Immunodiagnostics, Based on M. tuberculosis-Specific T Cell Recognition
Profiles
6.14.2
M. tuberculosis Stage-Specific Vaccines
6.14.3
Identification of M. tuberculosis Antigens that Selectively Induce a T Cell Phenotype
6.14.4
Identification of Improved Human Correlates of Protection and Disease
References
ch24
7 Unconventional T Cells
7.1 Introduction
7.2 CD1-Restricted T Cell Responses in M. tuberculosis and M. leprae Infection
7.2.1
Introduction to CD1-Restricted T Cells
7.2.2
Group I CD1-Restricted T Cell Responses
7.2.2.1 Regulation of Group I CD1 by M. tuberculosis and Toll-Like Receptor Ligands
7.2.2.2 Recognition of Mycobacterial Lipid Antigens by T Cells
7.2.2.3 CD1-restricted T Cells Recognize Infected Cells
7.2.2.4 Intracellular Trafficking of the Different CD1 Isoforms
7.2.2.5 Effector Functions of Mycobacteria-Specific CD1-Restricted T Cells
7.2.2.6 Frequency and Distribution of CD1-Restricted Mycobacteria Specific
T Cells in Infections
7.2.2.7 Animal Models of CD1-Restricted T Cells in Mycobacterial Infection
7.2.3
Group II CD1-Restricted T Cell Responses in M. tuberculosis
7.2.3.1 Regulation of CD1d by M. tuberculosis and TLR Ligands
7.2.3.2 Recognition of Mycobacterial Lipid Antigens by CD1d-Restricted T Cells
7.2.3.3 Antigen-Independent Activation of CD1d-Restricted T Cells
7.2.3.4 Relevant Effector Functions of CD1d-Restricted Mycobacterium-Specific T Cells
7.2.3.5 The Role of CD1d-Restricted NKT Cells is Host Resistance to TB
7.3 γδ T Cells and M. tuberculosis
7.3.1 General γδ T Cell Biology
7.3.1.1 γδ TCR and γδ T Cell Development?
7.3.1.2 γδ T Cell Phenotype and Function
7.3.2 γδ T Cell Antigens and Response to M. tuberculosis
7.3.2.1 Recognition of Phosphoantigens by Human Vγ9/Vδ2 T Cells
7.3.2.2 Human Vγ9/Vδ2 T Cell Responses to M. tuberculosis
7.3.3 γδ T Cells in Animal Models of M. tuberculosis Infection
7.3.3.1 γδ T Cells and Murine M. tuberculosis Infection
7.3.3.2 γδ T Cells and Mycobacterial Infection in Primates
7.4 Other Non-conventional T Cells: CD25+ CD4+ Tr , IL-17-Producing CD4+ T Cells (Th17), HLA-E-Restricted CD8+ T Cells and H2-M3-Restricted T Cells
7.4.1 Tr Cells
7.4.2
Th17
7.4.3 HLA-E-Restricted CD8+ T Cells and H2-M3-Restricted T Cells
7.5 Conclusions
References
ch25
8 Cytokines in Tuberculosis
8.1 Introduction
8.2 General Introduction to Cytokines in the Immune Response
8.2.1 Cytokines in the Innate Immune Response
8.2.1.1 Differential Expression of Toll-Like Receptors Determines the Production
of Cytokines by Macrophages and DCs
8.2.1.2 Intrinsic Capacity of Macrophages and DCs to Produce Different Cytokines
8.2.2
Cytokines in the Development of the Adaptive T Cell Response to Pathogens
8.2.2.1 Induction of Th1 and Th2 Responses and their Role in Infectious Diseases
8.2.2.2 The Th17 Response: Relationship with IL-23 and TGF-β
8.2.3
Role of IL-10 and Other Factors in Regulating Immune Responses to Pathogens
8.3 Cytokines in Innate and Adaptive Immunity to M. tuberculosis
8.3.1
Th1 T Cell Responses are Required for Protective Anti-Mycobacterial Responses
8.3.2 IFN-γ/IL-12 Axis and Mendelian Susceptibility to Mycobacterial Diseases
8.3.3 Production of IFN-γ During Active Tuberculosis
8.3.4 Depression of IFN-γ Responses in PBMCs from Active TB Patients
8.3.5
Suppressive Cytokines in Mycobacterial Infections
8.3.6
Th2 Cytokines and Tuberculosis
8.4 Effector Cytokines for Macrophage Activation and Regulation
8.4.1 IFN-γ
8.4.2
Other Cytokines Contributing to Macrophage Activation
8.5 Cytokines Required for Granuloma Formation
8.5.1 TNF Family Members
8.5.2 Chemokines and Granuloma Formation
8.6 Conclusions
References
ch26
9 The Antibody Response to Infection with Mycobacterium tuberculosis
9.1 Humoral Immunity and Tuberculosis
9.2 The Course of the Antibody Response
9.2.1 Natural Antibodies
9.2.2 T-Independent B Cell Responses
9.2.3 Latent Infection and Early Disease
9.2.4 Active Disease
9.2.5 Treatment
9.3 Antigen Specificity of The Antibody Response and Life Cycle of the Tubercle Bacillus
9.3.1 Antigen Production in Dormant M. tuberculosis
9.3.2 Antigen Production in Rapidly Dividing M. tuberculosis
9.3.3 Sources of Variation in Antibody Specificity: The Pathogen
9.3.3.1 Concurrent Bacterial Subpopulations
9.3.3.2 The Granuloma
9.3.3.3 Strain-Specific Differences
9.3.4 Sources of Variation in Antibody Specificity: The Human Host
9.3.4.1 Spectrum of Disease
9.3.4.2 Host Genetics
9.4 Antibodies and Pathogenesis
9.5 Antibodies and Diagnosis
9.6 Conclusions
References
ch27
10 Immunopathology of Tuberculosis
10.1 Introduction
10.1.1 Historical Perspective
10.1.2 Koch Phenomenon
10.1.3 Pathology of TB
10.2 Granuloma Development
10.2.1 The Immunopathology of TB Infection in Mice
10.2.2 Granuloma Development in Humans
10.2.3 Pathology of Early and Late Disease Progressors
10.2.4 Cellular and Cytokine Requirements for Granuloma Development
10.2.4.1 T Cells
10.2.4.2 Macrophages and DCs
10.2.4.3 B Cells
10.2.4.4 Cytokine Requirements for Granuloma Formation
10.2.4.5 Chemokine Requirements
10.3 Pathology of TB in Guinea Pigs Compared to Humans
10.3.1 Introduction
10.3.1.1 Course of the Infection in Guinea Pigs Exposed to Aerosol Infection
10.3.2 The Primary Lesion Complex
10.3.2.1 Pathology of Primary Pulmonary Lesions
10.3.2.2 Pathogenesis of Primary Pulmonary Lesions
10.3.2.3 Pathogenesis of Primary Lesion Necrosis
10.3.2.4 Hypoxia of Primary Lesions
10.3.2.5 M. tuberculosis-Derived Mediators of Inflammation
10.3.3 Chronic Infection
10.3.3.1 Iron Accumulation in Primary Lesions
10.3.3.2 Dystrophic Calcification of Primary Lesions
10.3.3.3 Pathology of Primary Lymph Node Lesions
10.3.3.4 Pathogenesis of Secondary Lesions
10.3.3.5 Pathogenesis of Extrapulmonary Lesions
10.3.3.6 Dissemination as a Determinate of Virulence
10.3.4 Pathology of the Primary Lesion Complex in the BCG Vaccinated Guinea Pig
10.3.5 Pathology of the Primary Lesion Complex in the Drug-Treated Guinea Pig
10.3.6 Alternative Methods for Lesion Evaluation in the Guinea Pig
References
ch28
11 Maintenance of Latent Infection, with Correlates of Protective Immunity
11.1 Definition and Evidence of Latency in Tuberculosis
11.2 Relative Contribution of Reactivation and New Infections
11.2.1 Evidence that Newly Transmitted TB Contributes to the Burden of Disease in Adults
11.2.2 Evidence that Reinfection with M. tuberculosis Contributes to Recurrent TB in Adults who have Completed Therapy for Active TB
11.3 Epidemiologic Risk Factors for Reactivation of Latent TB Infection
11.4 Mechanisms of Latency and Protective Immunity in TB
11.4.1 Bacterial Determinants of Establishment and Maintenance of Latency
11.4.2 Host Determinants of Maintenance of Latency
11.4.2.1 CD4+ T Lymphocytes
11.4.2.2 TNF (Tumor Necrosis Factor)
11.4.2.3 Correlates of Immunity and Latency Identified by Studies of Human Genetics
11.5 Vaccination-Induced Immune Correlates of Protection
11.5.1 Evidence from Animal Models
11.5.2 Human Studies of Vaccination-Induced Immune Correlates of Protection
11.6 Directions for Further Study
References
ch29
12 Genetic Control of Host Susceptibility to Tuberculosis
12.1 Introduction: The Aspects of Tuberculosis – General Categories
12.2 Genetic Analysis of TB Susceptibility Using Experimental Animal Models
12.3 Mouse Model of TB Infection: The Genetic Perspective
12.3.1 Natural Genetic Variation in the Laboratory Mice Allows Modeling Major Aspects of the Human Disease
12.3.2 Genetic Control of Host Resistance to TB Infection in the Mouse Model is Complex
12.3.3 Characterization of the Individual TB Resistance loci
12.3.3.1 Chromosome 17
12.3.3.2 Chromosome 7 Locus
12.3.3.3 The Chromosome 1 Loci: Bcg/Ity/Lsh (Nramp1 Gene) and sst1 (Ipr1 Gene)
12.3.3.4 The Bcg Locus and the Nramp1 Gene
12.3.3.5 The sst1 Locus and the Ipr1 Gene
12.3.4 Summary of the Experimental Genetic Analysis in Mice and Future Directions
12.4 The Genetic Spectrum of TB in Humans: From Mendelian Disease to Polygenic Trait
12.5 Strategies for the Molecular Identification of Alleles that Cause Increased Susceptibility to TB Disease
12.6 Gene Hunting: MSMD in TB
12.7 Gene Hunting: Major Susceptibility Genes in TB
12.8 Gene Hunting by Candidate Gene Studies: Polygenic Susceptibility in TB
12.8.1 HLA Class II loci
12.8.2 Cytokines and Their Receptors
12.8.3 Vitamin D Receptor
12.8.4 Toll-Like Receptors, their Signaling Pathways and Other Innate Immunity Genes
12.8.5 Additional Innate Immunity Genes
12.8.6 Candidate Genes Obtained from Mouse Studies: NRAMP1 and SP110
12.8.7 Genetic Control of Immune Responsiveness to Mycobacterial Antigens
12.9 Conclusions
References
ch30
13 Tuberculosis/Human Immunodeficiency Virus Coinfection and the Host Immune Response
13.1 The Problem
13.2 Why is the Combination of TB and HIV-1 So Deadly?
13.3 TB/HIV-1 Coinfection Targets CD4 T Cells
13.4 Mononuclear Phagocytes: A Home for Both TB and HIV-1
13.5 HAART in TB/HIV-1 Coinfection
13.6 PR in TB/HIV-1: A Clue to Immunopathogenesis of Coinfection
13.7 Conclusion
References
ch31
14 Novel Vaccination Strategies Against Tuberculosis
14.1 Introduction
14.2 Host Resistance, Latency and TB
14.3 The Two Major Vaccination Strategies Against TB
14.4 Attenuated Gene Deletion Mutants of M. tuberculosis as Vaccine Candidates
14.5 Improved Recombinant BCG as Vaccine Candidates (Table 14.1)
14.6 Subunit Vaccines (Table 14.1)
14.7 Boosting or Supplementing Immunity Induced by BCG Prime
14.8 Vaccine Strategies to Target Latent Infection
14.9 Entering the Clinic
14.10 Exploiting Biomarkers for Vaccine Trials?
14.11 Economic Considerations
References
ch32
15 Experimental Animal Models of Tuberculosis
15.1 Introduction
15.2 Murine Model of TB
15.2.1 Mouse and Bacterial Strains Used
15.2.2 Course of Infection in Mice
15.2.2.1 Route of Infection
15.2.2.2 Dynamics of Infection and Disease
15.2.3 Pathology
15.2.4 Uses of the Model
15.2.4.1 Immunology and Host Response
15.2.4.2 Pathogenesis
15.2.4.3 Drug development and Testing
15.2.4.4 Vaccine Development and Testing
15.3 The Guinea Pig Model
15.3.1 Strains of Guinea Pigs
15.3.2 Infection and Course of Disease
15.3.3 Immunologic Studies
15.3.4 Uses of the Model: Vaccine Testing
15.3.5 Pathology
15.3.6 Advantages and Limitations
15.4 The Rabbit Model
15.4.1 Rabbit and Mycobacterial Species
15.4.2 Uses of the Model
15.4.2.1 Experimental TBM
15.4.2.2 Experimental Pulmonary TB
15.5 The Non-human Primate Model
15.5.1 Non-human Primate and Mycobacterial Species
15.5.2 Course of Infection and Disease
15.5.3 Pathology
15.5.4 Uses of the Model
15.5.4.1 Immunology
15.5.4.2 Pathogenesis
15.5.4.3 Drug Testing
15.5.4.4 Vaccine Testing
15.5.4.5 A Model for AIDS and TB
15.5.5 Limitations to the Non-human Primate Model
15.6 Other Animal Model Systems
15.7 Conclusions
References
index2
Index
fmatter3
Half-Title Page
Series Page
Title Page
Copyright Page
Contents
List of Contributors
Foreword
Timeline
Introduction: On the Shoulders of Giants
Preface
ch33
1 Global Epidemiology and Control of Tuberculosis
1.1 Introduction
1.2 Global and Regional Dynamics
1.3 Progress in the Implementation and Impact of TB Control
1.3.1 Vaccination
1.3.2 Preventive Therapy (Treatment of Latent TB Infection)
1.3.3 Treatment of Active TB
1.3.3.1 Case Detection
1.3.3.2 Treatment Success
1.3.3.3 Impact of DOTS on Incidence, Prevalence and Mortality
1.4 Achieving the Millennium Development Goals by 2015
1.5 Eliminating TB in the 21st Century
1.6 Conclusions
References
ch34
2 Surveillance Studies and Interpretation
2.1 Introduction
2.2 Surveillance of TB Infection
2.2.1 Rationale for Surveys of TB Infection
2.2.2 Standardization
2.2.3 Sample Selection, Sample Size and Design
2.2.3.1 Prevalence of Infection
2.2.3.2 Trend in Prevalence
2.2.3.3 Incidence of Infection
2.2.4 Difficulties in Interpretation
2.2.5 Conducting the Survey
2.2.6 Analysis and Calculations
2.2.7 Alternative Methods
2.3 Surveys of TB Disease
2.3.1 Rationale for Surveys of TB Disease (Prevalence Surveys)
2.3.2 Sample Selection
2.3.3 Case Detection
2.3.3.1 Sputum Culture
2.3.3.2 Sputum Smear
2.3.3.3 Chest X-ray Screening
2.3.3.4 Symptom Screening
2.3.3.5 Tuberculin Skin Testing
2.3.4 Conducting the Survey
2.3.5 Analysis
2.4 Surveillance for Drug Resistant TB
2.4.1 Rationale for Drug Resistance Surveillance
2.4.2 Sample Selection
2.4.3 Laboratory Approach
2.5 Conclusion
References
ch35
3 Molecular Epidemiology of Mycobacterium tuberculosis
3.1 Introduction
3.2 The Purpose of Molecular Epidemiology
3.3 Requirements for the Successful Application of Molecular Epidemiology
3.3.1 The Marker
3.3.2 The Analytical Tools
3.4 Genotyping Methods
3.4.1 Repetitive Sequences
3.4.1.1 Polymorphic GC-rich Repetitive Sequence Typing
3.4.1.2 Variable Number Tandem Repeats (VNTR)
3.4.1.3 MIRU-VNTR
3.4.1.4 Spoligotyping
3.4.2 Insertion Sequences
3.4.2.1 IS6110 Restriction Fragment Length Polymorphism (RFLP)
3.4.2.2 Mixed Linker
3.4.3 Single Nucleotide Polymorphisms (SNPs)
3.4.4 FAFLP
3.5 Epidemiological Interpretation
3.5.1 Evolution of Genetic Markers and Nearest Genetic Distance
3.6 Application of Molecular Epidemiology
3.6.1 M. tuberculosis Population Structure
3.6.2 Transmission vs Reactivation
3.6.3 Casual Contact
3.6.4 Where Transmission Occurs
3.6.5 Mapping of Outbreaks
3.6.6 Risk Factors for Transmission
3.6.7 Transmission from Smear Negative Cases
3.6.8 Recurrent Tuberculosis
3.6.9 Mixed Infection
3.6.10 Laboratory Error
3.6.11 Drug Resistance
3.6.12 Insights into the Global TB Epidemic at the Level of the Pathogen
3.6.13 Genotype–Phenotype
3.6.14 Vaccines and Clinical Trials
3.7 Summary
References
ch36
4 Clinical Diagnosis of M. tuberculosis Infection
4.1 Introduction
4.2 Basic Diagnostic Algorithms
4.3 Sample Collection
4.4 Smear Microscopy
4.5 Culture
4.5.1 Solid Media
4.5.2 Liquid Media
4.6 Phage Tests
4.7 PCR
4.8 Radiology
4.9 Immunodiagnosis
4.10 The Tuberculin Skin Test
4.11 Interferon-γ Release Assays
4.12 Future Developments
References
ch37
5 Clinical Features of Tuberculosis
5.1 Introduction
5.2 Systemic Features of TB
5.3 Pulmonary TB
5.3.1 Medical History and Physical Examination
5.3.2 Radiographic Evaluation
5.3.3 Obtaining Specimens for Microbiological Evaluation
5.4 Extrapulmonary TB
5.5 Lymph Node TB
5.6 Pleural TB
5.7 Bone and Joint TB
5.8 Central Nervous System TB
5.9 Abdominal TB
5.10 Genitourinary TB
5.11 Pericardial TB
5.12 Disseminated TB
References
ch38
6 Tuberculosis Control: Good Clinical Care and Good Public Health
6.1 Introduction
6.2 The Need for Global TB Control
6.3 Identifying the Main Strategic Approaches to TB Control
6.3.1 The TB Disease Cycle
6.3.2 Main Strategic Approaches
6.3.2.1 BCG Immunization
6.3.2.2 Preventive Treatment
6.3.2.3 Physical Measures to Decrease Transmission
6.3.2.4 Case Detection and Successful Treatment
6.4 Basic Principles in TB Care
6.4.1 Establish Prompt and Accurate Diagnosis
6.4.1.1 Pulmonary TB
6.4.1.2 Extrapulmonary TB
6.4.2 Use Effective Standardized Drug Treatment
6.4.2.1 Effective Treatment Regimens
6.4.2.2 Comprehensive Approach to Promoting Adherence
6.4.2.3 Promoting Individual Civil Liberties and Public Health
6.4.2.4 Patients’ Rights and Responsibilities
6.4.2.5 Assessment of Adherence
6.4.2.6 Access to Treatment
6.4.3 Monitor the Response to Treatment
6.4.4 Carry Out Essential Public Health Responsibilities
6.4.4.1 Contact Tracing
6.4.4.2 Reporting
6.5 The Evolution of the Strategic Approach to Global TB Control
6.5.1 The Development of the DOTS Strategy
6.5.2 The WHO Stop TB Strategy
References
ch39
7 Chemotherapy of Tuberculosis
7.1 Introduction
7.1.1 Pre-Chemotherapy Era
7.1.2 The Chemotherapy Era
7.2 Current Therapy for TB
7.2.1 Drugs Used to Treat TB
7.2.2 General Principles for the Treatment of Pulmonary TB
7.2.3 Specific Regimens
7.2.4 Adherence
7.2.5 Dosing Schedules
7.2.6 Risk of Treatment Failure
7.2.7 Individual Drugs
7.2.7.1 Isoniazid
7.2.7.2 Rifampin
7.2.7.3 Pyrazinamide
7.2.7.4 Ethambutol
7.2.7.5 Streptomycin
7.2.7.6 Other Agents
References
ch40
8 TB Drug Discovery from Target Identification to Proof of Concept Studies
8.1 Introduction
8.2 The Evolution of Drug Discovery
8.3 Target Finding
8.4 Lead Finding
8.5 Lead Optimization
8.6 Proof of Concept Studies in Early Clinical Development
References
ch41
9 Latent Tuberculosis Infection
9.1 Background
9.2 Pathophysiology of Latent TB
9.3 Diagnosis of LTBI
9.4 Epidemiology of LTBI
9.4.1 Prevalence
9.4.2 Incidence
9.4.3 Risk of Reactivation TB among Individuals with LTBI
9.4.4 Risk Factors for Reactivation Disease
9.4.5 Treatment of LTBI
References
ch42
10 Clinical Management of Multidrug-Resistant Tuberculosis
10.1 Introduction
10.2 Epidemiology of MDR-TB
10.3 Diagnosis of Drug-Resistant TB
10.4 Treatment of Drug-Resistant TB
10.4.1 Directly Observed Therapy
10.4.2 Review of Antituberculous Agents
10.4.3 Individualized versus Standardized Approaches to MDR-TB Treatment
10.4.4 Initial Approach to MDR-TB Treatment
10.4.5 Principles of Foundation Design
10.4.5.1 Parenteral Agents
10.4.5.2 First-line Agents
10.4.5.3 Fluoroquinolones
10.4.5.4 Remaining Second-line Agents
10.4.6 Principles of Regimen Reinforcement
10.4.7 Design of the Definitive Regimen
10.4.8 MDR-TB in Pediatrics and Obstetrics
10.4.8.1 Treatment of Children with MDR-TB
10.4.8.2 MDR-TB and Pregnancy
10.4.9 MDR-TB and HIV
10.4.10 Corticosteroids
10.4.11 Surgery
10.4.12 Addressing Other Barriers to Treatment Success
10.4.13 Monitoring Treatment Response and Completion of Treatment
10.4.14 Management of Individuals Exposed to MDR-TB
10.5 Conclusion
References
ch43
11 Novel Treatment Strategies for TB Patients with HIV Co-infection
11.1 Introduction
11.2 Goals for Improving TB Treatment of Patients Co-infected with HIV
11.3 Approaches to Developing Improved Treatments for TB Patients Co-infected with HIV
11.4 Drugs in Clinical Development for a TB Indication and their Interactions with the Cytochrome P450 Enzymes
11.4.1 Fluoroquinolones: Gatifloxacin and Moxifloxacin
11.4.2 Diarylquinoline -TMC207
11.4.3 Nitroimidazoles – OPC67683 and PA-824
11.4.4 Pyrrole – LL-3858
11.4.5 Ethylenediamine – SQ109
11.5 Future Directions for Improving Treatment of TB Patients Co-infected with HIV
References
ch44
12 Mathematical Modeling of Tuberculosis Transmission Dynamics
12.1 Introduction
12.2 Models
12.2.1 Simple Compartmental Models
12.2.2 Individual-based and Network Models
12.3 Natural History of TB Infection and Population-level Dynamics
12.3.1 A Basic TB Model
12.4 Modeling Interventions for TB Control
12.4.1 DOTS Strategy and Extensions
12.5 Adding Complexity: Drug-resistant TB and TB/HIV
12.5.1 Drug-resistant TB
12.5.2 TB/HIV
12.6 Important Areas of Uncertainty
References
ch45
13 BCG Vaccination: Epidemiology and Immunology
13.1 Introduction and Brief History
13.1.1 Introduction
13.1.2 Brief History
13.2 Efficacy of BCG in Protecting against TB
13.2.1 Efficacy against Different Forms of Disease
13.2.2 Variations in BCG Efficacy against TB
13.2.3 Duration of Efficacy
13.2.4 Efficacy of a Second Dose of BCG
13.2.5 Protection against Other Diseases and Non-specific Effects caused by BCG
13.2.6 Scar Formation and Adverse Events
13.3 Recommendations and Current Practices in BCG Vaccination
13.3.1 Vaccination Schedules
13.3.2 Route of Vaccination
13.3.3 Contraindications and Safety of BCG Vaccination in HIV-infected Infants
13.4 Proposed Biological Mechanisms for BCG Protection
13.4.1 Importance of Cell-mediated Immunity
13.4.2 Insights into Mechanisms of BCG Protection from the Mouse Model
13.4.3 Role of CD8 T cells in BCG-induced Protection
13.5 BCG Strains
13.5.1 Origins of BCG Strains
13.5.2 Genetic and Phenotypic Differences among BCG Strains
13.5.3 Reactogenicity of BCG Strains
13.5.4 Strain Differences may Exist but there is no Evidence these Affect Protective Efficacy in Man
13.6 Biological Basis for Variation in BCG Protection Against Pulmonary Disease
13.6.1 The Role of Environmental Mycobacteria
13.6.2 Role of Helminth Infections
13.7 Correlates of Protection
13.7.1 Cell-mediated Immunity is Clearly Necessary for Protection
13.7.2 Delayed-Type Hypersensitivity (DTH) does not Provide a Useful Correlate of Protection
13.7.3 In vitro T-Cell Immune Responses in Vaccinated Adults
13.7.4 Immune Responses Induced by BCG in Vaccinated Infants
13.7.5 Beyond IFNγ: The Search for Correlates of Protection
13.7.6 Assays of Mycobacterial Growth Inhibition
13.8 Many of the New TB Vaccines under Development Aim to Improve the Immunity Given by BCG
References
index3
Index