| Preface | 6 |
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| Contents | 8 |
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| Contributors | 17 |
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| 1. Global Epidemiology of West Nile Virus | 20 |
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| 1 Introduction | 20 |
| 2 West Nile Virus in Africa, Asia, and Europe | 23 |
| 2.1 Africa | 23 |
| 2.2 Middle East, Russia, Asia, and Australia | 24 |
| 2.3 Europe | 25 |
| 3 West Nile Virus in the Americas | 26 |
| 3.1 United States | 26 |
| 3.1.1 Mosquitoes and Vertebrates | 26 |
| 3.1.2 Human Incidence and Distribution | 27 |
| 3.2 Canada | 30 |
| 3.3 Latin America and the Caribbean | 30 |
| 4 Clinical Epidemiology | 31 |
| 4.1 Risk Factors Associated with Human Disease | 31 |
| 4.2 Transmission Modes | 33 |
| 5 Summary | 35 |
| References | 35 |
| 2 . West Nile Virus: Molecular Epidemiology and Diversity | 43 |
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| 1 Overview of WNV Genetic Diversity at a Global Scale | 43 |
| 2 Molecular Epidemiology of WNV in the Americas | 45 |
| 2.1 Evidence for a Single Point Introduction | 45 |
| 2.2 Genetic Conservation and Diversification During Colonization | 46 |
| 2.3 Insights into WNV Population Dynamics | 48 |
| 2.4 Sampling Bias and Methodological Issues: Impact on Conclusions | 49 |
| 2.5 Implications for WNV Pathogenesis | 51 |
| 3 Ecology and Phylogeny: WNV Adaptation in the Western Hemisphere | 52 |
| 3.1 General Considerations | 52 |
| 3.2 Adaptation to Mosquito Hosts | 54 |
| 3.3 Adaptation to Avian Hosts | 54 |
| 4 Evolutionary Mechanisms in West Nile Virus | 55 |
| 5 Summary and Future Studies | 56 |
| References | 57 |
| 3 . Vector Biology and West Nile Virus | 62 |
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| 1 Introduction: Importance of Vector Biology in West Nile Virus Ecology | 62 |
| 2 Transmission of West Nile Virus | 63 |
| 2.1 Natural Transmission Cycle | 63 |
| 2.2 Vector Competence and Vectorial Capacity | 64 |
| 2.3 Mosquitoes Involved in Transmission of WNV | 66 |
| 2.4 Other Potential Arthropod Vectors | 68 |
| 2.5 Role of Vectors in Overwintering | 68 |
| 3 Genetics and Molecular Biology of Virus–Mosquito Interactions | 70 |
| 3.1 Influence of Mosquito Genetics on WNV Transmission | 70 |
| 3.2 Key Interaction: Infection of and Dissemination from the Midgut | 70 |
| 3.3 Transmission by Bite: Mosquito Salivary Proteins | 71 |
| 3.4 Potential Barriers to Infection: Mosquito Defense Mechanisms | 72 |
| 3.5 Pathogenesis in Mosquito Tissues | 75 |
| 3.6 Role of Virus Genetics in Vector Interactions | 76 |
| 4 Control of WNV Disease: Interruption of the Transmission Cycle | 77 |
| 5 Conclusion | 78 |
| References | 78 |
| 4. Clinical Manifestations of Neurological Disease | 85 |
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| 1 Introduction | 85 |
| 2 Epidemiology and Risk Factors for WNV Neuroinvasive Disease | 86 |
| 3 Clinical Manifestations | 88 |
| 3.1 West Nile Meningitis | 90 |
| 3.2 West Nile Encephalitis | 93 |
| 3.3 West Nile Acute Flaccid Paralysis | 97 |
| 3.4 Other Clinical Manifestations | 99 |
| 4 Outcomes and Prognoses | 100 |
| 5 Therapy of West Nile Virus Infection | 102 |
| References | 106 |
| 5. Molecular Biology of West Nile Virus | 112 |
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| 1 Introduction | 112 |
| 2 Virus Classification | 113 |
| 3 Genome RNA | 113 |
| 4 Virion Morphology and Proteins | 114 |
| 5 WNV Replication Cycle | 116 |
| 6 Viral Nonstructural Proteins | 119 |
| 7 In Vitro Polymerase Assays | 127 |
| 8 Conserved Viral RNA Terminal Structures and Sequences | 128 |
| 8.1 Conserved Sequences | 128 |
| 8.2 Secondary Structures | 130 |
| 8.3 Tertiary Structures | 131 |
| 9 Host Cell Proteins Interact with the WNV 3¢ Terminal SLs and Facilitate RNA Synthesis | 131 |
| 9.1 Cellular Proteins Bind to the 3' (+) SL RNA | 132 |
| 9.2 Cellular Proteins Bind to the 3' (–) SL | 134 |
| 9.3 Virus Interactions with the Host Cell | 136 |
| 9.4 Host Genetic Resistance to Flavivirus-Induced Disease | 137 |
| 9.5 Virulence Determinants | 138 |
| 10 Conclusions | 139 |
| References | 139 |
| 6. Virulence of West Nile Virus in Different Animal Hosts | 152 |
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| 1 Introduction | 152 |
| 2 Classification of West Nile Virus Strains: Antigenic and Nucleotide Sequence Diversity | 153 |
| 3 WNV: Natural Hosts, Animal Models and Disease | 155 |
| 3.1 WNV Disease in Humans | 155 |
| 3.2 Nonhuman Primates | 157 |
| 3.3 Avians | 157 |
| 3.4 Equines | 158 |
| 3.5 Chipmunks, Rabbits, and Tree Squirrels | 159 |
| 3.6 Small Animal Models: Mice and Hamsters | 159 |
| 4 Molecular Determinants of Natural Virulence Variations Between WNV Strains | 160 |
| 4.1 Contribution of Individual Viral-Encoded Proteins to WNV Virulence | 160 |
| 4.2 Comparative Studies of WNV Virulence in Mouse and Hamster Models | 161 |
| 4.3 Emergence and Characterization of Attenuated WNV Variants in the Americas | 162 |
| 4.4 Determinants of Virulence in Avians | 163 |
| 5 Summary | 164 |
| References | 164 |
| 7. Innate immune Response and Mechanisms of Interferon Antagonism Against West Nile Virus | 169 |
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| 1 Introduction | 169 |
| 2 Recognition of WNV by Cellular Sensors: Activation of the First Wave of the Innate Immune Response | 169 |
| 3 INF-alpha and IFN Stimulated Genes (ISGs) Are Essentialfor Survival of WNV Infections | 173 |
| 4 Effectors of the IFN Response | 174 |
| 5 Viral Antagonism of the IFN Response | 176 |
| 6 What Is the Mechanism Responsible for this Inhibition of the IFN Response? | 178 |
| 7 Implications for Natural Infections in Humans | 178 |
| References | 179 |
| 8. Innate Immune Responses to West Nile Virus Infection | 183 |
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| 1 Introduction | 183 |
| 2 Sensing WNV Infection: Role of Pattern-Recognition Receptors | 184 |
| 2.1 Toll-Like Receptors | 186 |
| 2.2 RNA Helicases | 188 |
| 2.3 Nonconventional PRRs | 189 |
| 3 Role of Innate Immune Cells in WNV Infection | 189 |
| 3.1 Macrophages | 189 |
| 3.2 Dendritic Cells | 190 |
| 3.3 Gamma/DeltaT Cells | 191 |
| 3.4 NK Cells | 192 |
| 4 Cytokines Involved in Innate Responses to WNV Infection | 193 |
| 4.1 Macrophage Migration Inhibitory Factor | 193 |
| 4.2 IFN- Gamma | 195 |
| 4.3 Other Inflammatory Cytokines | 195 |
| 5 Concluding Remarks | 196 |
| References | 197 |