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Influenza Pathogenesis and Control - Volume II - Michael B.A. Oldstone

Year 2015


Part I Innate Immunity1 Introduction2 Role of Cytokines and Chemokines in Immunopathology Versus Protection2.1 Interferon2.2 Interleukin-1 (IL-1) and Tumor Necrosis Factor Alpha (TNF-a)2.3 Interleukin-6 (IL-6)2.4 Chemokines2.5 Negative Regulatory Cytokines, Interleukin-10 (IL-10), and Tumor Growth Factor-Beta (TGF-b)3 The Role of Innate Immune Cells in Pathogenesis Versus Protection3.1 Macrophages/Monocytes3.2 Neutrophils3.3 Dendritic Cells4 Identifying Therapeutic Interventions to Blunt Immune Pathology5 Future PerspectivesReferencesInnate Immune Sensing and Response to Influenza1 Introduction2 Innate Immunity to Influenza Virus3 Cells of the Innate Immune System Involved in Immunity to Influenza3.1 Respiratory Epithelial Cells3.2 Neutrophils3.3 Macrophages (MU)3.4 Monocytes3.5 Dendritic Cells (DCs)3.6 Natural Killer (NK) Cells3.7 Natural Killer T (NKT) Cells3.8 Innate Lymphoid Cells (ILCs)3.9 Other Innate Immune Cells4 Virus Binding Surface Receptors4.1 Sialic Acid-Containing Receptors5 Virus Sensing Receptors5.1 C-Type Lectin Receptors (CLRs)5.2 Toll-Like Receptors (TLRs)5.3 RIG-I-Like Receptors (RLRs)5.4 NOD-Like Receptors (NLRs)6 Effector Molecules of Innate Immunity6.1 Cytokines and Chemokines6.2 Soluble Innate Mediators6.3 Intrinsic Antiviral Factors7 Innate Control of Adaptive Immunity to Influenza7.1 Innate Immune Cells7.2 Virus Sensing Receptors8 Pathogenic Role of Innate Immunity to Influenza Virus Infection9 Systems Vaccinology of Influenza Vaccines10 Conclusions and PerspectivesReferencesThe NS1 Protein: A Multitasking Virulence Factor1 The Road to Understanding NS1 Functions: The Non-Structural Protein that became Lindenmann's Reverse Interferon2 Sequence and Structure of NS13 The Great Antagonist: NS1 and the Innate Immune Response3.1 Pre-Transcriptional Inhibition: NS1 and the RIG-I Signaling Axis3.2 Coand Post-Transcriptional Inhibition: Limiting Host Gene Expression3.3 Post-Translational Inhibition of Antiviral Genes: PKR and OAS4 Additional Pro-Viral Functions of NS14.1 Activation of PI3K and Regulation of the Apoptotic Response4.2 Regulation of Viral RNA and Protein Synthesis4.3 Interactions with Other Host Cell Factors: the C-terminal PDZ Binding Motif5 Achieving Multifunctionality: Regulation of NS15.1 Intracellular Distribution5.2 Post-Translational Modifications5.3 Structural Versatility6 The NS1 Protein of Influenza B and C viruses7 Influenza Virus Control and NS17.1 Recombinant NS1-Modified Viruses as Vaccines7.2 Antiviral Compounds Targeting NS18 Concluding RemarksReferencesRole of NK Cells in Influenza Infection1 Introduction2 NK Cell Receptors3 NK Cells During Influenza Infection3.1 NK Cells in Mouse Models of Influenza Infection3.2 NK Cells in Human Influenza Infection4 Evasion of NK Cell Activity by Influenza Virus4.1 Mutation of Viral HA4.2 Role for Viral Neuraminidase (NA)4.3 Modulating HA Levels4.4 Seek and Destroy5 Role of NK Cells in Non-mouse, Non-human Influenza Infection6 Conclusions and Ways ForwardReferencesHost Detection and the Stealthy Phenotype in Influenza Virus Infection1 Introduction2 Influenza Virus Infection of Host Cell3 Host Cell Response to Influenza Virus3.1 Toll-Like Receptors3.2 RIG-I-Like Receptors (RLRs)3.3 Nod-Like Receptors (NLRs)4 Evasion Strategy by Influenza Virus4.1 Viral Determinant of Innate Immune Evasion4.2 Nonreductive Determinants of Viral Fitness5 Conclusion and Future DirectionReferencesPart II Vaccines and Adaptive ImmunityInactivated and Adjuvanted Influenza Vaccines1 Introduction2 The Inactivated Influenza Vaccines3 The Immune Response to Inactivated Influenza Vaccines4 Towards Better Inactivated Influenza Vaccines5 Adjuvanted Influenza Vaccines5.1 MF59-Adjuvanted Seasonal, Pandemic and Avian Vaccines5.2 AS03-Adjuvanted Influenza Vaccines5.3 AF03-Adjuvanted Influenza Vaccines6 Other Adjuvants7 Conclusions and PerspectivesReferencesLive Attenuated Influenza Vaccine1 Introduction2 Development of Cold-Adapted Ann Arbor Donor Viruses3 Genetic Basis of ca/ts/att Phenotypes of the Vaccine Donor Viruses3.1 MDV-A3.2 MDV-B4 LAIV by Reverse Genetics and Yearly LAIV Production Process5 Preclinical Studies of LAIV6 Clinical Studies of LAIV6.1 Safety6.2 Transmission and Genetic Stability6.3 Efficacy6.4 Immunogenicity7 Pandemic LAIV7.1 Preclinical Studies7.2 Clinical Studies8 Mediators and Correlates of Protection8.1 Studies in Animal Models8.2 Studies in Humans9 Future DirectionsReferencesDesign of Alternative Live Attenuated Influenza Virus Vaccines1 Introduction2 Production of LAIV Vaccines2.1 Alternative Strategies to Generate Influenza Virus Vaccines2.2 Adoption of Universal or Species-Specific Pol I Promoter for Virus Vaccine Generation2.3 Improving the Transfection Efficiency of the RG System in Vaccine-Producing Cells2.4 Strategies to Accelerate Vaccine Seed Stock Preparation3 Improving LAIV Vaccines: Attenuation Through the Modification of Gene Segments3.1 Modifying the NS Gene Segment3.2 Gene Knockout Strategies3.3 Viruses Possessing M2 Deletions3.4 Modifications in the HA Cleavage Site3.5 Adding Attenuating Features to the Influenza Genome4 Improving Virus Vaccines: Rearrangement of the Influenza Genome and Use of Viral Vectors4.1 Influenza Viruses Containing an Alternate Number of Gene Segments4.2 Generation Influenza Vaccines Containing Bicistronic Expression Cassettes4.3 Development of Influenza Vaccines Lacking the Ability to Reassort5 Conclusions and CommentaryReferencesRapid Production of Synthetic Influenza Vaccines1 Introduction2 The Current System of Seasonal, Pandemic, and Pre-Pandemic Influenza Surveillance and Vaccine Virus Generation3 The 2009 H1N1 Pandemic Response4 The Basic Technologies of Synthetic Influenza Vaccine Virus Generation5 Performance of Synthetic Technology in Vaccine Virus Generation6 Supporting Technologies for Optimal Implementation7 Quality, Regulatory, Safety, Security, Intellectual Property, Economic, and Diplomatic Aspects of Synthetic Vaccine Virus Generation8 Emerging Synthetic Influenza Vaccine Technologies9 ConclusionsReferencesInfluenza Neuraminidase as a Vaccine Antigen1 Introduction2 NA Structure and Function3 Antigenic Domains of NA4 Evidence of NA-Mediated Immunity4.1 Antigenic Drift4.2 Epidemiologic Evidence4.3 Clinical Challenge Studies4.4 Mouse Challenge Studies5 Immunogenicity of NA6 Mechanism of Action7 NA Content of Vaccines7.1 Human Experimental NA-Based Vaccine Studies7.2 Licensed Influenza Vaccines7.3 Development of New Vaccine Types8 Conclusions and Future PerspectivesReferencesAdvances in Universal Influenza Virus Vaccine Design and Antibody Mediated Therapies Based on Conserved Regions of the Hemagglutinin1 Introduction2 Neutralizing Antibodies Directed Against Conserved Regions of the influenza viruses HA2.1 Stalk-Reactive Neutralizing Monoclonal Antibodies2.2 Receptor Binding Site-Reactive Neutralizing Monoclonal Antibodies2.3 Vestigial Esterase Domain-Reactive Neutralizing Monoclonal Antibodies3 Induction of Stalk-Reactive Antibodies by Natural Infection and Standard Vaccination4 Stalk-Based Universal Influenza Virus Constructs4.1 Stalk-Based Vaccine Constructs Lacking the Hemagglutinin Globular Head4.2 Chimeric Hemagglutinin-Based Vaccine Constructs4.3 Other Approaches5 Conclusions and Future PerspectiveReferencesStructural Characterization of Viral Epitopes Recognized by Broadly Cross-Reactive Antibodies1 Introduction2 HA Head-Reactive Antibodies2.1 Receptor Binding Site-Targeted Antibodies2.2 Enhanced Affinity Through Avidity2.3 Receptor Mimicry by Antibodies3 HA Stem-Reactive Antibodies3.1 Group 1 HA Recognition3.2 Group 2 HA Recognition3.3 Pan-Influenza A and Type B Recognition4 Conclusions and Future DirectionsReferencesSkin Immunization with Influenza Vaccines1 Introduction2 Human Studies3 Animal Studies3.1 Mice3.2 Guinea Pigs3.3 Rats3.4 Chickens3.5 Non-human Primates4 Skin Immunization with Adjuvanted Vaccines5 Conclusions and Future DirectionsReferencesMucosal Immunization and Adjuvants1 Introduction2 The Use of Secretary IgA Antibodies for the Prevention of Influenza Virus Infection3 The Characteristics of IgA Antibodies4 IgA Antibody Production in Mucosal Tissues5 Innate Sensing and Mucosal Adjuvants6 Mucosal Vaccine DesignReferencesB Cell Responses to Influenza Infection and Vaccination1 Introduction2 Targets of Humoral Immunity in Influenza3 Humoral Correlates of Protection in Influenza4 The Generation of Antigen-Specific B Cells and Antibodies in Influenza Infection5 The Generation of Mucosal IgA+ B Cell Responses6 Replicating the B Cell Response to Natural Infection by Vaccination7 Unresolved Problems Remaining with Influenza Vaccination8 Overcoming Immunosenescence to Improve Protection9 Avenues to Overcoming Strain-Specific Immunity to Influenza10 Broadly Cross-Reactive Stem-Binding Antibodies11 Cross-Reactive Antibody Responses to Vaccination and the “Universal” Influenza Vaccine12 ConclusionReferencesMemory CD4 T Cells in Influenza1 Introduction2 Primary CD4 T Cell Responses to Influenza Infection3 Generation of Memory CD4 T Cells in Influenza Infection4 Heterogeneity of Memory CD4 T Cells4.1 Circulating Central and Effector Memory Subsets4.2 Tissue Resident Memory Subsets5 Mechanisms for Tissue Trafficking and Retention6 Memory CD4 T Cell Function in Influenza6.1 Helper Functions in Lymphoid Tissues6.2 Independent Effector Mechanisms in the Lung7 Implications for Vaccines8 ConclusionReferencesThe Effector T Cell Response to Influenza Infection1 Introduction2 Initiation of Adaptive Immunity2.1 Dendritic Cell Networking in the Steady-State and Inflamed Lung2.2 Activation of DCs and Antiviral Innate Immunity in the Lung2.3 Antigen Acquisition and Migration of Lung DCs2.4 Antigen Presentation and T Cell Activation in the DLNs3 Lymphocyte Migration into the IAV-Infected Lung4 Adaptive Immune-Mediated Antiviral Activity in the Lung4.1 T Lymphocyte Cytotoxic Mechanisms4.2 T Cell Soluble Mediators5 Regulation of Effector T cell Responses in the Lung5.1 Local Differentiation of Effector T Cells in the Lung5.2 Local Regulation of Proliferation and Survival of Effector T Cells5.3 Molecular Mechanisms Regulating Effector T Cell Responses in the Lung5.4 In Situ Control of Effector T Cell Activities by Different Types of APCs6 Conclusion and Future Avenues of ResearchReferencesPart III New Antiviral DiscoveryAntiviral Effects of Inhibiting Host Gene Expression1 Introduction2 Influenza A Virus and RNAi2.1 Influenza Virus Lifecycle2.2 RNAi to Interrogate Gene Function2.3 Genome-Wide Mammalian Cell-Based RNAi Screening2.4 The Appropriate Cell Line for HTS2.5 Choosing Appropriate Endpoint Assays for HTS2.6 Validation of HTS Findings3 Optimizing RNAi Genome-Wide Screens to Facilitate Drug Rescue and Repurposing3.1 Identifying Antiviral Drugs Affecting Influenza Virus Replication4 Host Factors and Drug Targets for Influenza Virus4.1 Host Genes Critical for Influenza Replication Are Not Universal for All Strains4.2 IFN Antiviral Host Pathways Responding to Influenza Virus Infection4.3 microRNA Screens5 Conclusions and Looking ForwardReferences
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