Emerging Infectious Diseases

Preface xxi

Part 1: Introduction and Genetic Insights 1

1 Introduction to Viral Storms: Infectious Disease 3
Shivaprasad Sirimalla, Sanjit Sah, Uday Venkat Mateti and Allen Pinto

1.1 Introduction to Infectious Disease 4

1.2 Virology: Overview of Virus, Virus Structure, Classification, Replication, and Transmission 6

1.2.1 Overview of the Virus 6

1.2.2 Virus Structure 7

1.2.3 Classification of Viruses 8

1.2.4 Viral Replication 14

1.2.5 Viral Transmission 15

1.3 Viral Storms (Major Pandemics) 17

1.3.1 The Spanish Flu (1918-1919) 17

1.3.2 HIV/AIDS Pandemic (1980s-Present) 18

1.3.3 Sars (2002-2003) 19

1.3.4 H1N1 Influenza (2009) 19

1.3.5 COVID-19 Pandemic (2019-Present) 20

1.4 Factors Contributing to Viral Storms 21

1.4.1 Environmental Factors, Climate Change, and Urbanization 21

1.4.2 Social Factors: Global Travel, Population Density, and Healthcare Access 22

1.4.3 Biological Factors: Viral Mutations and Host Immune Response 24

1.5 Norovirus 25

1.5.1 Introduction to Norovirus: Overview of the Virus and Its Significance 25

1.5.2 Epidemiology: Global Impact and Spread of Norovirus 26

1.5.3 Clinical Presentation: Symptoms, Severity, and Complications 27

1.5.4 Transmission and Prevention: Modes of Transmission and Strategies to Prevent Outbreaks 28

1.6 Summary of Key Points 29

1.7 Conclusion 30

References 31

2 Norovirus: Its Role in Gastroenteritis Outbreaks 39
Ranjana Rohilla and Shriyansh Srivastava

2.1 Infectious Etiology of Gastroenteritis 40

2.2 Introduction to Norovirus Gastroenteritis 41

2.3 History of Norovirus and Outbreaks 42

2.4 Epidemiology and Common Settings of Norovirus Outbreaks 44

2.4.1 Healthcare Facilities 46

2.4.2 Restaurants and Other Food Establishments 46

2.4.3 School and Child Day Care 48

2.4.4 Cruise Ships 48

2.5 Clinical Features 48

2.6 Gastroenteritis in Immunocompromised Individuals 49

2.7 Gastroenteritis in Immunocompetent Individuals 50

2.8 Economic Burden of Infection 51

2.9 Preparedness for Outbreaks 51

2.10 Conclusion 52

References 53

3 The Genetics of Norovirus: Understanding Its Genome and Genogroups 61
Naga Rani Kagithala, Rahul Sharma, Sasikanth Kothamasu, Shriyansh Srivastava and Ismail A. Ibrahim

3.1 Introduction 62

3.2 Norovirus Genome 64

3.2.1 Structure and Organizational Forms of the Norovirus Genome 64

3.2.2 RNA Genome Characteristics 64

3.2.3 Open Reading Frames (ORFs) 65

3.2.4 Non-Structural Proteins (ORF1) 65

3.2.5 Principal Capsid Protein (VP1): ORF 2 66

3.2.6 ORF3: VP2 or Minor Capsid Protein 66

3.3 Genetic Diversity in Norovirus 66

3.3.1 Genogroups and Genotypes 66

3.3.2 Mechanisms of Genetic Variation 67

3.3.3 Mutation Rates and Hotspots 68

3.3.4 Recombination Events 70

3.3.5 Evolutionary Dynamics of Norovirus 70

3.4 Norovirus Genogroups 71

3.4.1 Classification and Characteristics of Norovirus Genogroups 71

3.4.2 Classification of VP1 Sequences 72

3.4.3 RdRp Designations 72

3.4.4 Genogroup I (GI) 72

3.4.5 Genogroup II (GII) 73

3.4.6 Genogroup III (GIII) 73

3.4.7 Epidemiology of Norovirus Genogroups 74

3.5 Molecular Techniques for Norovirus Genetic Analysis 75

3.5.1 Sequencing Technologies 75

3.5.2 Next-Generation Sequencing (NGS) 76

3.5.3 Whole-Genome Sequencing (WGS) 80

3.5.4 Phylogenetic Analysis 80

3.5.5 Genotyping and Molecular Epidemiology 81

3.6 Implications of Norovirus Genetic Variability 82

3.6.1 Impact on Vaccine Development 82

3.6.1.1 Monovalent Vaccines 82

3.6.1.2 Bivalent Vaccines 83

3.6.2 Antiviral Drug Resistance 83

3.6.3 Public Health Challenges 84

3.7 Recent Advances in Norovirus Genetics 85

3.7.1 New Discoveries in Norovirus Genomic Research 85

3.7.2 Emerging Genogroups and Strains 86

3.7.3 Future Directions in Norovirus Genetics 86

3.8 Conclusion 87

Abbreviations 87

References 88

4 Environmental Factors in Norovirus Outbreaks: Temperature and Rainfall 99
Neeraj Kumar, Akanksha, Shriyansh Srivastava and Mohd Mujeeb

4.1 Introduction 100

4.2 Evolution of Norovirus 103

4.2.1 Antigenic Drift 103

4.2.2 Antigenic Shift 103

4.2.3 Recombination Events 104

4.2.4 Genetic Diversity 104

4.2.5 Mutation Rates 104

4.2.6 Pandemic Strains 105

4.2.7 Geographic Differences 105

4.2.8 Temporal Trends 105

4.3 Fatal Details Regarding the Norovirus 105

4.4 Mode of Transmission of Norovirus 106

4.4.1 Environmental Source 107

4.4.2 Influence of Temperature on Norovirus Outbreaks 108

4.5 Correlation Between Temperature Fluctuations and Outbreaks 109

4.6 Effect of Norovirus on Humidity 110

4.7 The Impact of Rainfall on the Spread of the Norovirus 110

4.8 The Impact of Water on the Spread of the Norovirus 111

4.9 Norovirus Combined Effects of Temperature and Rainfall 112

4.10 Stability of Norovirus 112

4.11 Case Study 113

4.12 Global Patterns in Temperature- and Rainfall-Related Outbreaks 120

4.13 Mitigation Strategies and Public Health Interventions 121

4.14 Conclusion 123

References 124

5 Zoonotic Transmission of Norovirus: Current Understanding and Future Implications 129
Vini Mehta, Sapna Negi, Snehasish Tripathy, Sarvesh Rastogi and Ankita Mathur

5.1 Brief Overview of Norovirus 130

5.2 Epidemiology of Norovirus 131

5.3 Symptoms of Norovirus-Associated Gastroenteritis 132

5.4 Mode of Transmission of Norovirus 132

5.4.1 Vomitus or Stool 132

5.4.2 Through Contaminated Food and Water 133

5.5 Zoonotic Transmission 134

5.5.1 Animal Reservoirs 135

5.5.2 Wild Animals 138

5.6 Zoonotic Transmission Mechanisms of Norovirus 139

5.6.1 Animal-to-Human Transmission 139

5.6.2 Human-to-Animal Transmission 140

5.7 Zoonotic Transmission Mechanism 141

5.8 Future Implications and Research Directions 142

5.9 Conclusion 143

Abbreviations 144

References 144

Part 2: Transmission, Dynamics and Environmental Impacts 151

6 Genetic Changes in Norovirus and Their Impact on Infectivity/Virulence 153
Soumya Patil, Vijayalaxmi Bangra Manjeshwara, Uday Venkat Mateti and Raushan Kumar Chaudhary

6.1 Introduction 154

6.2 Classification of NoV 155

6.3 Genomic Structure and Functions 156

6.3.1 ORF1: The Replication Engine 156

6.3.2 ORF2: The Master Builder 159

6.3.3 ORF3: The Stabilizer 159

6.3.4 ORF4: Murine Norovirus 159

6.4 NoV Life Cycle: Molecular Mechanism of NoV Genome Replication 159

6.5 Transmission 161

6.6 Molecular Diversity 162

6.7 Evolutionary Mechanisms and Dominance 163

6.7.1 Point Mutation 164

6.7.2 Recombination 167

6.7.2.1 Mechanisms of Recombination 168

6.8 Recent Epidemiological Trends 170

6.9 Global Impact and Challenges 174

6.10 Conclusion 176

Abbreviations 177

References 177

7 Bridging the Gap: One Health Approach in Norovirus 187
Sasikanth Kothamasu, Naga Rani Kagithala, Dheeraj Sharma, Shriyansh Srivastava, Aroop Mohanty and Rakesh Sahu

7.1 Overview of Norovirus: Structure and Epidemiology 188

7.2 Understanding the One Health Approach 190

7.2.1 Definition and Principles of One Health 190

7.2.2 Historical Context and Evolution of the One Health Concept 190

7.2.3 Relevance of One Health to Norovirus Control 191

7.2.3.1 Environmental Transmission Pathways 191

7.3 Transmission Pathways of Norovirus 194

7.3.1 Human-to-Human Transmission 194

7.3.2 Environmental Contamination and Spread 194

7.3.3 Zoonotic Potential and Animal Reservoirs 195

7.3.4 Role of Food and Water in Norovirus Outbreaks 195

7.4 Epidemiology of Norovirus: A Global Perspective 196

7.4.1 Geographic Distribution and Prevalence 196

7.4.2 Risk Factors for Infection 196

7.4.3 Seasonal and Regional Variations in Norovirus Incidence 197

7.5 The One Health Approach to Norovirus Surveillance 198

7.5.1 Integrating Human, Animal, and Environmental Surveillance Systems 198

7.5.2 Advances in Diagnostic Techniques for Norovirus Detection 199

7.5.3 Case Studies: Successful Implementation of One Health Surveillance 199

7.6 Prevention and Control Strategies 200

7.6.1 Hygiene and Sanitation Practices 200

7.6.2 Vaccination Development and Challenges 201

7.6.3 Environmental Management and Water Safety 201

7.6.4 Role of Policy and Legislation in Norovirus Prevention 202

7.7 Interdisciplinary Collaboration in One Health 202

7.7.1 Building Effective Partnerships Between Health Sectors 202

7.7.2 Case Studies of Multidisciplinary Efforts in Controlling Norovirus 203

7.7.3 Challenges and Opportunities in Collaborative Approaches 204

7.8 Case Studies: One Health Success Stories 205

7.8.1 Outbreak Response in Different Regions 205

7.8.2 Lessons Learned from Norovirus Control Efforts 206

7.8.3 Scaling Up One Health Strategies Globally 206

7.9 Future Directions in Norovirus Research and Control 207

7.9.1 Emerging Trends in Norovirus Epidemiology 207

7.9.2 Innovations in Vaccination and Treatment 207

7.9.3 The Role of Technology in Enhancing One Health Approaches 208

7.10 Conclusion 208

7.10.1 Summarizing the Impact of the One Health Approach on Norovirus Control 208

7.10.2 Recommendations for Future Action and Research 209

References 210

8 Recent Insights into the Dynamics of Norovirus Outbreak 221
Sejal Porwal, Sonali Sundram, Rishabha Malviya and Shriyansh Srivastava

8.1 Introduction 222

8.2 Symptoms Related to Norovirus 223

8.3 Epidemiology of Norovirus Outbreak 225

8.4 Norovirus Genome and Structure 226

8.5 Virion Morphology 227

8.6 Transmission Mechanism 227

8.6.1 Pattern of Viral Invasion into Host 229

8.7 Administration of Pharmaceuticals and Challenges in Vaccination 230

8.8 Immunity to Norovirus Infection 233

8.9 Public Health Measures to Avoid Being Infected with Norovirus 235

8.10 Conclusion 236

References 237

9 Norovirus Excretion Patterns and their Role in Spread 249
Cynthia Lizzie Lobo, Soumya Patil, Raushan Kumar Chaudhary and Pukar Khanal

9.1 Introduction 250

9.2 Routes of Norovirus Excretion 251

9.2.1 Fecal Shedding 251

9.2.2 Vomitus 253

9.2.3 Saliva 254

9.3 Duration of Noroviral Shedding 255

9.3.1 Factors Influencing Noroviral Shedding Patterns 255

9.3.1.1 Host Factors 255

9.3.1.2 Viral Factors 256

9.3.1.3 Environmental Factors 256

9.3.2 Asymptomatic Excretion of Norovirus 257

9.4 Quantitative Analysis of Noroviral Load 258

9.4.1 Measurement Techniques 258

9.4.1.1 Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) 258

9.4.1.2 Quantitative PCR (qPCR) 259

9.4.1.3 Immune Electron Microscopy (IEM) 259

9.4.1.4 Antigen Detection Immunoassays 259

9.4.1.5 Biosensors 260

9.4.2 Noroviral Load Decay Rates 261

9.5 Transmission Modes of Norovirus 261

9.5.1 Direct Person-to-Person Contact 261

9.5.2 Aerosolized Norovirus Particles 262

9.5.3 Contaminated Food or Water 263

9.5.4 Contaminated Surfaces 263

9.6 Role of Excretion Patterns in Norovirus Spread 264

9.6.1 Contribution to Disease Transmission 264

9.6.2 Environmental Contamination 264

9.7 Public Health Implications of Excretion Patterns 266

9.8 Research Gaps and Future Directions 267

Abbreviations 268

References 268

10 The Role of Rainfall in the Control of Norovirus Outbreaks 275
Sandhya Chaudhary, Rahul Kumar, Kalpana Rahate, Shriyansh Srivastava and Sathvik Belagodu Sridhar

10.1 Introduction 276

10.2 Characteristics of Norovirus 276

10.2.1 Classification 276

10.2.2 Structure of Norovirus 278

10.2.3 Characteristics of Virus 278

10.2.4 Viral Shedding and Transmission Potential 279

10.2.5 Duration of Development and Manifestations 280

10.3 Possible Environmental Markers for Outbreaks of the Human Norovirus 281

10.3.1 Temperature 281

10.3.2 Humidity 282

10.3.3 Rainfall 282

10.4 Relationship Between Rainfall and Norovirus Outbreaks 283

10.5 Public Health and Infrastructure Challenges 284

10.5.1 Water and Foodborne Transmission 285

10.5.2 Transmission Between Individuals 285

10.6 Prevention and Mitigation Strategies 285

10.6.1 Controlling the Occurrence 285

10.6.2 Sanitation 287

10.6.3 Cleaning and Sanitization 287

10.6.4 Colonization and Isolation 287

10.7 Future Directions and Research Needs 287

10.8 Conclusion 288

Abbreviations 288

References 289

11 The Impact of COVID-19 on Norovirus Circulation and Research 295
Laxmi, Shriyansh Srivastava, Sanjita Das, Malakapogu Ravindra Babu, Rishabha Malviya and S.K. Abdul Rahaman

11.1 Introduction 296

11.2 Norovirus: Characteristics and Epidemiology 297

11.2.1 Virology and Pathogenesis 298

11.2.2 Transmission Routes 299

11.2.3 Global Epidemiology of Norovirus 300

11.2.4 Seasonal Patterns and Outbreaks 300

11.3 The COVID-19 Pandemic: An Overview 302

11.3.1 Timeline of COVID-19 Spread 302

11.3.2 Public Health Interventions and Their Impact 303

11.3.3 Changes in Healthcare Systems 304

11.4 Effects of COVID-19 on Norovirus Circulation 304

11.4.1 Changes in Reporting and Surveillance 304

11.4.2 Impact of Non-Pharmaceutical Interventions (NPIs) 305

11.4.3 Predictions for Norovirus Resurgence Post-Pandemic 305

11.5 Research Trends and Findings 306

11.5.1 Changes in Norovirus Research Focus During Covid- 19 306

11.5.2 Advances in Norovirus Vaccine Development 307

11.5.2.1 Vaccine in Human Clinical Trials 307

11.5.2.2 Vaccines in Pre-Clinical Trials 310

11.5.3 Comparative Studies of Norovirus and Other Viruses 311

11.5.3.1 Sapoviruses 311

11.5.3.2 Lagovirus 311

11.5.3.3 Vesivirus 312

11.5.3.4 Nebovirus 312

11.6 Public Health Implications 312

11.6.1 Preparedness for Future Outbreaks 312

11.6.2 Strategies for Mitigating Norovirus Spread 313

11.6.3 Lesson Learned from COVID- 19 314

Conclusion 315

Abbreviations 315

References 317

Part 3: Cross-Species Studies and Therapeutic Development 327

12 Norovirus in Animals: Bovine, Murine, and Other Hosts 329
Aritra Banerjee, K.V. Leela, Shriyansh Srivastava, Pranav Gupta, Malakapogu Ravindra Babu and Ranjit Sah

12.1 Introduction 330

12.2 Genomic Organization and Virus 331

12.3 Interactions Between Viruses and Cells 332

12.4 Norovirus in Bovines 333

12.5 Bovine Norovirus Distribution 334

12.6 The Pathophysiology and Clinical Characteristics of Bovine Norovirus 335

12.7 Diagnosis of the Bovine Norovirus 337

12.7.1 Electron Microscopy 337

12.7.2 Molecular Methods 337

12.7.3 Antigen ELISAs 337

12.7.4 Antibody ELISAs 338

12.8 Norovirus in Murine 338

12.8.1 Murine Norovirus Identification 338

12.8.2 Structural Features of MNV 339

12.8.3 MNV Infection in Wild-Type Mice 340

12.8.4 To Control Norovirus Infection, Innate Immunity is Necessary 340

12.8.5 To Eradicate a Norovirus Infection, Adaptive Immunity is Required 341

12.9 Porcine Norovirus 341

12.10 In Lions, Norovirus 342

12.11 Conclusion 343

References 343

13 The Challenges of Developing Norovirus Vaccines and Therapies 359
Gita Chawla, Tathagata Pradhan and Ojasvi Gupta

13.1 Overview of Norovirus Epidemiology 359

13.2 Classification and Molecular Biology of Norovirus 361

13.3 Current Approaches to Norovirus Therapy 363

13.3.1 Symptomatic Treatment 363

13.3.2 Antiviral Drug Development 364

13.3.3 Passive Immunization Strategies 364

13.3.4 Vaccine Candidates 365

13.3.4.1 Virus-Like Particle (VLP) Vaccines 365

13.3.4.2 P Particle-Based Vaccines 367

13.3.4.3 Recombinant Protein Vaccines 367

13.3.4.4 Bivalent and Multivalent VLP Vaccines 367

13.3.4.5 Oral Vaccines 368

13.3.4.6 Plant-Derived Vaccines 368

13.3.5 Monoclonal Antibody-Based Passive Immunization 369

13.4 Challenges in Norovirus Vaccine Development 369

13.4.1 Genetic Diversity and Rapid Evolution 369

13.4.2 Lack of Long-Lasting Immunity 372

13.4.3 Absence of Reliable In Vitro Culture System 372

13.4.4 Unclear Correlates of Protection 372

13.4.5 Variation in Host Susceptibility 373

13.4.6 High Cost and Complexity of Clinical Trials 373

13.5 Conclusion and Future Perspectives 374

References 375

14 The Importance of Animal Models and In Vitro Cultivation for Norovirus Research 379
Prarambh S.R. Dwivedi, Masmarika Mohan, Pukar Khanal, Sanjit Sah and C.S. Shastry

14.1 Introduction 380

14.2 Importance of Animal and Cell Culture Models for Human Norovirus 381

14.2.1 Importance of Cell Culture Models 381

14.2.2 Importance of Animal Models 382

14.3 Animal Models of HuNoV Infection 383

14.3.1 Mice Model 384

14.3.2 Chimpanzee Model 388

14.3.3 Macaques Model 389

14.3.4 Gnotobiotic Calves and Pigs as Model 390

14.3.5 Zebrafish Model 391

14.3.6 Recovirus Model 392

14.4 Advancement of In Vitro Models for Norovirus 393

14.4.1 Early Attempts to Cultivate HuNoVs 393

14.4.2 Key Discoveries That Helped to Cultivate the Human Epithelial System 395

14.4.3 Reverse Genetic Systems 398

14.4.4 Human Norovirus Strains 399

14.5 Conclusion 402

Abbreviations 403

References 404

15 The Role of Human Intestinal Enteroids in Norovirus Research 413
Apeksha Shetty, Anushree Deshpande, Raushan Kumar Chaudhary and Prakash Patil

15.1 Introduction to Human Intestinal Enteroids (HIEs) 414

15.1.1 Definition and Significance of HIEs 414

15.1.2 The Components of HIEs: Enterocytes, Goblet Cells, Paneth Cells, and Germ Cells 416

15.1.3 Activity of HIEs: Ion Transport and Immune Function 417

15.2 Components Required for Norovirus Activation 419

15.2.1 Receptors and Ligands Involved in Norovirus Binding and Entry 419

15.2.2 Enzymes that are Required for Norovirus Replication 423

15.2.3 Cellular Factors Which Help in Regulating Norovirus Replication and Tropism 425

15.3 Pathophysiology of Norovirus Infection 425

15.3.1 Mechanism of Infection of Norovirus Into the Gut: Attachment, Internalization, and Replication 425

15.3.2 Immune Response to Norovirus Infection: Cellular and Humoral Immunity 428

15.3.3 Few Clinical Symptoms of Norovirus Infection: Diarrhea, Vomiting, and Dehydration 429

15.4 Norovirus Cell Tropism 430

15.4.1 Viral Tropism: Process of Norovirus Targeting Specific Cell Types in the Gut 430

15.4.2 Factors That Influence Norovirus Tropism: Age, Genetics, and Environment 431

15.5 Role of Additional Gastrointestinal Components in Norovirus Infection 432

15.5.1 Mechanisms Through Which Bile Acids Enhance Norovirus Replication 432

15.5.2 How the Bile Acids and the Ceramides Deal with the Entry Restriction for Norovirus 433

15.5.3 Potential Therapeutic Applications of Bile Acids and Ceramide in Treating Norovirus 434

15.6 Antiviral Compound Screening Using HIEs 435

15.6.1 Screening Methods of Antiviral Compounds Using HIEs 435

15.6.2 Examples of Antiviral Compounds Discovered by Using HIEs 436

15.6.3 Future Directions for Antiviral Compound Screening Using HIEs 437

15.7 Future Perspectives 438

15.8 Conclusion 439

Abbreviations 439

References 440

Index 447