Advances in Malaria Research

Deepak Gaur, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India. Chetan Chitnis, International Centre for Genetic Engineering and Biotechnology, New Delhi, India; Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France. Virander S. Chauhan is Director for the International Centre for Genetic Engineering and?Biotechnology, New Delhi Component. Dr. Chauhan's research focuses on Malaria vaccine and drug development. Dr. Chauhan has written numerous articles related to the Fields of malarial biology and drug discovery. Dr. Chaudan is also co-editor of Recombinant and Synthetic Vaccines (Springer 1995).

List of contributors xiii

Foreword xvii

Preface xix

1 Introduction: An overview of malaria and Plasmodium 1
Virander S. Chauhan, Chetan E. Chitnis, and Deepak Gaur

History 1

The life cycle of Plasmodium 3

A significant milestone in malaria research: Adaptation of Plasmodium to laboratory culture 4

The advent of present‐day technologies and their applications in malaria research 5

Bibliography 6

2 Exoerythrocytic development of Plasmodium parasites 9
Volker T. Heussler, Annika Rennenberg, and Rebecca R. Stanway

The sporozoite’s journey from the skin to the liver 10

Sporozoite invasion 14

Parasite development 15

Protein export from the parasite into the host cell 20

Parasite egress 23

The role of innate immune responses during merosome formation 26

Acknowledgments 27

Bibliography 27

3 Molecular basis of erythrocyte invasion by Plasmodium merozoites 33
Deepak Gaur, Chetan E. Chitnis, and Virander S. Chauhan

The structure of the merozoite 39

The steps of erythrocyte invasion 41

Redundancy and ligand–receptor interactions that mediate parasite adhesion during erythrocyte invasion 57

Signaling events during erythrocyte invasion by malaria parasites 74

Summary and conclusions 75

Bibliography 75

4 The biology of malaria transmission 87
Robert E. Sinden

Purpose 87

History 87

The current research agenda 88

Biology 88

Population dynamics 106

Transmission‐blocking interventions 110

Bibliography 114

5 Comparative and functional genomics of malaria parasites 125
Martine M. Zilversmit, Sittiporn Pattaradilokrat, and Xin‐zhuan Su

An Introduction to Plasmodium genomes 125

Genome structure of malaria parasites 127

From genome sequences to gene function 133

Summary 139

Acknowledgments 139

Bibliography 139

6 Gene regulation: New insights and possible intervention strategies 149
Artur Scherf, Nicholas A. Malmquist, Rafael M. Martins, Shruthi S. Vembar, and Jose‐Juan Lopez‐Rubio

Introduction 149

Modes of gene regulation 150

Drug targeting 164

Perspectives 169

Bibliography 171

7 Molecular genetic approaches to malaria research 179
Brendan Elsworth, Mauro F. Azevedo, Brendan S. Crabb, and Paul R. Gilson

Transfection methods 179

Genetic approaches for deriving gene function 184

Conditional knockdown of protein function 187

Protein reporters 190

Conclusions 192

Bibliography 192

8 Transcriptomics and proteomics 197
Archana P. Gupta, Zbynek Bozdech, and Peter R. Preiser

Transcriptional profiling throughout the parasite life cycle 198

Transcriptional regulation 201

Transcriptional variation 205

Biological insights 208

Proteomics 208

Translational regulation 209

Conclusion 212

Bibliography 212

9 The biochemistry of Plasmodium falciparum: An updated overview 219
Hagai Ginsburg

MPMP 219

Carbohydrates 219

Lipid metabolism 227

Amino acids 240

Nucleotide metabolism 252

Cofactors 256

Redox metabolism 265

Mitochondrial functions 268

Hemoglobin digestion and hemozoin production 273

Some reflections for the future 276

Bibliography 277

10 Signaling in malaria parasites 291
Pushkar Sharma and Sudhir Kumar

Protein phosphorylation in Plasmodium 291

Calcium‐mediated signaling in Plasmodium 292

Phosphoinositide signaling and trafficking in malaria parasites 295

Cyclic nucleotide signaling in the malaria parasite 296

Future challenges 300

Bibliography 300

11 Membrane transport proteins as therapeutic targets in malaria 307

Sanjay A. Desai, Kempaiah Rayavara, Paresh Sharma, Sayeed K. Syed, Wang Nguitragool, and Praveen Balabaskaran Nina

Host erythrocyte membrane: A shared ion and nutrient channel 308

Parasitophorous vacuolar membrane: Protein export and solute uptake 311

Parasite plasma membrane: Similar to other eukaryotic cells, but different 314

Digestive vacuole: A specialized lysosome‐equivalent in the parasite 316

Mitochondrial inner membrane: An unusual ATP synthase with uncertain function 318

Conclusions 319

Acknowledgments 319

Bibliography 319

12 The proteolytic repertoire of malaria parasites 325
Puran Singh Sijwali and Philip J. Rosenthal

Aspartic proteases 325

Cysteine proteases 330

Metalloproteases 333

Serine proteases 335

Threonine proteases 338

Roles of proteases in parasite development 340

Summary and conclusions 343

Acknowledgments 343

Bibliography 343

13 Development of medicines for the control and elimination of malaria 353
Jeremy N. Burrows and Timothy N. C. Wells

Targets for the development of future medicines for malaria 356

The process of drug development 359

Advances in drug development made in the 21st century 365

The global pipeline of new medicines for treating malaria 368

Medicines in the broader context of malaria eradication 370

Conclusion 377

Acknowledgments 377

Bibliography 377

14 Antimalarial drug resistance 383
Naman K. Shah and Neena Valecha

Background 383

Causes of drug resistance 386

Detection of drug resistance 390

Managing drug resistance 397

Conclusion 401

Disclosures 401

Bibliography 401

Further reading 407

15 Epidemiology of Plasmodium falciparum malaria 409
Alberto L. García‐Basteiro, Quique Bassat, and Pedro L. Alonso

Burden of disease 409

Geographical distribution of the disease 411

Chain of transmission and infection cycle 413

Malaria endemicity and malaria transmission 415

Malaria elimination and eradication 423

Bibliography 424

16 Malaria pathogenesis 427
Bronner P. Gonçalves, Michal Fried, and Patrick E. Duffy

Malaria illness 427

Host susceptibility 439

Parasite virulence 444

Conclusions 450

Bibliography 451

17 Host genetics 465
Thomas N. Williams

What evidence is there that the risk of malaria is genetically determined? 465

Identifying the genes involved 466

Why is genetic resistance important? 467

Genetic polymorphisms of the red blood cell 468

Hemoglobinopathies 474

G6PD deficiency 478

Non–red blood cell polymorphisms 479

Concluding remarks 481

Bibliography 481

18 The immune response in mild and severe malaria: Two sides of the same coin 495
Michael Waisberg, Peter D. Crompton, Louis H. Miller, and Susan K. Pierce

The picture of the acquisition of resistance to uncomplicated and severe malaria: Framing the questions 495

Searching for host genes that confer immune resistance to severe malaria 506

SLE susceptibility and resistance to severe malaria 507

The relationship between the pathogen environment and susceptibility to severe malaria 510

Summary 511

Acknowledgments 511

Bibliography 512

19 Progress in development of malaria vaccines 521
Chetan E. Chitnis, Deepak Gaur, and Virander S. Chauhan

Immunity to malaria 521

Life cycle of malaria parasites and points of intervention with vaccines 522

Pre‐erythrocytic stage vaccines 524

Blood‐stage vaccines 526

Transmission‐blocking vaccines 533

Live attenuated vaccines for malaria 534

Conclusion 535

Bibliography 535

20 Plasmodium vivax: Insights on burden and pathobiology 547
Ivo Mueller, Quique Bassat, Marcus V. G. Lacerda, and Hernando A. del Portillo

Burden of Plasmodium vivax infection and disease 547

Severe Plasmodium vivax malaria 550

Molecular basis of severe disease 552

Concluding remarks and outstanding research questions 558

Bibliography 558

Index 565