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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 presentday 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 Transmissionblocking interventions 110 Bibliography 114 5 Comparative and functional genomics of malaria parasites 125 Martine M. Zilversmit, Sittiporn Pattaradilokrat, and Xinzhuan 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 JoseJuan LopezRubio 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 Calciummediated 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 lysosomeequivalent 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. GarcíaBasteiro, 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 Preerythrocytic stage vaccines 524 Bloodstage vaccines 526 Transmissionblocking 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