Table Of ContentAdvances in Malaria Research
THE WILEY-IUBMB SERIES ON BIOCHEMISTRY AND
MOLECULAR BIOLOGY
Protein Kinase CK2
Edited by Lorenzo A. Pinna
Plant Phenolics and Human Health: Biochemistry, Nutrition and Pharmacology
Edited by Cesar G. Fraga
Advances in Malaria Research
Edited by Deepak Gaur, Chetan E. Chitnis and Virander S. Chauhan
Advances in Malaria
Research
EDitED by
Deepak Gaur
School of biotechnology, Jawaharlal Nehru University
New Delhi, india
Chetan E. Chitnis
Department of Parasites and insect Vectors, institut Pasteur, Paris, France
Virander S. Chauhan
international Centre for Genetic Engineering and biotechnology, New Delhi, india
Copyright © 2017 by John Wiley & Sons, inc. All rights reserved
Published by John Wiley & Sons, inc., Hoboken, New Jersey
Published simultaneously in Canada
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by
any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted
under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written
permission of the Publisher, or authorization through payment of the appropriate per‐copy fee to the
Copyright Clearance Center, inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978)
750‐4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be
addressed to the Permissions Department, John Wiley & Sons, inc., 111 River Street, Hoboken, NJ 07030,
(201) 748‐6011, fax (201) 748‐6008, or online at http://www.wiley.com/go/permissions.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in
preparing this book, they make no representations or warranties with respect to the accuracy or
completeness of the contents of this book and specifically disclaim any implied warranties of
merchantability or fitness for a particular purpose. No warranty may be created or extended by sales
representatives or written sales materials. the advice and strategies contained herein may not be suitable
for your situation. you should consult with a professional where appropriate. Neither the publisher nor
author shall be liable for any loss of profit or any other commercial damages, including but not limited to
special, incidental, consequential, or other damages.
For general information on our other products and services or for technical support, please contact our
Customer Care Department within the United States at (800) 762‐2974, outside the United States at (317)
572‐3993 or fax (317) 572‐4002.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may
not be available in electronic formats. For more information about Wiley products, visit our web site at
www.wiley.com.
Library of Congress Cataloging‐in‐Publication data applied for
9781118493793
A catalogue record for this book is available from the british Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not
be available in electronic books.
Cover image:
top image: Red blood cells. Scanning electron micrograph of Red blood cells clearly showing their
biconcave disc shape. (Source: Annie Cavanagh, Wellcome images)
Middle image: Plasmodium falciparum merozoite invading a red blood cell. Differential interference
contrast (DiC) microscopy image of a merozoite attached to the red blood cell during invasion. the 3-D
reconstruction of the confocal immunofluorescence image detected the leading vaccine antigen, PfRH5,
at the apical end of the merozoite surface (Source: Reddy et al. PNAS USA 2015)
bottom image: Mosquito, Anopheles stephensi in flight. A mosquito (Anopheles stephensi) in flight with its
abdomen full of blood. through its role in the transmission of malaria and yellow fever, it is claimed that
the mosquito has killed more than half the humans that have ever lived and it continues to kill between
one and two million people a year, mainly young children. this particular species, Anopheles stephensi,
is the insect vector that transmits malaria in india and Pakistan. (Source: Hugh Sturrock, Wellcome image
Award winner 2006)
Set in 10/12pt Meridien by SPi Global, Pondicherry, india
10 9 8 7 6 5 4 3 2 1
Dedicated to all our past and current students and group members
Contents
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
vii
viii Contents
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
Contents ix
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
x Contents
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
Contents xi
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
