Malaria: Drugs, Disease and Post-genomic Biology

447 Pages·2005·4.73 MB·English

by  F.R.C.P., P. G. Bray, S. A. Ward, P. M. O’Neill (auth.), R. W. Compans, M. D. Cooper, H. Koprowski, M. Potter, P. K. Vogt, F. MED. Sci. (eds.), T. Honjo, F. Melchers, S. Olsnes, H. Wagner, M. B. A. Oldstone, David J. Sullivan M.D., Sanjeev Krishna D. Phil

295
Current Topics
in Microbiology
and Immunology
Editors
R. W. Compans, Atlanta/Georgia
M. D. Cooper, Birmingham/Alabama
T. Honjo, Kyoto · H. Koprowski, Philadelphia/Pennsylvania
F. Melchers, Basel · M. B. A. Oldstone, La Jolla/California
S. Olsnes, Oslo · M. Potter, Bethesda/Maryland
P. K. Vogt, La Jolla/California · H. Wagner, Munich
D.J. Sullivan and S. Krishna (Eds.)
Malaria:
Drugs, Disease
and Post-genomic
Biology
With 40 Figures and 15 Tables
123
David J. Sullivan, M.D.
The Johns Hopkins University
Bloomberg School of Public Health
Department of Molecular Microbiology and Immunology
615 North Wolfe Street, E5628
Baltimore, MD 21205
USA
e-mail:
DS dedicates this volume to his parents, brothers and Lois,
Luke, Benjamin and Ronan and SK to his parents, Ash, Niraj,
Arti, Anand, Yasmin, and last, littlest but not least to Karim.
Preface
There are more than 120 species of Plasmodium, but only five naturally infect
humans. P. malariae, P. ovale, P. vivax and occasionally P. knowlesi cause
cyclical fevers, anemia and splenomegaly the classic triad associated with
the clinical syndrome of malaria. The fifth organism, P. falciparum is lethal
because it can achieve high parasitemias and additionally bind to endothelial
cells and disrupt organ function. P. falciparum was the first species for which
continuous in vitro cultivation was developed by William Trager and James
Jensen in 1976. This milestone in malariology launched an intense study
of biochemistry of parasites, identification of vaccine candidates and drug
targets and most recently completion of the P. falciparum genome. However,
despite rapid increases in knowledge, malaria continues to kill more than
a million people each year and to cause symptomatic disease in a further 300
million individuals.
Specific antimicrobial treatment for malaria was available hundreds of
years before Alphonse Laveran first described the etiologic agent in 1880.
P.G. Bray et al. begin this volume with an account of the history and biologic
chemistry of the widely used and highly effective quinoline and artemisinin
drug classes. P. falciparumhas evolved resistance tomost classes of antimalar-
ials, whichworsens clinical outcomes particularly in themost vulnerable pop-
ulations of women and children. A.-C. Uhlemann and S. Krishna describe the
mechanisms of drug resistancewith special attention to the hotbed of drug re-
sistance in southeast Asia, while C.V. Plowe outlines strategies for monitoring
and deterrence of drug resistance, chiefly in Africa.
There can be almost a trillion P. falciparum parasites in an infected in-
dividual equivalent to tens of milligrams of protein, distinguishing malaria
from bacterial infections where millions of bacteria produce nanograms of
protein.M.P.GrobuschandP.G.Kremsnerdescribe thediversity of syndromes
seen in uncomplicated malaria, while T. Planche et al. describe the metabolic
consequences of severe malaria. D.J. Roberts et al. highlight the pathogenesis
of severe anemia. P. falciparum exports adhesive ligands to the exterior of
the host erythocyte, a property associated with organ dysfunction affecting
lungs, kidneys, liver and brain. P.E. Duffy and M. Fried explain how these
mechanisms affect P. falciparum sequestration resulting in placental malaria.
The several-fold rise in P. falciparum numbers every 2 days in unrestricted
infections requires many unique metabolic adaptations to the hemoglobin
VIII Preface
rich erythrocyte. S.S. Oh and A.H. Chisti highlight host invasion receptors
and parasite ligands necessary for merozoite invasion of the erythrocyte.
Subsisting almost entirely on glycolysis, the intraerythrocytic parasite still
requires function from its single acristate mitochondrion. In close appo-
sition to the mitochondrion is the unique plant-derived plastid organelle.
A.B. Vaidya and M.W. Mather and S. Sato and R.J.M. Wilson describe the ge-
nomic framework for understanding plastid and mitochondrial physiology.
This has already been exploited by identifying new drug targets and addi-
tional unique vulnerable pathways are also being studied as future targets.
D.E.Goldberg catalogues the specific, efficient hemoglobinproteases that pro-
vide amino acids and space for the development of the Plasmodium parasite.
P.F. Scholl et al. detail the intersection of host and parasite iron pathways that,
for the parasite, center on heme crystal formation called hemozoin. K. Kirk et
al. review a “permeomic” description of membrane transport proteins criti-
cal to nutrient support of development, and that also affect antimalarial drug
action and resistance.
During the rapid asexual haploid replication that causes symptoms in pa-
tients, less than a thousandth of the total number of parasites differentiate
into the sexual gametocytes, which in turn are taken up in the bloodmeal of
the female Anophelesmosquito. From a few hundred gametes in a bloodmeal,
a handful of zygotes mature to ookinetes. J.M. Vinetz details ookinete biology
as it traverses from the gut to the outside of the stomach to form the oocyst.
The oocysts, in a few days time release thousands of sporozoites that migrate
to the salivary glands in preparation for inoculation. K.D. Vernick et al. ex-
plain the molecular genetics of mosquito-specific resistance to Plasmodium
survival in the vector. Finally a few hundred infectious sporozoites are in-
jected into the human bloodstream where only a couple will invade liver cells
within 90min. After 7–10 days the asymptomatic intrahepatic Plasmodium
has rapidly multiplied to several thousand schizonts, and soon releases infec-
tious merozoites to begin a cycle that has persisted in humans for millennia.
P.L. Blair and D.J. Carruci in a tour de force of mass spectrometry credential
the existence of protein products in the sporozoite and hepatic stages, which
have proved very difficult to cultivate.
There is much that is new, exciting and potentially of clinical relevance
since malaria parasites were first cultured. Some of these advances have been
superbly captured in the chapters presented in this volume. The editors par-
ticularly wish to thank Mrs. Rina Patel, whose assistance in preparing this
volume has been invaluable, and Gary Knight, whose photos on malaria are
well known, for publishing one here.
June 2005 David Sullivan and Sanjeev Krishna
List of Contents
Part I. Drugs and Drug Resistance
Quinolines and Artemisinin: Chemistry, Biology and History . . . . . . . . . . . . . . 3
P. G. Bray, S. A. Ward, and P. M. O’Neill
Antimalarial Multi-Drug Resistance in Asia: Mechanisms and Assessment . . . . . 39
A.-C. Uhlemann and S. Krishna
Antimalarial Drug Resistance in Africa: Strategies for Monitoring and Deterrence 55
C. V. Plowe
Part II. Malaria the Disease
Uncomplicated Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
M. P. Grobusch and P. G. Kremsner
Metabolic Complications of Severe Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
T. Planche, A. Dzeing, E. Ngou-Milama, M. Kombila, and P. W. Stacpoole
The Clinical and Pathophysiological Features of Malarial Anaemia . . . . . . . . . . 137
D. J. Roberts, C. Casals-Pascual, and D. J. Weatherall
Malaria in the Pregnant Woman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
P. E. Duffy and M. Fried
Part III. Biology
Host Receptors in Malaria Merozoite Invasion . . . . . . . . . . . . . . . . . . . . . . . . . 203
S. S. Oh and A. H. Chishti
A Post-genomic View of the Mitochondrion in Malaria Parasites . . . . . . . . . . . . 233
A. B. Vaidya and M. W. Mather
The Plastid of Plasmodium spp.: A Target for Inhibitors . . . . . . . . . . . . . . . . . . 251
S. Sato and R. J. M. Wilson
X List of Contents
Hemoglobin Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
D. E. Goldberg
Bioavailable Iron and Heme Metabolism in Plasmodium falciparum . . . . . . . . . 293
P. F. Scholl, A. K. Tripathi, and D. J. Sullivan
Plasmodium Permeomics: Membrane Transport Proteins in the Malaria Parasite 325
K. Kirk, R. E. Martin, S. Bröer, S. M. Howitt, and K. J. Saliba
Plasmodium Ookinete Invasion of the Mosquito Midgut . . . . . . . . . . . . . . . . . . 357
J. M. Vinetz
Molecular Genetics of Mosquito Resistance to Malaria Parasites . . . . . . . . . . . . 383
K. D. Vernick, F. Oduol, B. P. Lazzaro, J. Glazebrook, J. Xu, M. Riehle, and
J. Li
Functional ProteomeandExpressionAnalysis of Sporozoites andHepatic Stages
of Malaria Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
P. L. Blair and D. J. Carucci
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
List of Contributors
(Addresses stated at the beginning of respective chapters)
Blair, P. L. 419 O’Neill, P. M. 3
Bröer, S. 327 Oduol, F. 385
Bray, P. G. 3 Oh, S. S. 205
Carucci, D. J. 419 Planche, T. 107
Casals-Pascual, C. 139 Plowe, C. V. 57
Chishti, A. H. 205
Riehle, M. 385
Duffy, P. E. 171 Roberts, D. J. 139
Dzeing, A. 107
Saliba, K. J. 327
Fried, M. 171 Sato, S. 253
Scholl, P. F. 295
Glazebrook, J. 385 Stacpoole, P. W. 107
Goldberg, D. E. 277 Sullivan, D. J. 295
Grobusch, M. P. 85
Tripathi, A. K. 295
Howitt, S. M. 327
Uhlemann, A.-C. 41
Kirk, K. 327
Kombila, M. 107 Vaidya, A. B. 235
Kremsner, P. G. 85 Vernick, K. D. 385
Krishna, S. 41 Vinetz, J. M. 359
Lazzaro, B. P. 385 Ward, S. A. 3
Li, J. 385 Weatherall, D. J. 139
Wilson, R. J. M. 253
Martin, R. E. 327
Mather, M. W. 235 Xu, J. 385
Ngou-Milama, E. 107