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ScienceWeek
SCIENCEWEEK
ScienceWeek
September 12, 2003
Vol. 7 Number 37A
An Online Digest of Research in the Sciences
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Periodicity:
As the Earth turns
Each day
Two thousand children
Dead of malaria.
-- Anonymous
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Section 1
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Part A - Symposium: Malaria
1. Introduction
2. The Pathogenic Basis of Malaria
3. The Economic and Social Burden of Malaria
4. Progress and Challenges for Malaria Vaccines
5. The Anopheles Genome and Comparative Insect Genomics
6. Early Origin and Recent Expansion of Plasmodium Falciparum
7. On Insecticide Resistance
8. On Plasmodium Chloroquine Resistance
9. On the Malarial Parasite Genome
10. Malaria in Britain: Past, Present, and Future
Notices and Subscription Information
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Section 2
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1. INTRODUCTION
ON THE MALARIAL PATHOGEN
The disease malaria is caused by a type of protozoan with the
general name Plasmodium, an organism characterized by a sequence
of life cycles involving different organismic forms. The asexual
cycle occurs in the liver and red blood cells of vertebrates
(including humans), and the sexual cycle occurs in mosquitoes.
Essentially, the asexual form is ingested by blood-sucking
mosquitoes, and in the mosquito the asexual form is induced to
produce the sexual form necessary to complete the total life
cycle. The details of the process are as follows: Plasmodium
cells called "gametocytes" (precursors of gametes) in human blood
are ingested by the mosquito, and in the mosquito, apparently
within seconds, gametocytes are induced into "gametogenesis",
producing gametes. These gametes produce a cell-type called
"sporozoites", which accumulate in the salivary gland of the
mosquito, from where they are injected into the vertebrate blood
stream when the mosquito feeds on vertebrate blood. The
sporozoites accumulate in the vertebrate liver, where they
multiply and produce a form (merozoites) that invades red blood
cells, replicates, destroys red blood cells, and so on, with an
eventual decline in this asexual replication. However, after
invasion of red blood cells, some merozoites produce gametocytes,
which have the genomic potential for restarting the total life
cycle. These gametocytes cannot self-replicate, and they die
unless ingested by a mosquito, but once in the mosquito, the
total life cycle begins again. There are apparently 2 inducers of
gametogenesis in vivo (i.e., in the mosquito): one inducer is a
pH of 7.5 to 7.6, and the other inducer has been thought to be an
unknown mosquito-derived gametocyte-activating factor.
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ON MALARIAL MOSQUITOES AND MOSQUITO BITES
The following points are made by Stephen Budiansky (Science 2002
298:80):
1) After millions of years of coexistence, the lives of humans
and mosquitoes have become intricately intertwined. The
mosquito's ability to exploit almost any type of water -- natural
ponds and marshes or human creations such as irrigation ditches
and used tires -- is testimony to its evolutionary ingenuity To
say that the malaria-carrying mosquito Anopheles gambiae is well
adapted to its role as a human parasite is like saying that
Pavarotti is a pretty good singer.
2) An. gambiae, native to tropical Africa, is just one of about
60 anopheline mosquitoes throughout the world that can transmit
human malaria. But its unrelenting focus on human ways has made
it a prodigy as a disease vector. An. gambiae typically breed in
temporary, sunlit puddles and pools of a kind found in particular
near human habitations and usually directly associated with
humans' agricultural modification of the landscape: the water
that collects in irrigation ditches and even the small puddles
created where livestock have depressed the soil with their
hooves. Adult An. gambiae mosquitoes are commonly found
sheltering in huts during the heat of the day. At night they
emerge from their resting spots and, lured by the odor of human
feet and other scents, home in on their preferred prey.
3) The exquisite apparatus that the female employs to penetrate
the skin of its victim is less like a simple needle than one of
the complex devices surgeons snake through a body to perform
remote-control surgery. At the end of the mosquito's slender
proboscis are two pairs of cutting stylets that slide against one
another to slice through the skin -- like a pair of electric
carving knives. Once through the skin, the mosquito's proboscis
begins probing for a tiny blood vessel. If it does not strike one
on the first try, the mosquito will pull back slightly and try
again at another angle through the same hole in the skin. Inside
the proboscis are two hollow tubes, one that injects saliva into
the microscopic wound and one that withdraws blood. The
mosquito's saliva includes a combination of antihemostatic and
anti- inflammatory enzymes that disrupt the clotting process and
inhibit the pain reaction -- the better not to get swatted --
during the minute and a half or so while the insect is feeding.
(Only later does the leftover saliva provoke an allergic reaction
that often leaves the characteristic raised welt of the mosquito
bite.) Some researchers believe that the suite of enzymes
produced by particular species of mosquitoes is closely tailored
to the biochemistry of its chosen hosts. An. gambiae thus
probably produces enzymes that work best against the clotting and
inflammatory biochemical pathways of its preferred target:
humans.
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2. THE PATHOGENIC BASIS OF MALARIA
The following points are made by L.H. Miller et al (Nature 2002
415:673):
1) Millions of children die from malaria in Africa every year(1).
But the clinical outcome of an infection in a child depends on
many factors. These factors, often ill-defined, determine the
outcome in each child. The top priority must be disease
prevention because of the inability of the mothers to access or
afford optimal treatment, and the ever-evolving drug resistance.
Prevention may be effected through vector control such as
insecticide-treated bednets or through the development of
antimalarial vaccines.
2) Over the past 10 years, there have been several key shifts in
our understanding of what constitutes severe malaria, and these
shifts define the issues in pathogenesis that need to be explored
to develop better treatments for sick children. The first shift
is the increasing recognition that severe malaria is a disorder
that affects several tissues and organs, even when the most
marked manifestations may seem to involve a single organ such as
the brain. In particular, metabolic acidosis, often profound, has
been recognized as a principal pathophysiological feature that
cuts across the classical clinical syndromes of cerebral malaria
and severe malarial anaemia(2). It is the single most important
determinant of survival and leads directly to a common, but
previously poorly recognized, syndrome of respiratory
distress(3). In most cases, this is predominantly (but not
exclusively) a lactic acidosis(4). There are several causes of
lactic acidosis in children with severe malaria, from increased
production of lactic acid by parasites (through direct
stimulation by cytokines) to deceased clearance by the liver;
however, most important by far is probably the combined effects
of several factors that reduce oxygen delivery to tissues(5).
3) A key feature of the biology of Plasmodium falciparum is its
ability to cause infected red blood cells (RBCs) to adhere to the
linings of small blood vessels. Such sequestered parasites cause
considerable obstruction to tissue perfusion. In addition, in
severe malaria there may be marked reductions in the
deformability of uninfected RBCs. The pathogenesis of this
abnormality is not clear, but its strong correlation with
acidosis suggests that it may be involved in compromising blood
flow through tissues. Individuals affected with malaria are often
dehydrated and relatively hypovolemic, which potentially
exacerbates microvascular obstruction by reducing perfusion
pressure. The destruction of RBCs is also an inevitable part of
malaria, and anemia further compromises oxygen delivery.
4) The second and related shift in our concept of severe malaria
is the realization that there is no simple one-to-one correlation
between the clinical syndromes and the pathogenic processes.
Thus, severe anemia may arise from many poorly understood
mechanisms including acute hemolysis of uninfected RBCs and
dyserythropoiesis, as well as through the interaction of malarial
infection with other parasite infections and with nutritional
deficiencies. For many desperately sick children a simple "one
pathogen/one disease" model is not adequate, as bacteremia caused
by common pathogens may be present with acute malaria and may be
a factor in mortality. Even the rigorously defined syndrome of
cerebral malaria is used to describe children who have arrived at
the point of coma through different routes. In many of these
children, coma seems to be a response to overwhelming metabolic
stress rather than a primary problem in the brain. Such children
are often profoundly acidotic and may regain consciousness
remarkably quickly after appropriate resuscitation, suggesting
that cerebral malaria in this instance cannot be a consequence of
the classical histologic picture.
References (abridged):
1. Snow, R. W., Craig, M., Deichmann, U. & Marsh, K. Estimating
mortality, morbidity and disability due to malaria among Africa's
non-pregnant population. Bull. World Health Organ. 77, 624-640
(1999)
2. Marsh, K. et al. Indicators of life-threatening malaria in
African children. N. Engl. J. Med. 332, 1399-1404 (1995)
3. Taylor, T. E., Borgstein, A. & Molyneux, M. E. Acid-base
status in paediatric Plasmodium falciparum malaria. Q. J. Med.
86, 99-109 (1993)
4. English, M. et al. Deep breathing in children with severe
malaria: indicator of metabolic acidosis and poor outcome. Am. J.
Trop. Med. Hyg. 55, 521-524 (1996)
5. English, M. et al. Acidosis in severe childhood malaria. Q. J.
Med. 90, 263-270 (1997)
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3. THE ECONOMIC AND SOCIAL BURDEN OF MALARIA
The following points are made by J. Sachs and P. Malaney (Nature
2002 415:680):
1) Long before economists attempted to estimate the costs of
malaria, natural selection had already demonstrated the
phenomenal burden of the disease. Certain genetic polymorphisms,
such as sickle cell trait, were selected for because of their
protective effect against malaria when inherited from one parent,
even though the same allele inherited from both parents is fatal.
In essence, the chance of death from malaria was so high as to
justify welcoming a potentially fatal mutation into the gene
pool(1-3).
2) Given this evolutionary backdrop, it would indeed be
surprising if the economic and demographic toll of malaria were
not comparably dramatic. Sadly, malaria does little to
disappoint. The numbers are staggering: there are 300 to 500
million clinical cases every year, and between one and three
million deaths, mostly of children, are attributable to this
disease(4). Every 40 seconds a child dies of malaria, resulting
in a daily loss of more than 2,000 young lives worldwide. These
estimates render malaria the pre-eminent tropical parasitic
disease and one of the top three killers among communicable
diseases.
3) Although the last century witnessed many successful programs
at country level to eliminate the parasite, the world is now
facing a rapidly increasing disease burden(5). This has been
attributed to several causes, including population movements into
malarious regions, changing agricultural practices including the
building of dams and irrigation schemes, deforestation, the
weakening of public health systems in some poor countries, and
more speculatively, long-term climate changes such as more
pronounced El Nino cycles and global warming. Furthermore,
resistance to drugs and insecticides used to counter this disease
has been evolving in tandem with growing caseloads. With a
rapidly growing population in regions with high malaria
transmission, it has been estimated that in the absence of
effective intervention strategies the number of malaria cases
will double over the next 20 years(4).
4) The malaria burden is not evenly distributed. The global
pattern of malarial transmission suggests a disease centered in
the tropics, but with a reach into subtropical regions in five
continents. Attempts to eliminate or at least suppress the
disease have been an important public health story through much
of the last century. At malaria's furthest reaches, in temperate
zones characterized by strong seasonality and cold winters, these
attempts have been successful. Beyond any other factors, this
reflects the fact that the base case reproduction rate of malaria
is considerably lower in temperate regions than in the tropics,
so that moderately intensive efforts at vector control and case
management can lead to elimination of the disease. The remarkably
high transmission rates in sub-Saharan Africa also reflect the
particular capacity of Africa's main vector mosquitoes, the
Anopheles gambiae complex of species, with their remarkable
tendency towards human biting (anthropophily).
5. In summary: Where malaria prospers most, human societies have
prospered least. The global distribution of per-capita gross
domestic product shows a striking correlation between malaria and
poverty, and malaria-endemic countries also have lower rates of
economic growth. There are multiple channels by which malaria
impedes development, including effects on fertility, population
growth, saving and investment, worker productivity, absenteeism,
premature mortality and medical costs.
References (abridged):
1. Luria, S. E. 36 Lectures in Biology p. 439 (The MIT Press,
Cambridge, 1975)
2. Luzzatto, L. Genetics of red cells and susceptibility to
malaria. Blood 54, 961-976 (1979)
3. Hill, A. V. S. et al. Molecular analysis of the association of
HLA-B53 and resistance to severe malaria. Nature 360, 434-439
(1992)
4. Bremen, J. The ears of the hippopotamus: manifestations,
determinants, and estimates of the malaria burden. Am. J. Trop.
Med. Hyg. 64(1,2)S, 1-11 (2001)
5. World Health Organization. Factsheet No. 94 (World Health
Organization, Geneva, 1998)
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ON MALARIA IN AFRICA
The following points are made by L. H. Miller and B. Greenwood
(Science 2002 298:121):
1) The current focus of malaria control programs in Africa is
rightly on the management of sick children through early
treatment with effective antimalarial drugs. However, this cannot
be the final strategy. The two first-line drugs, chloroquine and
sulfadoxine/pyrimethamine (Fansidar), are no longer effective in
many parts of East Africa where chloroquine resistance
(introduced from Asia) is rampant. Combinations of new drugs may
help to slow the emergence and spread of resistant parasites (1),
but control strategies based on early treatment mean a never-
ending struggle to develop and deploy new drugs before the
Plasmodium malaria parasites become resistant to existing drugs.
Thus, the long-term control strategy must be to interrupt the
transmission of this parasite. Unfortunately, this will be
extremely difficult in parts of Africa where people may be bitten
as many as 1000 times a year by infected mosquitoes. Insecticide-
treated bed nets -- now being vigorously promoted in many parts
of Africa -- reduce bites from infected mosquitoes by as much as
90% (2). However, their effectiveness is already under threat as
a result of the emergence of pyrethroid resistance in Anopheles
funestus in Mozambique and in A. gambiae in agricultural areas of
West Africa (3). Household spraying with residual insecticides is
highly effective in reducing malaria in some parts of Africa, but
it is logistically demanding, costly, and may have adverse
environmental effects.
2) There are many ways to reduce malaria transmission, but none
can provide a complete block in transmission, particularly in the
highly endemic areas of Africa (4), and new approaches are
desperately needed (5). Publication of the Plasmodium falciparum
and Anopheles gambiae genomes represents a big step forward in
our search for new tools for controlling malaria. Combined
deployment of three strategies that each have the potential to
reduce malaria transmission by 90% -- drug treatment,
vaccination, and vector control -- should be sufficient to stop
transmission, even in highly endemic areas of Africa. We will
need to first test such strategies in areas with a low intensity
of transmission before attempting the challenging task of
preventing malaria transmission in the highly endemic areas of
Africa.
References (abridged):
1. N. J. White, Drug Resist. Updates 1, 3 (1998)
2. S. W. Lindsay, et al., Med. Vet. Entomol. 3, 263 (1989)
3. F. Chandre, et al., Bull. WHO 77, 230 (1999)
4. L. Molineaux, G. Gramiccia, The Garki Project (World Health
Organization, Geneva, Switzerland, 1980)
5. B. Greenwood and T. Mutabingwa, Nature 415, 670 (2002)
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ON THE EAST AFRICAN HIGHLANDS RESURGENCE OF MALARIA
The following points are made by S.I. Hay et al (Nature 2002
415:905):
1) The public health and economic consequences of Plasmodium
falciparum malaria are once again regarded as priorities for
global development. There has been much speculation on whether
anthropogenic climate change is exacerbating the malaria problem,
especially in areas of high altitude where P. falciparum
transmission is limited by low temperature(1-4). The
International Panel on Climate Change has concluded that there is
likely to be a net extension in the distribution of malaria and
an increase in incidence within this range(5).
2) The authors report they investigated long-term meteorological
trends in four high-altitude sites in East Africa, where
increases in malaria have been reported in the past two decades.
The authors demonstrate that temperature, rainfall, vapor
pressure and the number of months suitable for P. falciparum
transmission have not changed significantly during the past
century or during the period of reported malaria resurgence. A
high degree of temporal and spatial variation in the climate of
East Africa suggests further that claimed associations between
local malaria resurgences and regional changes in climate are
overly simplistic.
3) If climate has not changed at the four study sites, other
changes must have been responsible for the observed increases in
malaria. At Kericho, the evidence suggests that the control of
malaria implemented since the large epidemics of the 1940s has
failed recently because of a rise in antimalarial drug
resistance. Likewise, the resurgence of malaria in the Usambara
mountains of Tanzania has been linked to a rise in drug
resistance, casting doubt on the previous interpretation of local
changes in climate caused by deforestation. In southern Uganda,
epidemiological changes have been attributed to the shorter-term
climate phenomenon of El Nino, which is suggested to cause
changes in vector abundance. At Muhanga, both land use changes
and elevated temperatures have been proposed to have caused the
malaria increases. In other highland locations in Africa,
increases in malaria have been attributed to population migration
and the breakdown in both health service provision and vector
control operations. Economic, social and political factors can
therefore explain recent resurgences in malaria and other
mosquito-borne diseases with no need to invoke climate change.
4) In summary: The most parsimonious explanation for recent
changes in malaria epidemiology involves factors other than
climate change. The authors suggest that the more certain
climatologists become that humans are affecting global climates,
the more critical epidemiologists should be of the evidence
indicating that these changes affect malaria.
References (abridged):
1. Loevinsohn, M. E. Climatic warming and increased malaria
incidence in Rwanda. Lancet 343, 714-718 (1994).
2. McMichael, A. J., Haines, A., Sloof, R. & Kovats, S. Climate
Change and Human Health (World Health Organization, Geneva,
1996).
3. Epstein, P. R. et al. Biological and physical signs of climate
change: focus on mosquito-borne diseases. Bull. Am. Meteorol.
Soc. 79, 409-417 (1998).
4. Martens, P. How will climate change affect human health? Am.
Sci. 87, 534-541 (1999).
5. McCarthy, J. J., Canziani, O. F., Leary, N. A., Dokken, D. J.
& White, K. S. Climate change 2001: Impacts, Adaptation, and
Vulnerability -- Contribution of Working Group II to the Third
Assessment Report of the Intergovernmental Panel on Climate
Change (Cambridge Univ. Press, Cambridge, 2001).
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4. PROGRESS AND CHALLENGES FOR MALARIA VACCINES
The following points are made by T.L. Richie and A. Saul (Nature
2002 415:694):
1) Four species of malaria infect humans, which raises an initial
question of how many vaccines are needed. Studies in the 1950-
60s of sequential heterologous infections in malaria therapy
patients, such as Plasmodium vivax after Plasmodium
falciparum(1), and cross-species challenge experiments in the
1970s using the irradiated sporozoite vaccine(2) showed that
protection against several species will be difficult to achieve
with a single vaccine. Accordingly, species-specific vaccines for
P. falciparum and P. vivax -- the two parasites that contribute
most heavily to the malaria burden -- are being developed,
keeping open the possibility of combining the antigens into a
single formulation sometime in the future. Once successful
vaccines have been developed against P. falciparum and P. vivax,
it should be relatively straightforward to create similar
vaccines for Plasmodium malariae and Plasmodium ovale.
2) The P. falciparum parasite deserves particular attention
because of the variety and severity of disease syndromes that it
causes. Several risk groups are found among those living in
endemic areas who are subject to repeated P. falciparum
infections: infants and young children suffer particularly from
life-threatening anemia, older children from an induced coma(3),
and primagravida (first-time pregnancy) women from severe disease
related to placental sequestration(4). For each of these groups,
an anti-morbidity vaccine, possibly tailored to the underlying
pathophysiology, would be of great benefit. Malaria-naive
travelers, either crossing international borders or traveling
from malaria-free to malaria-endemic areas in their own
countries, constitute another risk group, and are susceptible to
severe disease after acquiring their first infection; for this
group, it is important to prevent malaria infection altogether.
3) Although practical considerations of both development and
production costs favor a single vaccine for P. falciparum, the
different risk groups and vaccine requirements have generated at
least three approaches for this species alone: an anti-infection
vaccine aimed at protecting malaria-naive travelers or residents
of low endemic areas from becoming infected; an anti-
disease/anti-mortality vaccine aimed at children, pregnant women
and migrants living in endemic areas; and an anti-mosquito-stage
vaccine aimed at preventing the transmission of malaria from one
person to another(5).
4) In summary: Malaria causes much physical and economic hardship
in tropical regions, particularly in communities where medical
care is rudimentary. Should a vaccine be developed, it is the
residents of these areas that stand to benefit the most. But the
vaccine, which has been promised to be "just round the corner"
for many years, remains elusive. It is important to ask why this
is so, when effective vaccines exist for many other infectious
diseases. What are the reasons for the slow rate of progress, and
what has been learned from the first clinical trials of candidate
malaria vaccines? What are the remaining challenges, and what
strategies can be pursued to address them? On the assumption that
at least some antimalarial vaccines will be efficacious, when can
we expect the vaccine? Even under the most optimistic scheme of
unlimited resources, it will still be many years from now,
requiring iterative testing of improved combinations and
formulations until sufficient efficacy is obtained. In the
meantime there is much to do to ensure that when the vaccines are
available, health infrastructures are in place to deliver
integrated programs that will use the vaccines effectively. That
may be as much of a challenge as the vaccine itself.
References (abridged):
1. Jeffery, G. M. Epidemiological significance of repeated
infections with homologous and heterologous strains and species
of Plasmodium. Bull. World Health Organ. 35, 873-882 (1966)
2. Clyde, D. F. Immunity to falciparum and vivax malaria induced
by irradiated sporozoites: a review of the University of Maryland
studies, 1971-75. Bull. World Health Organ. 68 (Suppl.), 9-12
(1990)
3. Marsh, K. & Snow, R. W. Malaria transmission and morbidity.
Parasitologia 41, 241-246 (1999)
4. Ricke, C. H. et al. Plasma antibodies from malaria-exposed
pregnant women recognize variant surface antigens on Plasmodium
falciparum-infected erythrocytes in a parity-dependent manner and
block parasite adhesion to chondroitin sulfate A. J. Immunol.
165, 3309-3316 (2000)
5. Carter, R., Mendis, K. N., Miller, L. H., Molineaux, L. &
Saul, A. Malaria transmission-blocking vaccines--how can their
development be supported? Nature Med. 6, 241-244 (2000)
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IN VITRO DEVELOPMENT OF MALARIA MOSQUITO
The following points are made by E.M. Al-Olayan et al (Science
2002 295:677):
1) For over a century, a major objective of malaria control
programs has been to block parasite transmission by mosquitoes.
Such approaches would clearly benefit from a better understanding
of parasite development within the vector, initiated when
gametocytes are taken up in a blood meal. Fertilization of
macrogametes within the mosquito midgut produces zygotes that
transform into motile and invasive ookinetes. These penetrate and
traverse the midgut epithelium and become sessile vegetative
oocysts lying beneath the midgut basement lamina, each
potentially producing 2 to 8000 sporozoites. Knowledge of the
mosquito-related factors regulating these processes is improving,
but it is difficult to determine the specific and separate
effects of these factors in vivo. Early events associated with
midgut invasion have recently been studied in vitro with the use
of midgut preparations or co-cultured mosquito cells, but these
systems do not sustain long-term development or simulate oocyst
interaction with the basal lamina and do not permit investigation
of sporozoite differentiation.
2) Fertilization and ookinete development can be achieved in
vitro for many malaria parasite species, including Plasmodium
berghei, a parasite of rodents. These culture systems have
facilitated the study of ookinete molecules that may be targeted
by antibodies induced by transmission-blocking vaccines or drugs.
After many pioneering attempts, it is only recently that in vitro
transformation of Plasmodium gallinaceum and Plasmodium
falciparum ookinetes into oocysts and sporozoites has been
achieved, but the numbers of oocysts produced are low and, more
importantly, the infectivity of these sporozoites has not been
demonstrated.
3) The authors report they have cultured gametocytes of
Plasmodium berghei through to infectious sporozoites with
efficiencies similar to those recorded in vivo and without the
need for salivary gland invasion. Oocysts developed
extracellularly in a system whose essential elements include co-
cultured Drosophila S2 cells, basement membrane matrix, and
insect tissue culture medium. Sporozoite production required the
presence of para-aminobenzoic acid. Thus the entire life cycle of
P. berghei, a useful model malaria parasite, can now be achieved
in vitro, and the authors suggest this immediately opens up
important new areas of investigation.
References (abridged):
1. P. F. Billingsley and R. E. Sinden, Parasitol. Today 13:297
(1997)
2. A. Ghosh, M. J. Edwards, M. Jacobs-Lorena, Parasitol. Today
16:196 (2000)
3. R. E Sinden and P. F. Billingsley, Trends Parasitol. 17:209
(2001)
4. M. Shahabuddin and P. F. Pimenta, Proc. Nat. Acad. Sci.
95:3385 (1998)
5. H. Zieler and J. A. Dvorak, Proc. Nat. Acad. Sci. 97:11516
2000)
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5. THE ANOPHELES GENOME AND COMPARATIVE INSECT GENOMICS
The following points are made by T.C. Kaufman et al (Science 2002
298:97):
1) The Phylum Arthropoda is the most species-rich and
morphologically diverse animal group on the planet. Since their
appearance in the Early Cambrian and their subsequent radiation,
arthropods have come to inhabit and dominate the vast majority of
ecological habitats. From the many different arthropod groups
that existed in the Early Cambrian, only four have survived to
the present: the Chelicerata, Myriapoda, Crustacea, and Insecta.
Members of these four groups plague us, transmit diseases,
benefit us, and feed us. The genome sequence of the African
malaria vector, the mosquito Anopheles gambiae, recently reported
(1), coupled with the Drosophila melanogaster genome sequence
(2), provides us with new insights into the genetic makeup of two
members of the Insecta, arguably the dominant group of
arthropods.
2) The genome sequences of A. gambiae and Plasmodium falciparum,
the malaria parasite it transmits (3,4), will yield fresh
insights into parasite and vector biology that will lead to more
efficient disease control strategies. A new approach to vector-
borne disease control based on the genetic manipulation of the
mosquito has already received considerable attention (5). The A.
gambiae genome sequence will accelerate efforts to identify
molecules that can inhibit parasite development in the vector and
subsequently prevent transmission to humans. Stable germline
transformation has been demonstrated for several vector
mosquitoes. This is encouraging news given that transgenic
anopheline mosquitoes engineered to express an anti-Plasmodium
molecule turn out to be inefficient vectors for disease
transmission in the laboratory.
3) Of the ~3500 mosquito species, molecular information exists
for only a small number, and even this is limited. The Anopheles
sequence will facilitate elucidation of biological processes
unique to mosquitoes, including genes and pathways associated
with blood feeding, host-seeking behavior, and immune responses
to pathogens. Comparison of orthologous genes should help to
illuminate the crucial and vexing issue of interspecific
variability in vector competence. Why is one species of mosquito
a fully competent vector for a given pathogen, whereas another is
completely refractory to infection?
4) The Anopheles genome sequence forms the foundation for
comparative genomic analyses across mosquito species. A. gambiae
represents the subfamily Anophelinae, which contains the primary
vectors of malaria parasites. But it is the subfamily Culicinae
that contains the majority of mosquito species, including the
primary vectors of several emerging or reemerging arbovirus
diseases (yellow fever, dengue fever, and West Nile encephalitis)
and also of lymphatic filariasis. These two mosquito subfamilies
appear to differ significantly in genomic structure -- gene order
conservation between A. gambiae and the culicine mosquito Aedes
aegypti (the primary vector of yellow and dengue fever viruses)
is characterized by extensive local rearrangements within
chromosomal arms. This is similar for the Drosophila and
Anopheles genomes, which show conservation of whole chromosome
arms but considerable local rearrangement within arms.
References (abridged):
1. R. A. Holt, et al., Science 298, 129 (2002)
2. M. D. Adams, et al., Science 287, 2185 (2000)
3. S. L. Hoffman, G. M. Subramanian, F. H. Collins, J. C. Venter,
Nature 415, 702 (2002)
4. World Health Organization, The World Health Report 2000,
Health Systems: Improving Performance (World Health Organization,
Geneva, 2000)
5. B. J. Beaty, Proc. Natl. Acad. Sci. U.S.A. 97, 10295 (2000)
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6. EARLY ORIGIN AND RECENT EXPANSION OF PLASMODIUM FALCIPARUM
The following points are made by D.A. Joy et al (Science 2003
300:318):
1) Estimating the timing of historical demographic events is
central to resolving the question of P. falciparum age and
genetic diversity. Recently it has been hypothesized, on the
basis of an analysis of polytene chromosomes in the mosquito
vector, that the African parasite population expanded
dramatically ~6000 years ago due to a series of changes involving
the emergence of agricultural societies and increased mosquito
transmission to humans (1,2). A related hypothesis ("Malaria's
Eve") posits that the worldwide parasite population is only ~6000
years old, either as a result of a severe bottleneck or because
the population was chronically small until that time (3,4).
Furthermore, a previous study of parasite mitochondrial (mt) DNA
supports a recent origin (5). However, this view has been
challenged by recent findings that suggest the current population
is much older (100,000 to 400,000 years).
2) The emergence of virulent Plasmodium falciparum in Africa
within the past 6000 years as a result of a cascade of changes in
human behavior and mosquito transmission has recently been
hypothesized. The authors provide genetic evidence for a sudden
increase in the African malaria parasite population about 10,000
years ago, followed by migration to other regions on the basis of
variation in 100 worldwide mitochondrial DNA sequences. However,
both the world and some regional populations appear to be older
(50,000 to 100,000 years old), suggesting an earlier wave of
migration out of Africa, perhaps during the Pleistocene migration
of human beings.
References (abridged):
1. M. Coluzzi, Parassitologia 41, 277 (1999)
2. M. Coluzzi, A. Sabatini, A. della Torre, M. A. Di Deco, V.
Petrarca, Science 298, 1415 (2002)
3. S. M. Rich, M. C. Licht, R. R. Hudson, F. J. Ayala, Proc.
Natl. Acad. Sci. U.S.A. 95, 4425 (1998)
4. S. K. Volkman, et al., Science 293, 482 (2001)
5. D. J. Conway, et al., Mol. Biochem. Parasitol. 111, 163 (2000)
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7. ON INSECTICIDE RESISTANCE
The following points are made by J. Hemingway et al (Science 2002
298:96):
1) The introduction of DDT for control of the mosquito vector of
malaria in the late 1940s, and the early eradication of malaria
from the periphery of its transmission range by residual house
spraying with this insecticide, led directly to the malaria
eradication campaign of the 1960s backed by the World Health
Organization. At the end of the 1960s, the concept of eradication
was formally dropped in favor of sustainable control, largely
because insecticide resistance was being selected for among the
mosquito species that transmit malaria. There has recently been a
resurgence in antimalarial activities with the Roll Back Malaria
initiative and Global Fund for Health, which support extensive
use of pyrethroid-impregnated bed nets for mosquito-control
campaigns in Africa and other malaria-endemic regions. It is not
clear how much the current large-scale pyrethroid resistance of
mosquitoes in West Africa will affect these efforts, and what
will replace the pyrethroid-treated nets if selection of
multiresistance mechanisms results in widespread failure of this
strategy (1).
2) Genomics will play an increasingly important part in the
development of new malaria control tools. Comparing the genomes
of the malaria vector Anopheles gambiae and of the fruit fly
Drosophila melanogaster will not only yield new hormonal,
neuronal, and regulatory molecular targets for the development of
new classes of insecticides, but will also allow us to attack
existing insecticide resistance and to boost the life-span of
currently available insecticides.
3) The resistant phenotype -- an insect that survives a dose of
insecticide that would normally have killed it -- is relatively
easy to monitor with direct insecticide bioassays. However, in
many cases the actual molecular mechanisms responsible for the
resistant phenotypes are still unknown. The availability of the
A. gambiae genome will allow us to determine the exact molecular
changes that have resulted in resistant phenotypes. For example,
up-regulation of one or more members of the cytochrome P450 gene
families can produce broad-spectrum insecticide resistance.
Currently, the mechanisms that regulate insecticide resistance
are poorly understood. Drosophila may not be a good model in this
respect because it is not an insect pest, and so is not subjected
directly to large-scale insecticide control programs. In
contrast, A. gambiae has multiple resistance mechanisms that have
been field-selected in both East and West Africa through exposure
to DDT and pyrethroids (2,3).
4) Research into insecticide resistance is obviously ripe for the
move from the static genome map to the functional genomics
approach, which will allow us to understand the evolution of
resistance in these complex organisms through modulation of gene
expression. Material from East Africa has already been subjected
to standard genetic quantitative trait loci (QTL) mapping, which
has defined a polytene chromosome region within which the
regulator of P450 gene expression must be encoded (4). The
availability of the A. gambiae genome sequence now allows us to
use new molecular microsatellite markers from the sequence to
narrow down this control region to a few kilobases of DNA. Open
reading frames can then be identified and candidate genes
analyzed for function with recently developed anopheline
transformation technology. Regulatory genes controlling the
expression of glutathione transferases (enzyme families that are
important for protecting insect cells from insecticides) will be
similarly defined from QTLs that are already mapped to the A.
gambiae polytene chromosomes.(5)
References (abridged):
1. C. F. Curtis, et al., Philos. Tran. R. Soc London Ser. B. 353,
1769 (1998)
2. H. Ranson, et al., Insect Mol. Biol. 9, 499 (2000)
3. F. Chandre, et al., Bull. WHO 77, 230 (1999)
4. H. Ranson, et al., Insect Mol. Biol. 11, 409 (2002)
5. R. L. Blackman, et al., Heredity 82, 80 (1999)
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8. ON PLASMODIUM CHLOROQUINE RESISTANCE
Chloroquine is a synthetic quinolene antimalarial drug with
action similar to quinine. It accumulates in the cells of the
malaria parasites, prevents digestion of host hemoglobin, and may
also disrupt parasite ribonucleotide metabolism.
The following points are made by Thomas E. Wellems (Science 2002
298:124):
1) The discovery of chloroquine and its subsequent worldwide use
against malaria in the 20th century produced one of the greatest
public health advances ever achieved by a drug against an
infectious disease. Chloroquine's efficacy, affordability, easy
administration, and low toxicity led to marked reductions in
morbidity and mortality across the Americas, Africa, Asia, and
Oceania. Chloroquine remained effective for decades. Despite its
distribution in massive quantities (including distribution in the
salt supplies of some countries), many years passed before
chloroquine resistance (CQR) began to spread.
2) Plasmodium falciparum, the most malignant of the four human
malaria parasite species, showed foci of CQR in Southeast Asia
and South America in the late 1950s, Papua New Guinea in the
1960s, and East Africa in the late 1970s. The steady and
unremitting spread of CQR from these foci could only be met by a
few alternative drugs, all of which were more expensive,
encountered resistance problems of their own, or were less safe
and more difficult to use than chloroquine itself. Morbidity and
mortality from P. falciparum malaria consequently resurged,
especially among children in Africa (1).
3) Malaria caused by Plasmodium vivax, second only to P.
falciparum malaria in its impact on health and economic
development, remained responsive to chloroquine everywhere until
a little over a decade ago, when chloroquine-resistant P. vivax
began to spread in Southeast Asia and probably South America (2).
Chloroquine-resistant Plasmodium malariae was also reported
recently in Indonesia (3). Of the four human malaria parasite
species, only P. ovale remains without reports of CQR.
4) The acute need for a replacement drug having the advantages
and efficacy that once characterized chloroquine is a driving
priority for malaria research. Success depends on the selection
of appropriate drug targets, identification of good drug
candidates that hit these targets with specific and prompt
action, and stable and continued susceptibility of these targets
when they are under therapeutic pressure. Fortunately, these
efforts are being supported by new research partnerships and are
beginning to benefit from modern tools of biomedical and
pharmaceutical discovery. Genomics and proteomics studies have
been receiving a particularly strong boost from results of the P.
falciparum genome sequencing project.(4,5)
References (abridged):
1. J. F. Trape, Am. J. Trop. Med. Hyg. 64, 12 (2001)
2. T. Nomura, et al., J. Infect. Dis. 183, 1653 (2001)
3. J. D. Maguire, et al., Lancet 360, 58 (2002)
4. M. J. Gardner, et al., Nature 419, 498 (2002)
5. A. Dorn, et al., Biochem. Pharmacol. 55, 727 (1998)
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9. ON THE MALARIAL PARASITE GENOME
The term "apicoplast" refers to a recently discovered organelle
of apicomplexan parasites such as the malarial parasites. The
organelle harbors its own genome of probably secondary
endosymbiotic chloroplast origin.
The following points are made by Dyann F. Wirth (Nature 2002
419:495):
1) The malaria parasite leads a complicated life, existing mainly
inside liver cells and red blood cells in its human host and,
when residing in mosquitoes (notably Anopheles gambiae), being
associated with the insect's gut and salivary glands. It
undergoes several transformations along the way. The stages of
its life cycle were originally described more than 100 years ago
and were given names based on morphology, such as merozoite,
trophozoite and gametocyte (in humans), and zygote, ookinete and
sporozoite (in mosquitoes). One of the most curious features of
the human stages is the human immune response -- there is much
immune activity, but this does not control the infection
effectively, nor afford protection against future infections.
2) Despite massive efforts to eradicate the disease in the 1950s
and early 1960s, more people are infected with malaria in Africa
today than at any other time in history. Over 500 million people
are infected with the disease worldwide, and one-quarter of the
population is at risk of infection. More than a million children
die of malaria each year, mostly in Africa. And those individuals
who survive suffer a combination of anaemia and immune
suppression that leaves them vulnerable to other fatal illnesses.
Alarmingly, drug resistance in the parasite is now widespread.
3) One notable feature of the parasite's genome(1) is the
apparent absence of genes for proteins that, in other species,
are key to metabolism and the energetics of mitochondria --
cellular powerhouses, which produce the energy-storing molecule
ATP. For example, the P. falciparum genome consortium found no
predicted genes for two protein components of ATP synthase, a
mitochondrial ATP-producing enzyme. (At present, many of the
genes are only "predicted": they have been identified by gene-
searching algorithms, but have not yet been confirmed as bona
fide genes.) Similarly, there are apparently no genes for
components of a conventional NADH dehydrogenase complex, another
key mitochondrial enzyme. Perhaps P. falciparum generates and
stores energy by using novel proteins or mechanisms -- potential
drug targets. That the mitochondria are active, at least in
sporozoites and gametocytes, seems likely, given that the
proteomics analyses(3) detected fragments of enzymes involved in
some typical mitochondrial processes, including the
tricarboxylic-acid cycle and oxidative phosphorylation.
4) Also interesting is the number of predicted genes -- some 10%
-- that encode proteins associated with the apicoplast(1). This
essential cellular compartment is known to be important for the
biosynthesis of fatty acids and isoprenoids, components of many
membrane proteins, and for iron metabolism. But analysis of these
genes should reveal other possible functions, and so new drug
targets. The genome sequence also identifies the molecules within
the apicoplast that are the targets of several existing drugs.
5) The complex life cycle of P. falciparum means that the
parasite has had to adapt to several different environments. So
it is also intriguing that, compared with the genome of the free-
living budding yeast, the parasite genome(1) encodes a limited
number of predicted transporter proteins for the active uptake of
nutrients from the environment. In fact, entire classes of
transporters seem to be missing. It may be that several genes in
this class have been overlooked because they are made up of many
small coding regions, which can be missed by gene-prediction
algorithms. But, taken at face value, this surprising finding
implies that adequate amounts of nutrients recognized by the
transporters must be present at all stages of the parasite life
cycle, so that there is no selective advantage in having many
transporters with differing substrate specificities.
Alternatively, the parasite may use previously identified pores
or channels to acquire nutrients.(1-5)
References (abridged):
1. Gardner, M. J. et al. Nature 419, 498-511 (2002)
2. Carlton, J. M. et al. Nature 419, 512-519 (2002)
3. Florens, L. et al. Nature 419, 520-526 (2002)
4. Hall, N. et al. Nature 419, 527-531 (2002)
5. Gardner, M. J. et al. Nature 419, 531-534 (2002)
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10. MALARIA IN BRITAIN: PAST, PRESENT, AND FUTURE
The following points are made by K.G Kuhn et al (Proc. Nat. Acad.
Sci. 2003 11 Aug. 10.1073/pnas1233687100):
1) The British Chief Medical Officer’s recent report asserted
that "by 2050 the climate of the UK may be such that indigenous
malaria could become re-established". This prediction was based
on model simulations derived from only a subset of the possible
links between climate and malaria. To be confident in future
predictions, we first need to understand the past by quantifying
the factors that governed the disappearance of malaria from
Britain.
2) From historical records, we know that a malarious illness
referred to as "the ague" or "intermittent fever" caused high
levels of mortality in the British marshlands and fens from the
15th to the 19th century. Robust evidence that the illness was
malaria emerged in the early 19th century, when the increasing
use of quinine and advances in fever diagnosis and pathology
created a distinct separation from other acute fevers.
Definitions of ague in 19th-century medical textbooks uniquely
indicate malaria, since they invariably refer to noncontagious
transmission, distinctive cold, hot, and sweating stages, tertian
onset of symptoms, cycling relapses, anemia, splenomegaly or
"ague cake", and susceptibility to quinine.
3) The remarkable virulence of this disease in England, given
that the pathogen responsible was presumably Plasmodium vivax,
has never been explained satisfactorily. The situation in Britain
was not unique. In Holland at the end of the 19th century,
equally high death rates were reported from intermittent fevers,
believed to be caused by P. vivax. Although currently responsible
for 80 million annual cases of malaria worldwide, P. vivax is not
now a lethal parasite. One possible explanation for the high
malaria mortality rates observed in 19th-century Europe is the
high likelihood of coinfections with pathogens associated with
poor sanitation.
4) In summary: There has been much recent speculation that global
warming may allow the reestablishment of malaria transmission in
previously endemic areas such as Europe and the United States.
The authors report they analyzed temporal trends in malaria in
Britain between 1840 and 1910 to assess the potential for
reemergence of the disease. The authors report the results
demonstrate that at least 20% of the drop-off in malaria was due
to increasing cattle population and decreasing acreages of marsh
wetlands. Although both rainfall and average temperature were
associated with year-to-year variability in death rates, there
was no evidence for any association with the long-term malaria
trend. Model simulations for future scenarios in Britain suggest
that the change in temperature projected to occur by 2050 is
likely to cause a proportional increase in local malaria
transmission of 8 to 14%. The authors suggest that the current
risk is negligible, as >52,000 imported cases since 1953 have not
led to any secondary cases. The authors suggest that the
projected increase in proportional risk is clearly insufficient
to lead to the reestablishment of endemicity.
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ON THE GLOBAL SPREAD OF MALARIA IN A FUTURE WARMER WORLD
The following points are made by D.J. Rogers and S.E. Randolph
(Science 2000 289:1763):
1) The authors point out that predictions of global climate
change have stimulated forecasts that *vector-borne diseases will
spread into regions that are at present too cool for their
persistence. For example, life-threatening cerebral malaria,
caused by P. falciparum transmitted by anopheline mosquitoes, is
predicted to reach the central or northern regions of Europe and
large parts of North America. Despite the high incidence and
large number of deaths each year caused by malaria, like many
other vector-borne diseases, the epidemiology of malaria remains
inadequately understood. Only the most general of maps for its
worldwide distribution are available, and its global transmission
patterns cannot be modeled satisfactorily because crucial
parameters and their relations with environmental factors have
not yet been quantified. Most importantly, absolute mosquito
abundance has not yet been related to multivariate climate.
2) The authors point out that the frequent warnings that global
climate change will allow falciparum malaria to spread into
northern latitudes, including Europe and large parts of the US,
are based on biological transmission models driven principally by
temperature. The authors report they have assessed these models
for their value in predicting present, and therefore future,
malaria distribution. In the alternative statistical approach of
the authors, the recorded present-day global distribution of
falciparum malaria was used to establish the current multivariate
climate constraints. The authors report that when these results
were applied to future climate scenarios to predict future
distributions, model malaria distributions exhibited remarkably
few changes from the present distribution, even under the most
extreme scenarios.
3) The authors conclude: "The quantitative model presented here
contradicts prevailing forecasts of global malaria expansion. It
highlights the use of multivariate rather than univariate
constraints in such applications, and the advantage of
statistical rather than biological approaches in situations where
biological knowledge is incomplete. Whatever the method adopted,
the usefulness of global circulation models as a basis for making
predictions about the future of biological systems needs further
clarification. The current low spatial resolution of such models
hides considerable local variation and represents mean conditions
across large geographical areas, conditions that may not occur in
many places within them. Furthermore, the accuracy of global
circulation models in predicting covariation of climate
variables, to which biological systems are very sensitive, is
unknown."
--------------------------------
Notes:
morbidity and mortality: In general, "morbidity" refers to a
diseased state; in particular, the term refers to the ratio of
the diseased population to the well population in a community.
The term "mortality", in contrast, refers to the number of deaths
from the disease.
vector-borne diseases: In this context, the term "vector-borne"
refers to a disease or infection transmitted by an invertebrate
carrier (vector).
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