EHP Library Malaria Bulletin 41 – July 19-Aug 4, 2002
Molecular Approaches to Malaria 2004 (MAM2004)
1st - 5th February 2004, Lorne, Australia
- First Announcement -
The Organising Committee and the International Steering Committee is
pleased to announce the 'Molecular Approaches to Malaria 2004'
conference which will be held in Australia 1st-5th February 2004.
MAM2004 will provide a forum for the presentation of recent advances in
malaria research, focussing on molecular insights and approaches to
illuminate a variety of areas including pathogenesis, sexual stage
parasite development, drug design, bioinformatics, genomics, proteomics
and progress toward a malaria vaccine.
The meeting will be held in the same location and at the same time of
year (mid-summer) as the successful MAM2000 meeting that attracted
almost 300 delegates from around the world. Situated in the delightful
beach resort town of Lorne, on The Great Ocean Road, just 2 hours drive
south west of Melbourne, the venue has recently undergone extensive
renovations and provides high standard accommodation and conference
facilities situated in an idyllic beach setting.
For further information, visit our conference website regularly:
We look forward to welcoming you all in Lorne.
Dr. Brian M. Cooke
Molecular & Cellular Rheology Laboratory
Department of Microbiology
P.O. Box 53
Victoria 3800 Tel: IDD+ 61 3 9905 4827
Australia Fax: IDD+ 61 3 9905 4811
Social sciences and malaria
The Partnership for Social Sciences in Malaria Control (PSSMC) is happy to
Announce the creation of a website for its Social Science and Malaria Literature
Citation Database. One of the objectives of the PSSMC was to establish a clearinghouse
for social science and malaria literature.
So far we have over 500 data entries of published and unpublished papers,
technical reports, and oral/poster presentations from regional, national and international
meetings. This citation database can now be accessed from the Malaria Foundation's
website at www.malaria.org http://www.malaria.org scroll to the bottom of the page and click on the PSSMC logo.
We would love to include your paper, or presentation in this citation
database. If you or anyone you know has any social science and malaria research
papers, technical reports or presentations and would like to have it included in this citation database please kindly send me an email either with a copy of your paper or the citation reference.
Please be advised that, at this time, we are currently focused on social science and malaria research in Sub Saharan Africa only!!!!
We strongly encourage you to send in unpublished papers such as thesis,
which are often the most difficult to access. Please include the information below as it applies to your paper
Name of author
Title of Paper
Year/month/date of Publication
Name of Conference
Year of Conference
Location of Conference
Feel free to send me an email with any questions
Thanks in advance for your participation and contribution
Research Assistant - PSSMC
Malaria Epidemiology Branch
Centers for Disease Control
Mail Stop F-22
4770 Buford Hwy, NE
Atlanta, GA 30341
email: [email protected]
Soc Sci Med 2002 Aug;55(3):403-13
Medical syncretism with reference to malaria in a Tanzanian community.
Muela SH, Ribera JM, Mushi AK, Tanner M.
Swiss Tropical Institute, Department of Public Health and Epidemiology, Basel.
What happens when new health information is introduced into a community? We have
explored this question in a semi-rural community of Southeastern Tanzania whose
population has been in contact with biomedicine for many decades. With the
example of malaria, we illustrate how biomedical knowledge transmitted in health
messages coexists, interacts and merges with local pre-existing ideas and
logics. The results are syncretic models, which may deviate considerably from
what health promoters intended to transmit. Some of those may have implications
for treatment of malaria, which may include delay in seeking treatment and
non-compliance with therapy. Analysing this medical syncretism clearly
demonstrates that even if comprehension of health messages is accurate, the way
in which people interpret these messages may not be. Disentangling syncretic
processes permits us to understand the dynamics of how information is processed
by the recipients, and provides orientations for health promoters for adapting
messages to the local context.
Health Policy Plan 2002 Sep;17(3):225-34
The emergence of global disease control priorities.
Shiffman J, Beer T, Wu Y.
Department of Public Administration, The Maxwell School of Syracuse University,
Syracuse, NY, USA.
How do global disease control priorities emerge? This paper examines the
post-World War II histories of efforts to control three diseases - polio,
malaria and tuberculosis - to investigate this issue. The paper draws from the
policy studies literature to evaluate three models of the priority generation
process. A rational model suggests logical selection based on global burden and
the availability of cost-effective interventions. An incremental model suggests
a drawn out process in which health priorities emerge gradually and
interventions reach affected populations through slow diffusion. A punctuated
equilibrium model suggests a more complex pattern: long periods of stability
during which interventions are available only to select populations, punctuated
by bursts of attention as these interventions spread across the globe in
concentrated periods of time. The paper finds that the punctuated equilibrium
model corresponds most closely to efforts to control these three diseases.
Bursts are associated with the convergence of three conditions: the widespread
acceptance of the disease as a threat; a perception that human interventions can
control disease transmission; and the formation of a transnational coalition of
health actors concerned with fighting the disease. The generation of each
condition requires considerable groundwork, the reason for long periods of
stability. Initiatives take off rapidly when the conditions couple, the reason
for bursts. The paper aims to spark additional research on the subject of global
disease control agenda setting, a neglected issue in the health policy
J Physiol 2002 Aug 1;542(Pt 3):795-801
A stretch-activated anion channel is up-regulated by the malaria parasite
Egee S, Lapaix F, Decherf G, Staines HM, Ellory JC, Doerig C, Thomas SL.
Centre National de la Recherche Scientifique, UPR 9042, Station Biologique,
Place G.Teissier, B. P. 74, 29682 Roscoff cedex, France.
A recent study on malaria-infected human red blood cells (RBCs) has shown
induced ion channel activity in the host cell membrane, but the questions of
whether they are host- or parasite-derived and their molecular nature have not
been resolved. Here we report a comparison of a malaria-induced anion channel
with an endogenous anion channel in Plasmodium falciparum-infected human RBCs.
Ion channel activity was measured using the whole-cell, cell-attached and
excised inside-out configurations of the patch-clamp method. Parasitised RBCs
were cultured in vitro, using co-cultured uninfected RBCs as controls.
Unstimulated uninfected RBCs possessed negligible numbers of active anion
channels. However, anion channels could be activated in the presence of protein
kinase A (PKA) and ATP in the pipette solution or by membrane deformation. These
channels displayed linear conductance (~15 pS), were blocked by known anion
channel inhibitors and showed the permeability sequence I(-) > Br(-) > Cl(-). In
addition, in less than 5 % of excised patches, an outwardly rectifying anion
channel (~80 pS, outward conductance) was spontaneously active. The host
membrane of malaria-infected RBCs possessed spontaneously active anion channel
activity, with identical conductances, pharmacology and selectivity to the
linear conductance channel measured in stimulated uninfected RBCs. Furthermore,
the channels measured in malaria-infected RBCs were shown to have a low
open-state probability (P(o)) at positive potentials, which explains the inward
rectification of membrane conductance observed when using the whole-cell
configuration. The data are consistent with the presence of two endogenous anion
channels in human RBCs, of which one (the linear conductance channel) is
up-regulated by the malaria parasite P. falciparum.
Malar J 2002 Jun 21;1(1):8
Advantages of larval control for African malaria vectors: Low mobility and
behavioural responsiveness of immature mosquito stages allow high effective
Killeen GF, Fillinger U, Knols BG.
Department of Tropical Medicine, School of Public Health and Tropical Medicine,
Tulane University Health Sciences Centre, 1430 Tulane Avenue, New Orleans,
Louisiana 70112, USA. [email protected]
BACKGROUND: Based on sensitivity analysis of the MacDonald-Ross model, it has
long been argued that the best way to reduce malaria transmission is to target
adult female mosquitoes with insecticides that can reduce the longevity and
human-feeding frequency of vectors. However, these analyses have ignored a
fundamental biological difference between mosquito adults and the immature
stages that precede them: adults are highly mobile flying insects that can
readily detect and avoid many intervention measures whereas mosquito eggs,
larvae and pupae are confined within relatively small aquatic habitats and
cannot readily escape control measures. PRESENTATION OF THE HYPOTHESIS: We
hypothesize that the control of adult but not immature mosquitoes is compromised
by their ability to avoid interventions such as excito-repellant insecticides.
TESTING THE HYPOTHESIS: We apply a simple model of intervention avoidance by
mosquitoes and demonstrate that this can substantially reduce effective
coverage, in terms of the proportion of the vector population that is covered,
and overall impact on malaria transmission. We review historical evidence that
larval control of African malaria vectors can be effective and conclude that the
only limitations to the effective coverage of larval control are practical
rather than fundamental. IMPLICATIONS OF THE HYPOTHESIS: Larval control
strategies against the vectors of malaria in sub-Saharan Africa could be highly
effective, complementary to adult control interventions, and should be
prioritized for further development, evaluation and implementation as an
integral part of Rolling Back Malaria.
Malar J 2002 Jul 9;1(1):9
Research that influences policy and practice - characteristics of operational
research to improve malaria control in Mpumalanga Province, South Africa.
Durrheim DN, Speare R, Harries AD.
Director, World Health Organization Lymphatic Filariasis Collaborating Centre,
and Professor, School of Public Health and Tropical Medicine, James Cook
University, Townsville, 4811, Australia. [email protected]
BACKGROUND: Much communicable disease control research has had little impact on
local control programme policy and practice for want of an operational
component. The operational research model - the systematic search for knowledge
on interventions, tools or strategies that enhance programme effectiveness - is
gaining recognition as an appropriate method for addressing perplexing questions
within public health programmes. METHODS: A series of operational research
studies were conducted to refine malaria diagnosis in Mpumalanga Province, South
Africa between 1995 and 1999. The grounded theory approach was used with groups
of experienced Masters of Public Health students in South Africa and Australia
to analyse a compilation of these studies for determining positive and negative
attributes of operational research that affect its ability to influence
communicable disease control policy and practice. RESULTS: The principal
positive attributes of the operational research studies were high local
relevance, greater ability to convince local decision-makers, relatively short
lag-time before implementation of findings, and the cost-effective nature of
this form of research. Potential negative features elicited included
opportunities forfeited by using scarce resources to conduct research and the
need to adequately train local health staff in research methodology to ensure
valid results and accurate interpretation of findings. CONCLUSIONS: Operational
research effectively influenced disease control policy and practice in rural
South Africa, by providing relevant answers to local questions and engaging
policy-makers. This resulted in accelerated inclusion of appropriate measures
into a local communicable disease control programme.
Afr J Health Sci 1994 Aug;1(3):112-115
In vivo seasonal assessment of Plasmodium falciparum sensitivity to chloroquine
in two different malaria endemic communities in Southern Ghana.
Afari EA, Dunyo S, Appawu M, Nkrumah FK.
Noguchi Memorial Institute for Medial Research, University of Legon, P. O. Box
A two year (1992 to 1993) in vivo assessment of Plasmodium falciparum
sensitivity to chloroquine was conducted in two communities at Dodowa
(hyperendemic) and Prampram (mesoendemic) in Southern Ghana. A slightly modified
World Helath Organization standard field test (7 day test) for response of
Plasmodium falciparum asexual parasites to chloroquine was used for the survey.
In 1992, 16.2% (12/74) responses were classified as exhibiting chloroquine
resistance at RI (14.8% ) and RII (1.4%) in the dry season and 8.2% (10/122)
responses at RI in the wet season in the hyperendemic community. Only a single
response (1/144; 0.7%) at RI showed resistance in the mesoendemic community. The
rest of the responses in both communities were classified as sensitive to
chloroquine. In the hyperendemic community, 8.4% (13/154) of responses in the
dry season showed resistance at RI and 1.3% (82/150) at RI (0.7%) and RII (0.7%)
in the wet season in 1993. In the mesoendemic community 1 (1.0%) response was
resistant at RI in the wet season. The rest of the responses were classified as
sensitive responses to chloroquine. No RIII response was encountered in any of
the communities. The pattern of RI and RII responses did not show any seasonal
variations in the mesoendemic community. However, they were generally higher in
the dry season than in the wet season in the hyperendemic community.
Lancet Infect Dis 2002 Aug;2(8):472-8
The immune response to Plasmodium falciparum malaria.
Malaguarnera L, Musumeci S.
LM is at the Department of Biomedical Sciences, University of, Catania, Italy
Malaria is still a major cause of severe disease which is responsible for
millions of deaths, mostly in children under 5 years old, in tropical countries,
especially sub-Saharan Africa. Complications of severe anaemia and cerebral
malaria are thought to be the major cause of morbidity and mortality but recent
evidence suggests that the host's immunological response could also contribute
to the pathophysiology of the disease in human beings. Intensive studies of the
immune response to malaria parasites in human beings have provided a wealth of
information about the cells and cytokines implicated in the pathophysiology of
survival and fatal outcome in severe infections. This review focuses on the
pivotal role of macrophages and other important cellular effectors, molecules,
and cytokines involved in the activation of the immune response at the different
stages of human falciparum malaria. Our understanding of the putative mechanisms
by which cytokines may mediate beneficial and harmful effects, through
activation of phagocytic cells, could help to develop new treatment strategies,
regardless of the emergence of parasite multidrug resistance.
Afr J Health Sci 1994 Feb;1(1):20-26
Pharmacology of absorption and distribution: optimal use of antimalarial drugs
in the treatment of severe falciparum malaria in Kenya.
Watkins WM, Winstanley PA, Marsh K.
Kenya Medical Research Institute, P.O. Box 54840, Nairobi, Kenya. Department of
Pharmacology & Therapeutics, University of Liverpool, UK.
Since 1989, a project at the KEMRI CRC Unit at Kilifi has focused on the design
of appropriate and practicable regimens for the treatment of severe falciparum
malaria. Initially, there was no data describing the absorption, distribution
and elimination of quinine in Kenyan children, who constitute the great majority
of patients. Pharmacokinetic studies were conducted to define these variables,
which formed the basis for the design of appropriate and practicable treatment
regimens. Even with optimal clinical management, the majority is high in cases
of severe malaria treated with quinine at Kilifi. Alternative drugs have been
studied in a search for a therapeutic regimen that will further reduce
Blood 2002 Aug 15;100(4):1478-1483
Sequestration of Plasmodium falciparum-infected erythrocytes to chondroitin
sulfate A, a receptor for maternal malaria: monoclonal antibodies against the
native parasite ligand reveal pan-reactive epitopes in placental isolates.
Lekana Douki JB, Traore B, Costa FT, Fusai T, Pouvelle B, Sterkers Y, Scherf A,
Unite de Parasitologie Experimentale, Faculte de Medecine, Universite de la
Mediterranee (Aix-Marseille II), Marseille, France; Unite de Biologie des
Interactions Hote-Parasite, Institut Pasteur, Paris, France; and Unite de
Parasitologie, Marseille, France.
Plasmodium falciparum parasites express variant adhesion molecules on the
surface of infected erythrocytes (IEs), which act as targets for natural
protection. Recently it was shown that IE sequestration in the placenta is
mediated by binding to chondroitin sulfate A via the duffy binding-like
(DBL)-gamma3 domain of P falciparum erythrocyte membrane protein 1
(PfEMP1(CSA)). Conventional immunization procedures rarely result in the
successful production of monoclonal antibodies (mAbs) against such
conformational vaccine candidates. Here, we show that this difficulty can be
overcome by rendering Balb/c mice B cells tolerant to the surface of human
erythrocytes or Chinese hamster ovary (CHO) cells before injecting P falciparum
IEs or transfected CHO cells expressing the chondroitin sulfate A (CSA)-binding
domain (DBL-gamma3) of the FCR3 var(CSA) gene. We fused spleen cells with P3U1
cells and obtained between 20% and 60% mAbs that specifically label the surface
of mature infected erythrocytes of the CSA phenotype (mIE(CSA)) but not of other
adhesive phenotypes. Surprisingly, 70.8% of the 43 mAbs analyzed in this work
were IgM. All mAbs immunoprecipitated PfEMP1(CSA) from extracts of (125)I
surface-labeled IE(CSA). Several mAbs bound efficiently to the surface of
CSA-binding parasites from different geographic areas and to placental isolates
from West Africa. The cross-reactive mAbs are directed against the
DBL-gamma3(CSA), demonstrating that this domain, which mediates CSA binding, is
able to induce a pan-reactive immune response. This work is an important step
toward the development of a DBL-gamma3-based vaccine that could protect pregnant
women from pathogenesis. (Blood. 2002;100:1478-1483)
Blood 2002 Aug 15;100(4):1172-1176
Hemoglobin E: a balanced polymorphism protective against high parasitemias and
thus severe P falciparum malaria.
Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J,
Looareesuwan S, White N.
Faculty of Tropical Medicine, Department of Pathobiology, Faculty of Science,
and Office for Research and Development, Faculty of Medicine, Mahidol
University, Bangkok, Thailand; and the Nuffield Department of Medicine, John
Radcliffe Hospital, Oxford University, Oxford, United Kingdom.
Hemoglobin E is very common in parts of Southeast Asia. The possible malaria
protective effects of this and other inherited hemoglobin abnormalities
prevalent in Thailand were assessed in a mixed erythrocyte invasion assay. In
vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded
normal (HbAA) compared to abnormal hemoglobin (HbH, AE, EE, HCS,
beta-thalassemia E) red cells (HRBCs). The median (range) ratio of
parasitization of HRBCs (n = 109) compared to the controls of different major
blood groups was 0.40 (0.08, 0.98), less than half that of the normal red cells
(NRBCs) compared to their controls 0.88 (0.53, 1.4; P =.001). The median (range)
parasitemia in the HRBCs was 2% (0.1%-9%) compared to 5.2% (1.2%-16.3%) in the
NRBCs (P =.001). The proportion of the RBC population that is susceptible to
malaria parasite invasion can be described by a selectivity index (SI; observed
number of multiply invaded RBCs/number predicted). The heterozygote AE cells
differed markedly from all the other cells tested with invasion restricted to
approximately 25% of the RBCs; the median (range) SI was 3.8 (1-15) compared
with 0.75 (0.1-0.9) for EE RBCs (P <.01). Despite their microcytosis, AE cells
are functionally relatively normal in contrast to the RBCs from the other
hemoglobinopathies studied. These findings suggest that HbAE erythrocytes have
an unidentified membrane abnormality that renders the majority of the RBC
population relatively resistant to invasion by P falciparum. This would not
protect from uncomplicated malaria infections but would prevent the development
of heavy parasite burdens and is consistent with the "Haldane" hypothesis of
heterozygote protection against severe malaria for hemoglobin E. (Blood.
Bull Soc Pathol Exot 2002 Jun;95(2):89-94
An epidemiological study on malaria
[Article in French]
Nzeyimana I, Henry MC, Dossou-Yovo J, Doannio JM, Diawara L, Carnevale P.
Centre Pierre Richet., 01 B.P. 1500, Bouake 01, Cote d'Ivoire.
An epidemiological study on malaria was undertaken between July 1995 and July
1996 in two villages (Zaipobly and Gahably) and their encampments (Kouassikro,
Hamanikro and Konankro), in the south-western forest area of Cote d'Ivoire
(region of Tai). The parasitological scheme comprised a total of 2023 tests
performed on children aged from 0 to 14 years. The species found were Plasmodium
falciparum, P. malariae and P. ovale with a proportion of 84%, 14% and 2%
respectively. The global parasite prevalence of all Plasmodium species was 85%
and malaria was holoendemic. The average parasitic density decreased
progressively as the age increased, in contrast to the plasmodic index which did
not vary. All the malarial indexes were similar in the villages and their
encampments. Only overall fever prevalence was permanent and in all age groups
it was higher in the encampments than in the villages. The entomological
findings showed that transmission was permanent and intense throughout the year,
with a recrudescence during the rainy season. Transmission was attributed to
Anopheles gambiae s.l. in 85% of the cases whereas An. funestus played a
secondary role. The average sporozoitic index was 7.6% and varied between 1.1%
and 16.7%. The entomological inoculation rate was of 400 infected bites per
person-year for An. gambiae s.l. In such conditions of intense transmission,
acquisition of premunition starts at a very early age. This assertion is
verified by the average parasite density and the frequency of high parasitic
densities which were at their maximum between 1 and 4 years of age and decreased
thereafter as the age increased. The paludometric and entomologic indexes
obtained are the most elevated ever to have been observed in Cote d'Ivoire, as a
result of considerable ecological changes linked to the deterioration of the
forest environment over the past 30 years. This deterioration has probably been
caused by demographic pressure resulting from internal and foreign immigration
to the Tai region and more especially by the influx of Liberian refugees.
Bull Soc Pathol Exot 2002 Jun;95(2):86-8
History of the use of Artemisia annua
[Article in French]
L'Institut national de malariologie, de parasitologie et d'entomologie
Conseiller, programme national de lutte antipaludique 6 av. Ly Thuong-Kiet,
The long history of the use of Artemisia annua L. to treat malaria (called
Quinghao in China and Thanh hao in Vietnam) has led Vietnamese scientists to
manufacture locally preparations of artemisinim and artesunate, to test their
tolerance for human beings as well as their efficiency in treating P. falciparum
and P. vivax infections. Associating these drugs with antibiotics (such as
tetracycline or doxycycline) could be an interesting topic for future research.
Under the auspices of the National Program against Malaria, specialists will try
to prevent the occurrence of drug resistance in Plasmodium and to propose new
associations of drugs.
Insect Mol Biol 2002 Aug;11(4):291-7
Germ-line transformation of the South American malaria vector, Anopheles
albimanus, with a piggyBac/EGFP transposon vector is routine and highly
Perera OP, Harrell II RA, Handler AM.
Center for Medical, Agricultural, and Veterinary Entomology, Agricultural
Research Service, U. S. Department of Agriculture, Gainesville, FL, USA.
Stable and efficient germ-line transformation was achieved in the South American
malaria vector, Anopheles albimanus, using a piggyBac vector marked with an
enhanced green fluorescent protein gene regulated by the Drosophila melanogaster
polyubiquitin promoter. Transgenic mosquitoes were identified from four
independent experiments at frequencies ranging from 20 to 43% per fertile G0.
Fluorescence was observable throughout the body of larvae and pupae, and
abdominal segments of adults. Transgenic lines analysed by Southern
hybridization had one to six germ-line integrations, with most lines having
three or more integrations. Hybridized transposon vector fragments and insertion
site sequences were consistent with precise piggyBac-mediated integrations,
although this was not verified for all lines. The piggyBac/PUbnlsEGFP vector
appears to be a robust transformation system for this anopheline species, in
contrast to the use of a piggyBac vector in An. gambiae. Further tests are
needed to determine if differences in anopheline transformation efficiency are
due to the marker systems or to organismal or cellular factors specific to the
J Med Entomol 2002 Jul;39(4):621-30
A continental risk map for malaria mosquito (Diptera: Culicidae) vectors in
Kuhn KG, Campbell-Lendrum DH, Davies CR.
Disease Control and Vector Biology Unit, London School of Hygiene and Tropical
Medicine, UK. [email protected]
Although malaria was officially declared eradicated from Europe in 1975, its
former vectors, mainly members of the Anopheles maculipennis (Meigen) complex,
are still distributed throughout the continent. The present situation of
Anophelism without malaria indicates that current socio-economic and
environmental conditions maintain the basic case reproduction number, Ro, below
1. Recently, it has been speculated that predicted climate changes may increase
anopheline abundance and biting rates (as well as reduce the Plasmodium parasite
extrinsic incubation period), allowing the reemergence of malaria transmission
in Europe. As a preliminary step toward predicting future scenarios, we have
constructed models to test whether the current distribution of the five former
European malaria vectors [An. atroparvus (Van Thiel),An. labranchiae
(Falleroni), An. messeae (Swellengrebel & De Buck), An. sacharovi (Favr) and An.
superpictus (Grassi)] can be explained by environmental parameters, including
climate. Multivariate logistic regression models using climate surfaces derived
from interpolation of meteorological station data (resolution 0.5 x 0.5 degrees)
and remotely sensed land cover (resolution 1 x 1 km) were fitted to 1,833
reported observations of the presence and absence of each species across Europe.
These relatively crude statistical models predicted presence and absence with a
sensitivity of 74-85.7% and specificity of 73.4-98.1% (with climate a
significantly better predictor than land cover type). A geographically
independent validation of the models gave a sensitivity of 72.9-88.5% and a
specificity of 72.7-99.6%. This allowed us to generate risk maps for each
species across Europe. Assuming that high risk equates with the potential for
high abundance, these models should permit the development of risk maps for
European mosquitoes under future climate scenarios. These techniques would be
equally useful for estimating the risk of reemergence in other nonendemic areas
such as the United States and Australia, as well as changes to risk within
J Med Entomol 2002 Jul;39(4):583-6
Potential for Anopheles campestris (Diptera: Culicidae) to transmit malaria
parasites in Pa Rai subdistrict (Aranyaprathet, Sa Kaeo Province), Thailand.
Apiwathnasor C, Prommongkol S, Samung Y, Limrat D, Rojruthai B.
Department of Medical Entomology, Faculty of Tropical Medicine, Mahidol
University, Bangkok, Thailand. [email protected]
Member(s) of the Anopheles barbirostris group Reid, particularly Anopheles
barbirostris and Anopheles campestris Reid are the suspected vectors of
Plasmodium vivax in Pa Rai (Aranyaprathet, Sa Kaeo province). To determine if
An. barbirostris, An. campestris, or both, are present in Pa Rai and to
determine their potential to transmit malaria, a field and laboratory study was
conducted. Isofemale colonizations of wild caught mosquitoes captured by landing
catches were made for species confirmation and to determine the mosquito life
cycle. Pupal morphology indicated all mosquitoes were An. campestris. During the
late rainy season (October and November), An. campestris populations comprised
78.6% of all females captured by human landing catches and 7.1% of mosquitoes in
a cow-baited trap. The biting activity cycle peaked between 2000 and 0100 hours
and was highest (17.6 bites per person per hour) at 2300 hours. More An.
campestris bit people indoors (nine bites per person per hour) than outdoors
(four bites per person per hour). Immature An. campestris were found in ponds,
swamps, rice-fields, puddles, marshes, ground pools, and pits with open sunlight
to partial shade. The time from egg hatch to adult was 18-47 d and 14-22 d under
laboratory (25.0-27.0 degrees C) and ambient (26-32 degrees C) conditions,
respectively. The fecundity of An. campestris ranged from 173 to 311 eggs. Based
on experimental infections, An. campestris was able to support the sporogonic
cycle of P. vivax with 76.2 and 23.8% oocyst and sporozoite formation rate,
respectively. An. campestris shows high potential as a malaria vector in Pa Rai.
J Med Entomol 2002 Jul;39(4):568-73
Stable chromosomal inversion polymorphisms and insecticide resistance in the
malaria vector mosquito Anopheles gambiae (Diptera: Culicidae).
Brooke BD, Hunt RH, Chandre F, Carnevale P, Coetzee M.
Department of Clinical Microbiology and Infectious Diseases, School of Pathology
of the National Health Laboratory Service and the University of Witwatersrand,
Johnnesburg, South Africa. [email protected]
Anopheles gambiae Giles has been implicated as a major vector of malaria in
Africa. A number of paracentric chromosomal inversions have been observed as
polymorphisms in wild and laboratory populations of this species. These
polymorphisms have been used to demonstrate the existence of five reproductive
units in West African populations that are currently described as incipient
species. They have also been correlated with various behavioral characteristics
such as adaptation to aridity and feeding preference and have been associated
with insecticide resistance. Two paracentric inversions namely 2La and 2Rb are
highly ubiquitous in the wild and laboratory populations sampled. Both
inversions are easily conserved during laboratory colonization of wild material
and one shows significant positive heterosis with respect to Hardy-Weinberg
proportions. Inversion 2La has previously been associated with dieldrin
resistance and inversion 2Rb shows an association with DDT resistance based on
this study. The stability and maintenance of these inversions as polymorphisms
provides an explanation for the transmission and continued presence of DDT and
dieldrin resistance in a laboratory strain of An. gambiae in the absence of
insecticide selection pressure. This effect may also be operational in wild
populations. Stable inversion polymorphism also provides a possible mechanism
for the continual inheritance of suitable genetic factors that otherwise
compromise the fitness of genetically modified malaria vector mosquitoes.
Am J Epidemiol 2002 Aug 1;156(3):230-8
Determinants of treatment response to sulfadoxine-pyrimethamine and subsequent
transmission potential in falciparum malaria.
Mendez F, Munoz A, Carrasquilla G, Jurado D, Arevalo-Herrera M, Cortese JF,
Secretaria Departamental de Salud del Valle, Cali, Colombia.
Drug resistance is contributing to increasing mortality from malaria worldwide.
For assessment of the role of resistance-conferring parasite mutations on
treatment responses to sulfadoxine-pyrimethamine (SP) and transmission
potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura,
Colombia, were treated with SP and followed for 21 days in the period February
1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum
dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer
resistance to pyrimethamine and sulfadoxine, respectively. Although SP was
highly efficacious (96.7%), the presence together of DHFR mutations at codons
108 and 51 was associated with longer parasite clearance time (relative hazard =
0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p
= 0.188). This association remained after controlling for potential confounders.
Infections with these mutations were also associated with the presence of
gametocytes, the sexual form of the parasite responsible for transmission, 14
and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher
gametocytemia is probably due to DHFR mutations prolonging parasite survival
under drug pressure, resulting in longer parasite clearance time and allowing
asexual parasites to differentiate into gametocytes. These results suggest that
even when SP efficacy is high, DHFR mutations that are insufficient to cause
therapeutic failure may nevertheless increase malaria transmission and promote
the spread of drug resistance.
Genes Immun 2002 Aug;3(5):286-91
CD40L association with protection from severe malaria.
Sabeti P, Usen S, Farhadian S, Jallow M, Doherty T, Newport M, Pinder M, Ward R,
Wellcome Trust Centre for Human Genetics, Oxford, UK, and Institute of
Biological Anthropology, Oxford University, Oxford, UK.
CD40 ligand (CD40L), a glycoprotein involved in B cell proliferation, antigen
presenting cell activation, and Ig class switching, is important in the immune
response to infection. Rare coding mutations in CD40L can lead to
life-threatening immunodeficiency but the potential for common variants to alter
disease susceptibility remains to be explored. To identify polymorphisms in
CD40L, we sequenced 2.3 kb of the 5' flanking region and the first exon of the
gene in DNA samples from 36 Gambian females and one chimpanzee. Diversity was
lower than the average reported for other areas of the X chromosome, and only
two polymorphisms were identified. The polymorphisms were genotyped in DNA
samples from 957 Gambian individuals, cases and controls from a study of severe
malaria. A significant reduction in risk for severe malaria (OR = 0.52, P =
0.002) was associated with males hemizygous for the CD40L-726C. Analysis by
transmission disequilibrium test of 371 cases, for whom DNA from both parents
was also available, confirmed the result was not due to stratification (P =
0.04). A similar but non-significant trend was found in females. This
preliminary association of a common variant in CD40L with a malaria resistance
phenotype encourages further genetic characterization of the role of CD40L in
Am J Trop Med Hyg 2002 Mar;66(3):314-6
Short report: Field evaluation of posttreatment sensitivity for monitoring
parasite clearance of Plasmodium falciparum malaria by use of the Determine
Malaria pf test in central India.
Singh N, Shukla MM.
Malaria Research Centre, Field Station, Indian Council of Medical Research,
Jabalpur, Madhya Pradesh. [email protected]
The posttreatment performance of the Plasmodium falciparum histidine-rich
protein rapid diagnostic test Determine Malaria pf (Abbott Laboratories, Tokyo,
Japan) was assessed in 70 patients in central India with uncomplicated
falciparum malaria who were treated with chloroquine, sulfadoxine-pyrimethamine,
and arteether. Data were compared with those of microscopy. Results revealed
that the sensitivity for predicting recrudescence by means of the Determine test
after treatment with chloroquine on Day 14 was 75%, with 50% specificity.
However, antigenemia was detected in 16% of patients as late as Day 21 in
sulfadoxine-pyrimethamine-treated subjects with a drug-sensitive response.
Clearance of parasitemia in thick blood smear and clearance of antigenemia
appeared to parallel each other only in arteether-treated subjects. The observed
diagnostic trends therefore mean that the potential of the Determine test to
detect recrudescent infection is limited.
Am J Trop Med Hyg 2002 Mar;66(3):310-3
A high malaria reinfection rate in children and young adults living under a low
entomological inoculation rate in a periurban area of Bamako, Mali.
Sagara I, Sangare D, Dolo G, Guindo A, Sissoko M, Sogoba M, Niambele MB, Yalcoue
D, Kaslow DC, Dicko A, Klion AD, Diallo D, Miller LH, Toure Y, Doumbo O.
Malaria Research and Training Center, Departement d'Epidemiologie des Affections
Parasitaires, Faculte de Medicine, de Pharmacie et d'Odonto-Stomatologie,
Universite du Mali, Bamako.
In areas of intense malaria parasite transmission, preliminary studies of the
rate of reinfection after curative therapy suggest that small sample size
studies of vaccine efficacy are feasible. However, the effect of transmission
rate, which may vary considerably between transmission seasons, on reinfection
rate has not been assessed in areas of mesoendemicity with seasonal
transmission. To address this question, the Plasmodium falciparum reinfection
rate after curative therapy was measured in Sotuba, a Malian village with
historically low transmission rates, as estimated by the entomological
inoculation rate (EIR). The reinfection rate after curative Fansidar
(sulfadoxine-pyrimethamine) treatment was 80.7% (88/109). The EIR during the
13-week study period (seasonal transmission) varied between 1 and 4.5 infected
bites/person/month. The finding that reinfection rates were high despite low
EIRs suggests that a low EIR may be sufficient to support small sample size
vaccine efficacy trials in mesoendemic areas.
Am J Trop Med Hyg 2002 Mar;66(3):304-9
Helminth infections are associated with protection from cerebral malaria and
increased nitrogen derivatives concentrations in Thailand.
Nacher M, Singhasivanon P, Traore B, Vannaphan S, Gay F, Chindanond D, Franetich
JF, Mazier D, Looareesuwan S.
Unite INSERM 511: Immunobiologie Cellulaire et Moleculaire des Infections
Parasitaires, Faculte de Medecine Pitie-Salpetriere, Paris, France.
Following a study showing an association between Ascaris and protection from
cerebral malaria, we hypothesized helminths may have induced protection through
immunoglobulin E (IgE) and the CD23/NO pathway. We compared the prevalence of
helminth infections in 67 cerebral malaria patients and 217 hyperparasitemic
controls with no complications. For 24 cerebral malaria cases and 56 controls,
we compared reactive nitrogen intermediates (RNI) concentrations and their
correlations to total IgE and sCD23 concentrations in helminth-infected and
noninfected patients. We observed a dose-dependent association between helminth
infections and protection from cerebral malaria (adjusted odds ratio [OR] =
0.36, 95% CI = 0.19-0.7, P = 0.002, linear trend P = 0.0007). Helminth-infected
controls had higher RNI concentrations than those without helminths: 72 OD +/-
19 SD and 57 OD +/- 20 SD, respectively (P = 0.006). Logistic regression,
including interaction terms between RNI and sCD23, showed that an increase of
RNI could be both protective and pathogenic depending on the concentration of
sCD23. Helminths increasing both the CD23 receptor and its ligand may have a
role in the establishment of malaria tolerance through the CD23/NO pathway.
Am J Trop Med Hyg 2002 Mar;66(3):299-303
Low cellular response in vitro among subjects with long-term exposure to malaria
transmission in Brazilian endemic areas.
Braga EM, Carvalho LH, Fontes CJ, Krettli AU.
Departamento de Parasitologia, Universidade Federal de Minas Gerais, Belo
The cellular and humoral immune responses to Plasmodium falciparum and P. vivax
recombinant circumsporozoite (rCS) proteins were studied in two populations in
the Brazilian malaria-endemic region. One group of subjects lived in an urban
area that was free from the risk of malaria and was exposed to the disease
through short visits to the endemic area. The other group had lived for
approximately 10 years in a rural area, where they were continuously exposed to
transmission. Proliferative responses to rCS proteins were observed in 50% of 16
adults not continuously exposed to malaria but in only five of 48 subjects (10%)
resident in the transmission area. The antibody responses to rCS proteins were
approximately 50% in both groups. The interferon-gamma (IFN-gamma) response
evaluated only among continuously exposed subjects was low. There was no
association between the presence of antibodies and the detection of
proliferative or IFN-gamma T cell responses. These findings suggest that
continuous exposure to malaria in areas of low endemicity may lead to a specific
decrease of the in vitro T cell function.
Am J Trop Med Hyg 2002 Mar;66(3):293-8
Comparison of the cardiac effects of the antimalarials co-artemether and
halofantrine in healthy participants.
Bindschedler M, Lefevre G, Degen P, Sioufi A.
Novartis Pharma Ltd., Research and Development Department, Horsham, United
Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120
mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some
chemical similarities to halofantrine (Halfan), an antimalarial known for QTc
prolongation. Effects on the QTc interval of fed single oral doses of 500 mg
halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a
randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded
from 48 hours before dosing until 48 hours thereafter. The maximum QTc interval
(QTc = QT/square root(RR)) was compared before and after treatment and between
treatments, fitting a general linear model. Drug plasma concentrations were
determined concomitantly. After halofantrine, all participants showed an
increase in the QTc interval; the mean maximum increase was 28 ms. The length of
the QTc interval was positively correlated to halofantrine exposure. The QTc
interval remained unchanged after co-artemether. The difference between
treatments was statistically significant. In conclusion, halofantrine caused a
significant, exposure-dependent increase in the QTc interval. No such effect was
seen with co-artemether.
Am J Trop Med Hyg 2002 Mar;66(3):287-92
Epidemic malaria in the Menoreh Hills of Central Java.
Barcus MJ, Laihad F, Sururi M, Sismadi P, Marwoto H, Bangs MJ, Baird JK.
U.S. Naval Medical Research Unit # 2, Jakarta, Indonesia.
After more than 50 years of effective management, resurgent malaria threatens
residents in the Menoreh Hills and the foothills of the Dieng Plateau of Central
Java, Indonesia. The Dieng Plateau dominates the highland center of Central
Java. The steep Menoreh Hills, surrounded by rice paddy habitats, cover
approximately 500 km2 with no peaks greater than 1,000 m. We studied epidemic
malaria in Purworejo district, one of the three districts containing the Menoreh
Hills. Between 1986 and 1995, the annual parasite incidence (API) in Purworejo
ranged from 2 to 11 cases per 1,000 residents per year and was typically
approximately 5 per 1,000. In 2000 the API was 44.5. This sharp increase was
confined to subdistricts in and around the Menoreh Hills and Dieng Plateau
foothills. The primary vectors of malaria, those favoring steep, forested
hillsides on Java, were Anopheles maculatus and Anopheles balabacensis.
Deterioration of vector control activity, followed by a severe economic downturn
in 1997, may explain the epidemic. Malaria in the Menoreh Hills and lower Dieng
Plateau threatens surrounding areas of rice paddy inhabited by Anopheles
aconitus as well as a nearby coastal habitat where the even more efficient
vector Anopheles sundaicus occurs in abundance. Most of the 130 million people
living on Java never experienced the hyper- and holoendemic malaria that
occurred throughout most of the island before the effective DDT spraying and
chloroquine treatment campaigns of the 1950s. Reintroduced endemic malaria
threatens the island of Java.
Am J Trop Med Hyg 2002 Mar;66(3):280-6
Seasonal malaria attack rates in infants and young children in northern Ghana.
Baird JK, Agyei SO, Utz GC, Koram K, Barcus MJ, Jones TR, Fryauff DJ, Binka FN,
Hoffman SL, Nkrumah FN.
Naval Medical Research Center, Silver Spring, Maryland, USA.
The incidence density of infection and disease caused by Plasmodium falciparum
in children aged six to 24 months living in the holoendemic Sahel of northern
Ghana was measured during the wet and dry seasons of 1996 and 1997. At the
beginning of each season, a cohort composed of 259 and 277 randomly selected
children received supervised curative therapy with quinine and Fansidar and
primaquine for those with normal glucose-6-phosphate dehydrogenase activity. The
20 weeks of post-therapy follow-up consisted of three home visits weekly and
examination of Giemsa-stained blood films once every two weeks. Blood films were
also taken from children brought to clinic with illness. The incidence density
of parasitemia after radical cure was 4.7 infections/person-year during the dry
season and 7.1 during the wet season (relative risk = 1.51, 95% confidence
interval [CI] = 1.25-1.81; P = 0.00001). Although the mean parasitemia count at
time of reinfection in the dry season (3,310/microl) roughly equaled that in the
wet season (3,056/microl; P = 0.737), the risk ratio for parasitemia >
20,000/microl during the wet season was 1.71 (95% CI = 1.2-2.4; P = 0.0025). The
risk ratio for parasitemia > 20,000/microl with fever during the wet season was
2.45 (95% CI = 1.5-4.1; P = 0.0002). The risk ratio for anemia (hemoglobin < 8
g/dl) at first post-radical cure parasitemia showed no difference between
seasons (1.0; 95% CI = 0.73-1.4; P = 0.9915). We did not see seasonal
differences in anemia known to exist in this region, probably because the
longitudinal cohort design using first parasitemia as an end point prevented the
subjects from developing the repeated or chronic infections required for anemia
induction. These findings bear upon the design of malaria drug and vaccine
trials in holoendemic areas.
Anal Chem 2002 Jul 15;74(14):3262-6
Detection of malaria parasites in blood by laser desorption mass spectrometry.
Demirev PA, Feldman AB, Kongkasuriyachai D, Scholl P, Sullivan D Jr, Kumar N.
Applied Physics Laboratory, Johns Hopkins University, Laurel, Maryland 20723,
USA. [email protected]
A novel method for the in vitro detection of the protozoan Plasmodium, the
causative agent of malaria, has been developed. It comprises a protocol for
cleanup of whole blood samples, followed by direct ultraviolet laser desorption
(LD) time-of-flight mass spectrometry. Intense ion signals are observed from
intact ferriprotoporphyrin IX (heme), sequestered by malaria parasites during
their growth in human red blood cells. The LD mass spectrum of the heme is
structure-specific, and the signal intensities are correlated with the sample
parasitemia (number of parasites per unit volume of blood). Parasitemia levels
on the order of 10 parasites/microL blood can be unambiguously detected by this
method. Consideration of laser beam parameters (spot size, rastering across the
sample surface) and actual sample consumption suggests that the detection limits
can be further improved by at least an order of magnitude. The influence of
experimental factors, such as desorbed ion polarity, laser exposure and fluence,
sample size, and parasite growth stage, on the threshold for parasite detection
is also addressed.
Cochrane Database Syst Rev 2002;(3):CD003341
High first dose quinine regimen for treating severe malaria (Cochrane Review).
Lesi A, Meremikwu M.
Department of Paediatrics, College of Medicine, University of Lagos, Lagos,
NIGERIA. [email protected]
BACKGROUND: Quinine is used for treating severe malaria. There are arguments for
giving an initial high dose. We examined the evidence for and against this
policy. OBJECTIVES: To assess clinical outcomes and adverse events of a high
first (loading) dose regimen of quinine with a uniform (no loading) dose regimen
in people with severe malaria. SEARCH STRATEGY: We searched the Cochrane
Infectious Diseases Group specialized trials register (May 2002), The Cochrane
Controlled Trials Register (Issue 2, 2002), MEDLINE (1966 to April 2002), EMBASE
(1988 to March 2002), LILACS (www.bireme.br; accessed February 2002), and
conference proceedings for relevant abstracts. We also contacted researchers
working in the field and checked the reference lists of all studies. SELECTION
CRITERIA: Randomized controlled trials. DATA COLLECTION AND ANALYSIS: Two
reviewers independently assessed the methodological quality of the trials and
extracted data. Review Manager (Version 4.1) was used to analyse the data:
Relative Risk for binary data and weighted mean difference (WMD) for continuous
data. Study authors were contacted for additional information. MAIN RESULTS:
Three small trials, with two contributing to a meta-analysis of 72 participants.
Loading dose was associated with fewer deaths, but this was not statistically
significant (RR 0.43; 95% confidence interval (CI) 0.09 to 2.15). Loading dose
was associated with faster clearance of parasites (WMD 7.44; 95% CI 1.64 to 13.2
hours), resolution of fever (WMD 11.11; 95% CI 2.18 to 20.04 hours), and
transient hearing loss (RR 3.14; 95% CI 1.05 to 9.38). No significant difference
was detected for recovery of consciousness, neurological sequelae, or
convulsions, but the numbers were small. REVIEWER'S CONCLUSIONS: Quinine loading
dose reduced fever clearance time and parasite clearance time. Data are
insufficient to confirm or refute whether a loading dose reduced the risk of
death or convulsions.
Cochrane Database Syst Rev 2002;(3):CD003125
Artemether-lumefantrine for treating uncomplicated falciparum malaria (Cochrane
Omari AA, Preston C, Garner P.
International Health Research Group, Liverpool School of Tropical Medicine,
Pembroke Place, Liverpool, UK, L3 5QA. [email protected]
BACKGROUND: Artemether-lumefantrine is being promoted by the World Health
Organization for treating uncomplicated malaria. It is expensive. We sought
evidence of its superiority over existing treatment regimens. OBJECTIVES: To
compare artemether-lumefantrine with other antimalarial drugs for treating
uncomplicated falciparum malaria. SEARCH STRATEGY: We searched the Cochrane
Infectious Diseases Group specialized trials register (April 2002), the Cochrane
Controlled Trials Register (Issue 2, 2002), MEDLINE (1966 to April 2002), EMBASE
(1988 to April 2002), conference proceedings, and reference lists of articles.
We contacted experts in malaria research and the pharmaceutical company that
manufactures artemether-lumefantrine. SELECTION CRITERIA: Randomized and
quasi-randomized trials comparing artemether-lumefantrine administered orally
with standard treatment regimens (single drug or combination). DATA COLLECTION
AND ANALYSIS: Two reviewers independently applied inclusion criteria to
potentially relevant trials, assessed trial quality, and extracted data.
Parasitaemia on day 28 (day 42 for sulfadoxine-pyrimethamine and day 63 for
mefloquine) was the primary outcome. Adverse event information was collected
from the studies. MAIN RESULTS: Eight trials (2117 participants) met the
inclusion criteria. In the four studies against single agents, failure rates for
artemether-lumefantrine tended to be higher in comparisons against
sulfadoxine-pyrimethamine, halofantrine, and mefloquine. This difference was
statistically significant for mefloquine. When compared with chloroquine,
artemether-lumefantrine was better in two studies, but the failure rate for
chloroquine at these sites was over 50%. All single agent studies used four
doses of artemether-lumefantrine. In comparisons against combination treatment,
three trials tested artemether-lumefantrine against mefloquine-artesunate and
showed that artemether-lumefantrine was inferior for day 28 cure (Relative Risk
6.33, 95% confidence interval 3.08 to 13.01). If this comparison is confined to
the two trials where participants received six doses, artemether-lumefantrine
was associated with higher cure rates, but this was not statistically
significant (Relative Risk 4.20, 95% confidence interval 0.55 to 31.93).
REVIEWER'S CONCLUSIONS: Artemether-lumefantrine is more effective than
chloroquine in chloroquine resistant areas. Artemether-lumefantrine is less
effective than mefloquine or mefloquine combined with artesunate. We found no
evidence to confirm or refute whether artemether-lumefantrine was better than
46: Am J Trop Med Hyg 2002 Feb;66(2):140-2
Short report: hepatitis b infection and severe Plasmodium falciparum malaria in
Barcus MJ, Hien TT, White NJ, Laras K, Farrar J, Schwartz IK, Corwin A, Baird
US Naval Medical Research Unit 2, Jakarta, Indonesia.
We investigated the prevalence of infection with hepatitis B virus among adult
Vietnamese patients hospitalized for severe Plasmodiumfalciparum malaria. Sera
from patients admitted with severe malaria in Ho Chi Minh City, Vietnam, between
May 1991 and January 1996 were assayed for hepatitis B surface antigen (HB(s)Ag)
by a commercial enzyme-linked immunosorbent assay kit. The overall prevalence of
HB(s)Ag was 23.77% (77 of 324). This was higher than reported estimates of
prevalence in the general catchment population for the study hospital (mean,
9.8%; range, 9-16%). No association was found between risk of death caused by
severe malaria and HB(s)Ag. Patients admitted with cerebral malaria had a
slightly greater risk of registering positive for HB(s)Ag (relative risk, 1.28;
95% confidence interval, 1.04-1.58) relative to other manifestations of severe
malaria. Chronic infection with hepatitis B virus may be a risk factor for
Am J Trop Med Hyg 2002 Feb;66(2):137-9
Short report: differential evolution of immunoglobulin G1/G3 antibody responses
to Plasmodium falciparum MSP1(19) over time in malaria-immune adult Senegalese
Diallo TO, Spiegel A, Diouf A, Lochouarn L, Kaslow DC, Tall A, Perraut R,
Unite d'Immunologie, Institut Pasteur, Dakar, Senegal.
This study examined the evolution of immunoglobulin (Ig) G1 and IgG3 antibodies
against the asexual stage Plasmodium falciparum protein, MSP1(19), before and
after a heavy malaria transmission period in clinically immune Senegalese
subjects living under different epidemiological conditions. Plasma was tested
for antibodies to a yeast-produced, recombinant PfMSP1(19) antigen (the Q-KNG
allelic variant) that has previously been demonstrated to react with IgG1, IgG3,
or both in the majority of these people. Anti-P. falciparum antibodies of the
IgG1 and IgG3 subclasses, previously reported to be associated with protection,
were shown to evolve independently one from another after the transmission
period in both settings. These results suggest differential regulation of
MSP1(19)-specific IgG1 and IgG3. The precise role of these antibody isotypes in
maintaining malaria immunity remains to be determined.
Am J Trop Med Hyg 2002 Feb;66(2):124-9
Family analysis of malaria infection in Dienga, Gabon.
Domarle O, Migot-Nabias F, Pilkington H, Elissa N, Toure FS, Mayombo J, Cot M,
Centre International de Recherches Medicales de Franceville, Gabon, France.
Fifty children from 9 families were enrolled in a longitudinal study of 8 months
to evaluate individual levels of Plasmodium falciparum density in blood during
asymptomatic infections. Individual parasite densities were adjusted for age and
date of blood intake. The arithmetic means of these adjusted parasite densities
(MAPD) were not influenced by sickle cell trait nor by G6PD enzyme activity. On
the contrary, family analysis revealed the presence of similar MAPD values
according to the sibships. Moreover, sibships frequently infected with P.
malariae exhibited the highest P. falciparum MAPDs. The difference in
aggressiveness of malaria vectors between the northern and southern halves of
the village did not explain the distribution of MAPD, nor did it explain the
differences in mean frequency of P. malariae infection among the sibships. We
conclude that the familial characteristic of susceptibility to both P.
falciparum and P. malariae infections is more likely influenced by the host's
genetic background than by differences in the levels of malaria transmission.
Am J Trop Med Hyg 2002 Feb;66(2):117-23
Molecular epidemiology of malaria in cameroon. IX. Characteristics of
recrudescent and persistent Plasmodium falciparum infections after chloroquine
or amodiaquine treatment in children.
Basco LK, Ndounga M, Keundjian A, Ringwald P.
Institut de Recherche pour le Developpement and Laboratoire de Recherche sur le
Paludisme, Organisation de Coordination de la lutte contre les Endemies en
Afrique Centrale OCEAC, Yaonde, Cameroon, France.
In the absence of a firmly established gene responsible for chloroquine and
amodiaquine resistance in Plasmodium falciparum, surveillance of resistance to
these first-line drugs in Cameroon needs to be performed by in vivo or in vitro
tests for drug resistance. These 2 methodological approaches to define drug
resistance were shown to be complementary and concordant in a majority of cases
at our study sites, but discordant results may be observed in a few cases,
probably as a result of acquired immunity and low plasma drug levels. To further
examine the nature of recrudescent and persistent parasitemia after treatment
with chloroquine or amodiaquine, the clinical response of children aged < 5
years, presumably with insufficient immune response, was assessed, and the in
vitro response of the corresponding isolates was determined if treatment or
parasitological failure occurred. Genotyping of pretreatment and posttreatment
isolates was performed by polymerase chain reaction to distinguish between
recrudescence and reinfection. Plasma drug levels were measured at the time of
therapeutic failure by high-performance liquid chromatography. All cases of
therapeutic or parasitological failure observed on or before Day 14 were due to
the persistence or recrudescence of the original parasite populations present
before treatment, with or without selection and appearance of new populations.
Most parasites were characterized by elevated 50% inhibitory concentrations for
chloroquine and amodiaquine at the time of clinical or parasitological failure.
In some children, recrudescence was explained by the absence of drug in the
plasma. The simultaneous analysis of clinical and in vitro responses, plasma
drug level measurement, and genotyping may yield results that may explain the
reasons for therapeutic failure, help establish the threshold level for in vitro
resistance, and provide a set of more accurate tools to describe the
epidemiology of drug-resistant P. falciparum while awaiting for the
identification of the chloroquine and amodiaquine resistance gene or genes.
Am J Trop Med Hyg 2002 Jan;66(1):56-60
HIV infection, malaria, and pregnancy: a prospective cohort study in Kigali,
Ladner J, Leroy V, Simonon A, Karita E, Bogaerts J, De Clercq A, Van De Perre P,
Dabis F; The Pregnancy and HIV Study Group (EGE).
Medical Information Unit, Centre Hospitalier de Kigali, Rwanda.
In order to study the relation between human immunodeficiency virus (HIV)
infection and malaria in women, during and after pregnancy, a prospective cohort
study was initiated at the Centre Hospitalier de Kigali in Rwanda through
routine voluntary and confidential HIV screening in antenatal clinics. At
inclusion in the cohort of all HIV-positive and an equivalent number of
HIV-negative pregnant women, between 21 and 28 weeks of gestation,
sociodemographic characteristics and medical history during the current
pregnancy were collected; screening for malaria (tick blood smear) and anemia
and a CD4 lymphocyte count were systematically performed. Each woman enrolled
had a monthly follow-up until 6 months after delivery. A clinic was implemented
that was accessible and free of charge to every woman during the study period
between scheduled visits. Malaria infection was systematically screened in case
of fever or other compatible symptoms. The cohort included 228 HIV-positive and
229 HIV-negative women. At inclusion, malaria prevalence was 8.0% in
HIV-positive women and 3.5% in HIV-negative women (P < 0.04). Over the study
period, the incidence of malaria was 6.2 per 100 women-months in the
HIV-positive group and 3.5 in the HIV-negative group (relative risk [RR] = 1.7,
95% confidence interval [CI] = 1.4-2.3). The bulk of the difference occurred
postpartum. The Kaplan-Meier 9-month probability of remaining free of malaria
infection was 51.8% in HIV-positive women and 65.2% in HIV-negative women (P =
0.013). When taking account in the same multivariate model (including HIV
infection, primiparity, CD4 lymphocytes, anemia, and education level), positive
HIV serostatus remained the only factor significantly associated with malaria
infection (RR = 1.4, CI = 1.1-1.6; P = 0.016). Our study prospectively documents
the association between malaria and maternal HIV infection and highlights the
increased risk of malaria occurrence in all HIV-infected women. Strategies to
reduce the malaria morbidity during pregnancy should be reinforced in areas of
high HIV seroprevalence.
Am J Trop Med Hyg 2002 Jan;66(1):2-6
Impact of the malaria control campaign (1993-1998) in the highlands of
Madagascar: parasitological and entomological data.
Romi R, Razaiarimanga MC, Raharimanga R, Rakotondraibe EM, Ranaivo LH, Pietra V,
Raveloson A, Majori G.
Laboratorio di Parassitologia, Istituto Superiore di Sanita, Roma, Italy.
Malaria transmission in the central highlands of Madagascar was interrupted in
the 1960s by a national control program that used DDT indoor spraying and mass
treatment with chloroquine. At the end of the 1980s in this region, epidemic
malaria reappeared. Italian health authorities provided technical assistance to
the National Malaria Control Program since the beginning of the resurgence of
malaria in the central highlands. Yearly residual house spraying performed for 5
years (1993-1998) and the availability of antimalarial drugs reduced malaria
transmission to very low levels, with improvement in parasitologic and
entomologic indexes. A significant reduction of malaria prevalence was observed
in the villages located at altitudes of 1,000-1,500 m, corresponding to the
stratum of unstable malaria that was the main target of the antivector
interventions. A significant reduction of malaria prevalence was also observed
in the villages located at altitudes of 900-1,000 m, where malaria transmission
is stable. The main vector Anopheles funestus was dramatically reduced in
abundance and distribution in the sprayed areas.
Am J Trop Med Hyg 2002 Jan;66(1):18-22
Emergence of a new neotropical malaria vector facilitated by human migration and
changes in land use.
Conn JE, Wilkerson RC, Segura MN, de Souza RT, Schlichting CD, Wirtz RA, Povoa
Department of Biology, University of Vermont, Burlington 05405-0086, USA.
In a region of northeastern Amazonia, we find a species previously of minor
importance, Anopheles marajoara, to be the principal malaria vector. In a total
of five collections during 1996-97 in three replicated sites near the city of
Macapa, Amapa state, this species occurs in much greater abundance compared with
the presumed vector Anopheles darlingi. Also, a significantly higher proportion
of An. marajoara is infected with malaria parasites, determined by the ELISA
technique. This appears to be the result of increased abundance of An. marajoara
due to alterations in land use, invasion of its primary breeding sites by human
immigrants, and its anthropophilic behavior. This discovery highlights one of
the challenges of Neotropical malaria control, namely that the targeting of
specific vectors may be complicated by a changing mosaic of different locally
important vectors and their interactions with human populations.
Am J Trop Med Hyg 2002 Jan;66(1):13-7
Outbreak of vivax malaria in areas adjacent to the demilitarized zone, South
Lee JS, Lee WJ, Cho SH, Ree HI.
Department of Medical Zoology, National Institute of Health, Seoul, Korea.
Malaria had been eradicated in the Republic of Korea (South Korea) by the late
1970s. In 1993, a soldier was infected with Plasmodium vivax malaria in the
Demilitarized Zone (DMZ; the border area between North and South Korea), and
since then, the number of cases has been steadily increasing year after year. In
1998, 3,932 vivax malaria cases were microscopically confirmed, affecting 2,784
(70.8%) soldiers (including discharged soldiers) and 1,148 (29.2%) civilians.
These cases occurred throughout the year, peaking in July (30.1%) and August
(30.5%). Most of the patients were infected in areas in or near the DMZ. Taking
into consideration entomologic, socioecologic, and epidemiologic factors, it is
postulated that there has been an epidemic of malaria in North Korea since 1993,
with the number of cases increasing yearly; the continuous infiltration across
the DMZ from North Korea of infected female mosquitoes of the vector species
Anopheles sinensis resulted in an outbreak of vivax malaria in the DMZ of South
Int J Biometeorol 2002 May;46(2):81-9
The El Nino Southern Oscillation and malaria epidemics in South America.
Gagnon AS, Smoyer-Tomic KE, Bush AB.
Department of Geography, University of Toronto, Ontario, Canada.
A better understanding of the relationship between the El Nino Southern
Oscillation (ENSO), the climatic anomalies it engenders, and malaria epidemics
could help mitigate the world-wide increase in incidence of this
mosquito-transmitted disease. The purpose of this paper is to assess the
possibility of using ENSO forecasts for improving malaria control. This paper
analyses the relationship between ENSO events and malaria epidemics in a number
of South American countries (Colombia, Ecuador, French Guiana, Guyana, Peru,
Suriname, and Venezuela). A statistically significant relationship was found
between El Nino and malaria epidemics in Colombia, Guyana, Peru, and Venezuela.
We demonstrate that flooding engenders malaria epidemics in the dry coastal
region of northern Peru, while droughts favor the development of epidemics in
Colombia and Guyana, and epidemics lag a drought by 1 year in Venezuela. In
Brazil, French Guiana, and Ecuador, where we did not detect an ENSO/malaria
signal, non-climatic factors such as insecticide sprayings, variation in
availability of anti-malaria drugs, and population migration are likely to play
a stronger role in malaria epidemics than ENSO-generated climatic anomalies. In
some South American countries, El Nino forecasts show strong potential for
informing public health efforts to control malaria.
J Infect Dis 2002 Aug 1;186(3):436-40
Expression of Tissue Factor, the Clotting Initiator, on Macrophages in
Plasmodium falciparum-Infected Placentas.
Imamura T, Sugiyama T, Cuevas LE, Makunde R, Nakamura S.
Division of Molecular Pathology, Department of Neuroscience and Immunology,
Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
The expression of tissue factor (TF), the initiator of the clotting system, was
investigated by immunohistochemical staining for its role in clotting mechanisms
of Plasmodium falciparum-infected placenta. Most mononuclear cells in the
intervillous space of infected placentas stained with an anti-TF monoclonal
antibody (MAb) and were positive for antimacrophage MAb. The intervillous space
of infected placentas had significant fibrin deposition. In contrast, only small
amounts of leukocytes, TF-positive cells, and fibrin were seen in the
intervillous space in noninfected placentas. These results indicate that
macrophages accumulated in infected placentas express TF and that subsequent
perivillous fibrin clot formation leads to a narrowing and plugging of the
intervillous space and disturbance of the blood supply. Macrophage TF expression
in placentas could be associated with retarded placental growth and low birth
weight in malaria infection and should be further investigated.
AIDS 2002 Jul 26;16(11):1503-9
Immune activation and induction of HIV-1 replication within CD14 macrophages
during acute Plasmodium falciparum malaria coinfection.
Pisell TL, Hoffman IF, Jere CS, Ballard SB, Molyneux ME, Butera ST, Lawn SD.
HIV and Retrovirology Branch.
OBJECTIVES: To determine the impact of Plasmodium falciparum malaria coinfection
and its treatment on cellular reservoirs of viral replication in HIV-1-infected
persons and to relate this to changes in systemic immune activation. METHODS:
Plasma samples were obtained from HIV-1-infected individuals (n = 10) at
diagnosis of acute malaria, 4 weeks after parasite clearance and from
HIV-infected aparasitemic controls (n = 10). Immunomagnetic HIV-1 capture
analysis was used to determine the cellular origin of cell-free virus particles
present in all 30 plasma samples and indices of immune activation were measured
using enzyme-linked immunosorbent assays. RESULTS: Compared with controls, the
detectable proportion of HIV-1 particles derived from CD14 macrophages and CD26
lymphocytes was increased in persons with acute malaria coinfection and
correlated with markedly increased plasma concentrations of both proinflammatory
cytokines and soluble markers of macrophage and lymphocyte activation. Parasite
clearance following treatment with antimalarial drugs resulted in decreased
detection of HIV-1 particles derived from the CD14 macrophage cell subset and
correlated with a marked diminution in systemic immune activation. CONCLUSIONS:
Acute P. falciparum malaria coinfection impacts virus-host dynamics in
HIV-1-infected persons at the cellular level, notably showing a reversible
induction of HIV-1 replication in CD14 macrophages that is associated with
changes in immune activation.
J Vector Ecol 2002 Jun;27(1):63-9
Role of residual spraying for malaria control in Belize.
Roberts DR, Vanzie E, Bangs MJ, Grieco JP, Lenares H, Hshieh P, Rejmankova E,
Manguin S, Andre RG, Polanco J.
Department of Preventive Medicine and Biometrics, Uniformed Services University
of the Health Sciences, Bethesda, MD 20814-4799, USA.
We studied the impact of reduced residual spraying in Belize by developing a
logistic regression model on relationships between numbers of houses sprayed
(mostly with DDT) and numbers of malaria cases. We defined the "minimum
effective house spray rate" (MEHSR) as the level of spraying that will prevent
increases in malaria rates for a defined population. Under the total coverage
approach (all houses sprayed), the MEHSR for Belize was 134.6. The model also
showed that the odds for decreasing malaria is 1.086 for each increase of 10
houses sprayed per 1,000 population. In further testing, highly significant and
differential changes in malaria rates were documented for paired groups of years
with house spray rates that were either above or below the MEHSR. Numbers of
malaria cases since 1995 are used to show how stratification methods are used in
Belize to spray fewer houses (at levels below the MEHSR of 134.6).
J Vector Ecol 2002 Jun;27(1):102-6
Malaria vectors in Bioko Island (Equatorial Guinea): PCR determination of the
members of Anopheles gambiae Giles complex (Diptera: Culicidae) and pyrethroid
knockdown resistance (kdr) in An. gambiae sensu stricto.
Berzosa PJ, Cano J, Roche J, Rubio JM, Garcia L, Moyano E, Guerra A, Mateos JC,
Petrarca V, Rosario VD, Benito A.
Laboratorio de Malaria, Servicio de Parasitologia, Centro Nacional de
Microbiologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Anopheles gambiae sensu lato Giles, 1902 and Anophelesfunestus Giles, 1900 are
the main malaria vectors on the island of Bioko (Equatorial Guinea). This study
was carried out to determine: a) members of the An. gambiae complex that may be
present on the island of Bioko and, b) the sensitivity of An. gambiae sensu
stricto to pyrethroids. The analysis by PCR detected the presence of An. gambiae
s.s. as the major vector of the complex and the "forest chromosomal form" was
demonstrated by cytogenetic analysis. The presence of Anopheles melas in the
southwest, north and southeast of the island justifies its study as a vector.
The molecular characterization of pyrethroid knockdown resistance (kdr) showed
that the populations of An. gambiae s.s. were sensitive and no mutations were
found. This fact justifies the implementation on a large scale of
pyrethroid-impregnated bednets within the framework of the Malaria Control
Program of Equatorial Guinea.
Indian J Malariol 2001 Sep-Dec;38(3-4):91-8
Dynamics of malaria transmission under changing ecological scenario in and
around Nanak Matta Dam, Uttaranchal, India.
Shukla RP, Sharma SN, Kohli VK, Nanda N, Sharma VP, Subbarao SK.
Malaria Research Centre (Field Station), Inderjeet Garden, Bhotia Parao,
Haldwani-263 141, India.
To understand the transmission dynamics of malaria in three different ecotypes,
namely watershed (forest), seepage (Nanak Matta Dam) and plain (non-forest,
non-dam) areas of Nainital and Udham Singh Nagar districts of Uttaranchal,
entomological and parasitological investigations were carried out from July 1996
to June 1997. In the three ecotypes, average per man hour densities of adult
vector species in human dwellings and cattlesheds recorded were high for
Anopheles culicifacies from April to September and October to March for An.
fluviatilis. Prevalence of both An. culicifacies and An. fluviatilis was higher
in the forest area as compared to other two areas. Observations on gonotrophic
condition revealed endophilic tendency of both vector species. Higher number of
both vector species were found in outdoor than indoor during night human bait
collections. Out of 864 specimens of An. fluviatilis dissected, one showed
natural infection of sporozoites in salivary glands in the month of November
from the forest area only. Sibling species study of An. fluviatilis revealed the
presence of species S for the first time in the forest area. Parasitological
investigations also depicted high incidence of malaria in the forest area as
compared to other two areas. Overall results from the study indicated active
malaria transmission in the forest area.
Indian J Malariol 2001 Sep-Dec;38(3-4):84-90
Serological appraisal of malaria status in tribal area of Orissa, India.
Roy A, Tyagi P, Sharma SK.
Malaria Research Centre (ICMR), Immunology Division, 22-Sham Nath Marg,
A cross-sectional seroepidemiological study conducted in 173 tribal residents
(including all age groups) from three villages of Sundergarh district of Orissa
using ELISA as a tool revealed high levels of antibody titres against both AR1
and Pf antigens. The mean +/- S.D. ELISA O.D. obtained for AR1 were 0.73 +/-
0.2, 1.037 +/- 0.196, 1.05 +/- 0.42 and for Pf, 0.70 +/- 0.2, 1.0 +/- 0.28, 0.94
+/- 0.4 respectively for Badramoli, Jharbeda and Boneikela population.
Parasitological results showed high incidence of malaria in < 5 years age group
in Badramoli and Boneikela villages when compared to other age groups. An.
fluviatilis was found to be the principle malaria vector as found in the HBI
results. High ELISA O.D. and high equivalent transmission index (ETI) indicate a
high malaria transmission in the area. Seroepidemiological studies could be used
for effective surveillance and stratification of endemicity in a given area
which can help in executing intervention strategy for malaria control.
Indian J Malariol 2001 Sep-Dec;38(3-4):76-83
Plasmodium falciparum dihydrofolate reductase Val-16 and Thr-108 mutation
associated with in vivo resistance to antifolate drug: a case study.
Malaria Research Centre, 22-Sham Nath Marg, Delhi-110 054, India.
Due to increasing trend in chloroquine resistance, the antifolate
(sulpha-pyrimethamine combination) drugs are gaining more importance in the
treatment of uncomplicated falciparum malaria. The efficacy of
sulpha-pyrimethamine combinations in the treatment is compromised by the
development of resistance in parasite. The occurrence of mutations at active
sites in Plasmodium falciparum gene sequences coding for dihydrofolate reductase
(DHFR) and dihydropteroate synthetase (DHPS) confer resistance to pyrimethamine
and sulphadoxine. This study presents the characterization of a P. falciparum
sample from a patient who did not respond to standard doses of a
pyrimethamine/sulpha regimen. Although parasitaemia fell rapidly, the infection
had not resolved six days later as because the response to treatment selected
resistant sub-population. The in vitro drug sensitivity assays demonstrated
resistance to pyrimethamine, sulphadoxine and cycloguanil; while polymerase
chain reaction (PCR) and restriction digest based methods indicated that at
known drug resistant loci the isolate had a genotype of DHFR Val-16 and Thr-108
previously only associated with cycloguanil resistance. As per the published
reports this type of paired mutations in natural isolates are rare. It is of
considerable interest to carry out studies on alleles on alleles of this gene in
relation to resistance at epidemiological level.
Indian J Malariol 2001 Sep-Dec;38(3-4):61-75
Impact of urbanization on bionomics of An. culicifacies and An. stephensi in
Batra CP, Adak T, Sharma VP, Mittal PK.
Malaria Research Centre, 2-Nanak Enclave, Delhi-110 009, India.
Study on bionomics of malaria vectors was carried out in riverine and
non-riverine areas, on account of tremendous ecological changes in the
topography of Delhi. The densities of adult anophelines were estimated by two
techniques, hand catch and total catch index. Percentage of An. stephensi
(15.68) collected by both the techniques was more than An. culicifacies (3.16)
in both the areas. Day-time resting preferences of vector species in human
dwellings and cattlesheds did not differ significantly. Preferred larval
habitats of An. culicifacies in riverine area shifted to large lakes, channels
and ponds. In malaria transmission, An. culicifacies played a role only in the
northern part of the riverine area where water pollution was at minimal level,
while An. stephensi played an equal role in the malaria transmission in both the
areas. High sporozoite rates were found in type form of An. stephensi in
localities where its proportion was high, thus confirming its active role in
malaria transmission. The overall sporozoite rate of vectors was 0.7 per cent
and P. falciparum sporozoite infections of the vectors were detected in An.
stephensi only. P. vivax and P. falciparum infections were found in the ratio of
68:32. The non-riverine area was more malarious than the riverine area.
Methods Mol Med 2002;72:535-54
Erythrocytic malaria growth or invasion inhibition assays with emphasis on
suspension culture GIA.
Haynes JD, Moch JK, Smoot DS.
Department of Immunology, Walter Reed Army Institute of Research, Malaria
Program, Naval Medical Research Center, Silver Spring, MD, USA.
Erythrocytic cycle malaria parasite growth or invasion inhibition assays (GIA)
compare the effects of various test and control substances on malaria parasite
growth in erythrocytes or invasion into erythrocytes in vitro. Although
inhibitions by antimalarial drugs in vitro correlate well with drug protective
levels required in vivo, as yet there are too few data to know how well
inhibitions by antibodies in vitro correlate with the types and degrees of
immune protection in vivo. Antibody-mediated GIA is frequently complicated by
parasite strain-specific inhibitions, as well as nonspecific inhibitory factors
generated in sera collected or stored under nonoptimal conditions. In this
chapter, we describe methods for collecting and processing sera, for using
different strains of parasite, and a simplified method for staining parasite DNA
with Hoechst dye 33342 before quantitating parasites using ultraviolet
(UV)-excited flow cytometry. We also describe a new type of GIA using suspension
cultures in a 48-well plate. Critical to this method is enclosing the plate in a
gassed, heat-sealed plastic bag, which, being low mass, can easily be rested at
a 13.5 degrees angle on a rotor platform (114 rpm with 1-in. displacement) to
produce gentle pulsatile waves of media in each well. The suspension GIA, which,
relative to the static GIA, increased inhibition by one antibody and decreased
inhibition by another (Table 1), may better simulate in vivo blood flow and may
thus better predict in vivo efficacy.
Nature 2002 Jul 18;418(6895):323-4
Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum.
Mu J, Duan J, Makova KD, Joy DA, Huynh CQ, Branch OH, Li WH, Su XZ.
Laboratory of Malaria and Vector Research, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland
The Malaria's Eve hypothesis, proposing a severe recent population bottleneck
(about 3,000 5,000 years ago) of the human malaria parasite Plasmodium
falciparum, has prompted a debate about the origin and evolution of the
parasite. The hypothesis implies that the parasite population is relatively
homogeneous, favouring malaria control measures. Other studies, however,
suggested an ancient origin and large effective population size. To test the
hypothesis, we analysed single nucleotide polymorphisms (SNPs) from 204 genes on
chromosome 3 of P. falciparum. We have identified 403 polymorphic sites,
including 238 SNPs and 165 microsatellites, from five parasite clones,
establishing chromosome-wide haplotypes and a dense map with one polymorphic
marker per approximately 2.3 kilobases. On the basis of synonymous SNPs and
non-coding SNPs, we estimate the time to the most recent common ancestor to be
approximately 100,000 180,000 years, significantly older than the proposed
bottleneck. Our estimated divergence time coincides approximately with the start
of human population expansion, and is consistent with a genetically complex
organism able to evade host immunity and other antimalarial efforts.
Nature 2002 Jul 18;418(6895):320-3
Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.
Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ.
Computational Biology Branch, National Center for Biotechnology Information,
National Library of Medicine, National Institutes of Health, Bethesda, Maryland
Widespread use of antimalarial agents can profoundly influence the evolution of
the human malaria parasite Plasmodium falciparum. Recent selective sweeps for
drug-resistant genotypes may have restricted the genetic diversity of this
parasite, resembling effects attributed in current debates to a historic
population bottleneck. Chloroquine-resistant (CQR) parasites were initially
reported about 45 years ago from two foci in southeast Asia and South America,
but the number of CQR founder mutations and the impact of chlorquine on parasite
genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic
microsatellite markers from a genetic map, here we show that the level of
genetic diversity varies substantially among different regions of the parasite
genome, revealing extensive linkage disequilibrium surrounding the key CQR gene
pfcrt and at least four CQR founder events. This disequilibrium and its decay
rate in the pfcrt-flanking region are consistent with strong directional
selective sweeps occurring over only approximately 20 80 sexual generations,
especially a single resistant pfcrt haplotype spreading to very high frequencies
throughout most of Asia and Africa. The presence of linkage disequilibrium
provides a basis for mapping genes under drug selection in P. falciparum.