Environmental risk factors for clinical malaria: a case-control study in the Grau region of Peru.


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Environmental risk factors for clinical malaria: a case-control study in the Grau region of Peru.

Guthmann JP, Hall AJ, Jaffar S, Palacios A, Lines J, Llanos-Cuentas A.

Department of Infectious and Tropical Disease, Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, UK. [email protected]

The role of environmental risk factors in clinical malaria has been studied mainly in Africa and Asia, few investigations have been carried out in Latin America. Field observations in northern coastal Peru, where the prevalence of malaria is high during the agricultural season, suggested that the risk of disease varied according to the characteristics of the house and the house environment. Environmental determinants of the risk of clinical malaria were therefore investigated through a case-control study: 323 clinical cases of malaria, recruited through community-based active case-finding, and 969 age-, sex- and village-matched controls were recruited into the study over a period of 12 months ending June 1997. Residual spraying of houses in the previous 6 months, living more than 100 m from a canal, a level of education equal to primary school or above and working in agriculture conferred significant protection from the risk of developing clinical malaria. The presence of spaces between the wall and roof in the subject’s bedroom (eaves) and a house aged > 4 years statistically significantly increased the risk of disease. Based on these results we discuss possible control measures for malaria in this area of the country.

J Biosoc Sci 2002 Jan;34(1):109-31

Intra-household relations and treatment decision-making for childhood illness: a Kenyan case study.

Molyneuxt CS, Murira G, Masha J, Snow RW.

Kenya Melical Research Institute, Centre for Geographic Medicine Research, Kilifi.

This study, conducted on the Kenyan coast, assesses the effect of intra-household relations on maternal treatment-seeking. Rural and urban Mijikenda mothers’ responses to childhood fevers in the last 2 weeks (n=317), and to childhood convulsions in the previous year (n=43), were documented through survey work. The intra-household relations and decision-making dynamics surrounding maternal responses were explored through in-depth individual and group interviews, primarily with women (n=223). Responses to convulsions were more likely than responses to fevers to include a healer consultation (p<0.0001), and less likely to include the purchase of over-the-counter medications (p<0.0001). Mothers received financial or advisory assistance from others in 71% (n=236) of actions taken outside the household in response to fevers. In-depth interviews suggested that general agreement on appropriate therapy results in relatively few intra-household conflicts over the treatment of fevers. Disputes over perceived cause and appropriate therapy of convulsions, however, highlighted the importance of age, gender and relationship to household head in intra-household relations and treatment decision-making. Although mothers’ treatment-seeking preferences are often circumscribed by these relations, a number of strategies can be drawn upon to circumvent ‘inappropriate’ decisions, sometimes with implications for future household responses to similar syndromes. The findings highlight the complexity of intra-household relations and treatment decision-making dynamics. Tentative implications for interventions aimed at improving the home management of malaria, and for further research, are presented.


Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):677-80

Ex-vivo short-term culture and developmental assessment of Plasmodium vivax.

Chotivanich K, Silamut K, Udomsangpetch R, Stepniewska KA, Pukrittayakamee S, Looareesuwan S, White NJ.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [email protected]

A simple reproducible method for short-term ex-vivo Plasmodium vivax culture is presented in which glucose, ascorbic acid, thiamine, hypoxanthine, and 50% human AB+ serum are added to the standard P. falciparum in-vitro culture medium. Culture of freshly obtained blood samples from patients with acute vivax malaria with > 0.5% parasitaemia resulted in > 95% complete schizogony. Culture could be continued for 5-6 cycles without the addition of red cells. Criteria for staging the erythrocytic development of P. vivax in the first schizogonic cycle based on synchronous ex-vivo culture are presented. The asexual cycle was divided into 7 morphological stages: tiny ring (0-6 h), small ring (6-12 h), large ring (12-18 h), early trophozoite (18-28 h), late trophozoite (28-36 h), early schizont (36-42 h) and mature schizont (42-48 h). This simple method of culturing P. vivax ex vivo is suitable for antimalarial susceptibility and immunoparasitology studies.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):661-7

A randomized controlled trial on the efficacy of alternative treatment regimens for uncomplicated falciparum malaria in a multidrug-resistant falciparum area of Bangladesh–narrowing the options for the National Malaria Control Programme?

Rahman MR, Paul DC, Rashid M, Ghosh A, Bangali AM, Jalil MA, Faiz MA.

Department of Medicine, Chittagong Medical College, Chittagong 4000. [email protected]

We performed an open, randomized chemotherapy trial comparing the recommended first-, second- and third-line drug regimens, as well as mefloquine, for uncomplicated falciparum malaria in Bangladesh in 1996-97. The regimens were chloroquine for 3 days (CQ, Group I), quinine sulphate for 3 days followed by single-dose sfulfadoxine-pyrimethamine (Q3 + SP, Group II), quinine for 7 days (Q7, Group III), and mefloquine 20 mg/kg single dose (MEF, Group IV). Subjects were symptomatic patients, aged > or = 12 years, with parasite density 500-250,000/mm3 and no history of taking antimalarials during the previous week. Drug administration was supervised and subjects were followed clinically and with blood slides in the hospital for 8 days, then as outpatients on days 14, 21 and 28. A total of 413 subjects (149, 145, 49 and 70 in Groups I-IV, respectively) completed the study. Early treatment failures (persistent or worsening clinical manifestations by day 3 confirmed with parasitological examinations) occurred only in the chloroquine group. RII and RIII parasitological failures occurred in 56%, 12%, 8% and 14% in Group I-IV, respectively. There were significantly more clinical and parasitological failures with chloroquine than with Q3 + SP, which we now recommend as a better (but far from ideal) choice for first-line therapy. The alternative compounds show parasitogical evidence of Plasmodium falciparum resistance. Further studies are needed to determine the optimum treatment for malaria in Bangladesh.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):657-60

Co-trimoxazole compared with sulfadoxine-pyrimethamine in the treatment of uncomplicated malaria in Kenyan children.

Omar SA, Bakari A, Owiti A, Adagu IS, Warhurst DC.

Centre for Biotechnology Research Development, Kenya Medical Research Institute, P.O. Box 54840, Mbagathi Road, Nairobi, Kenya. 
[email protected]

Sulfadoxine-pyrimethamine (SP) and co-trimoxazole were both effective in reducing fever, clearing parasitaemia and improving anaemia in children aged < 5 years with uncomplicated malaria in 2 Kenyan endemic sites, Oyugis in the west and Tiwi on the coast. We compared the efficacy of these 2 regimens (in May-July 1998) by evaluating clinical and parasitological responses over 14 days. The combined incidence of parasitological failure for the combined sites for co-trimoxazole was 14/123 (11%) and for SP 23/145 (16%) (RR 0.72, 95% confidence interval [CI] 0.31-1.46, P = 0.289). The 14-day clinical failure rate for the combined sites for co-trimoxazole was 4/123 (3.3%), and for SP 8/145 (5.5%), (RR 1.69, 95% CI 0.91-3.15, P = 0.129). The results indicate that the risk of treatment failure for the 2 regimens was similar. The antimalarial use of co-trimoxazole in uncomplicated malaria needs further investigation, since the 10-12-h elimination half-life of both components should reduce selective pressure for resistance. In addition, use of a 2-day high-dose course, tested previously, requires further study to demonstrate its efficacy.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):651-6

Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy.

McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, Looareesuwan S, White NJ, Nosten F.

Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot 63110, Thailand.

In areas where multidrug-resistant Plasmodium falciparum (MDR-Pf) is prevalent, only quinine is known to be safe and effective in pregnant women. On the western border of Thailand, 7 days of supervised quinine (30 mg/kg daily) cures two-thirds of P. falciparum-infected women in the 2nd and 3rd trimesters of pregnancy. Artesunate is effective against MDR-Pf and the limited data on its use in pregnancy suggest it is safe. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) in combination with clindamycin (5 mg/kg every 8 h) for 7 days (QC7) versus artesunate 2 mg/kg per day for 7 days (A7) was conducted in 1997-2000 in 129 Karen women with acute uncomplicated falciparum malaria in the 2nd or 3rd trimesters of pregnancy. There was no difference in the day-42 cure rates between the QC7 (n = 65) and A7 (n = 64) regimens with an efficacy of 100% in both, confirmed by parasite genotyping. The A7 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for A7 was 3 (95% CI 0-19) and for QC7 was 39 (95% CI 21-66) per 1000 person-weeks, respectively (P < 0.01). There was no difference in gastrointestinal symptoms between the groups but there was significantly more tinnitus in the QC7 group compared to the A7 group (44.9% vs 8.9%; RR 5.1; 95% CI 1.9-13.5; P < 0.001). The favourable results with quinine-clindamycin mean that there is a useful back-up treatment for women with falciparum malaria who experience quinine and artesunate failures in pregnancy. Adherence to the 7-day regimen and cost (US$18.50 per treatment) are likely to be the main obstacles to this regimen.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):637-50

A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria.

Artemether-Quinine Meta-analysis Study Group.

We conducted a meta-analysis using individual patient data from randomized controlled trials comparing artemether and quinine in severe falciparum malaria. Eleven trials were identified, of which 8 were clearly randomized. Original individual patient data on 1919 patients were obtained from 7 trials, representing 85% of the patients in the original 11 studies. Overall there were 136 deaths among the 961 patients treated with artemether, compared with 164 in the 958 treated with quinine [14% vs 17%, odds ratio (95% confidence interval) 0.8 (0.62 to 1.02), P = 0.08]. There were no differences between the 2 treatment groups in coma recovery or fever clearance times, or the development of neurological sequelae. However, the combined ‘adverse outcome’ of either death or neurological sequelae was significantly less common in the artemether group [odds ratio (95% CI) 0.77 (0.62 to 0.96), P = 0.02], and treatment with artemether was associated with significantly faster parasite clearance [hazard ratio (95% CI) 0.62 (0.56 to 0.69), P < 0.001]. In subgroup analyses artemether was associated with a significantly lower mortality than quinine in adults with multisystem failure. In the treatment of severe falciparum malaria artemether is at least as effective as quinine in terms of mortality and superior to quinine in terms of overall serious adverse events. There was no evidence of clinical neurotoxicity or any other major side-effects associated with its use.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):618-21

Correlation of retinal haemorrhages with brain haemorrhages in children dying of cerebral malaria in Malawi.

White VA, Lewallen S, Beare N, Kayira K, Carr RA, Taylor TE.

Departments of Pathology and Ophthalmology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada.

Retinal haemorrhages increase in number with severity of Plasmodium falciparum malaria and occur in 35-40% of children with cerebral malaria. We performed clinical retinal examinations and histopathological examinations of retina, and parietal and cerebellar sections of the brains, in 33 children in Malawi who died with cerebral malaria, severe malaria anaemia, or coma of other causes. Haemorrhages were counted in a standardized fashion: the Spearman correlation coefficient between the number of haemorrhages in retina and brain was 0.741 for parietal tissue and 0.703 for cerebellar (P < 0.01 for both). Severity of haemorrhage in the retina correlates well with that in the brain. Retinal examination in cerebral malaria is a useful tool in predicting some of the pathophysiological processes occurring in the brain.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):611-7

Acute haemolysis in childhood falciparum malaria.

Ekvall H, Arese P, Turrini F, Ayi K, Mannu F, Premji Z, Bjorkman A.

Unit of Infectious Diseases, Karolinska Institutet, Karolinska Hospital, 171 76 Stockholm, Sweden. 
[email protected]

Acute haemolysis associated with clinical episodes of high-level Plasmodium falciparum parasitaemia was studied in 20 children from an holoendemic area (coastal Tanzania). The change in blood haemoglobin (Hb) concentration ranged from -46 to g/L during the 72-h observation period and was linearly related to maximum parasitaemia. Balance studies between loss of blood Hb, increase in plasma Hb and appearance of Hb in the urine indicated that extravascular clearance of red cells was the predominant mode of erythrocyte clearance. Most subjects, however, showed minor signs of intravascular haemolysis. The plasma Hb was << 1% of blood Hb and haemoglobinuria was detected in 14/20 children but the excretion of Hb in urine was < 0.5% of total Hb loss. Haemoglobinuria was, however, a marker of severe haemolysis, since the maximum blood Hb loss in children without haemoglobinuria was 10 g/L. Erythrocyte-bound opsonins known to induce erythrophagocytosis, i.e., complement C3c fragments and autologous IgG, were increased in all patients. In the patients with major haemolysis, the changes correlated to the haemolysis over time. Hence, a similar mechanism for predominantly extravascular erythrocyte clearance may be operative in acute malarial anaemia, normal erythrocyte senescence and other forms of acute haemolysis.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):587-90

Evidence for memorized site-fidelity in Anopheles arabiensis.

McCall PJ, Mosha FW, Njunwa KJ, Sherlock K.

Division of Parasite and Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. [email protected]

A mark-recapture experiment was carried out in northern Tanzania to determine whether Anopheles arabiensis exhibits memory, by investigating if bloodfed individuals would return to either the location or the host where or on which they had obtained a previous bloodmeal, behaviours termed site-fidelity and host-fidelity respectively. Over 4300 mosquitoes were collected from 2 houses, marked with different fluorescent colours according to whether they were caught in cattle sheds, ‘cattle-fed’, or within human bednets, ‘human-fed’, at either location, then released from a third location. Over 17,000 mosquitoes were collected and examined over the next 8 days. In total, 1% of released mosquitoes were recaptured. Of these, 68% had returned to the house where they were first caught, demonstrating site-fidelity (P = 0.007). However, 86% of recaptured mosquitoes were caught on cattle regardless of where they were initially caught (P = 0.185). Bloodmeal identification showed that a high proportion of mosquitoes classed as human-fed contained bovine blood, thereby confounding the investigation into host-fidelity. Notably, the proportion of mosquitoes with mixed bloodmeals depended on the proximity of cattle and humans, with significantly higher proportions of mixed bloodmeals occurring when cattle and humans slept in close proximity. The effects of the observed behaviours on malaria epidemiology are discussed.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):584-6

The feeding behaviour and Plasmodium infection of Anopheles mosquitoes in southern Ethiopia in relation to use of insecticide-treated livestock for malaria control.

Habtewold T, Walker AR, Curtis CF, Osir EO, Thapa N.

FARM-Africa, 9 Southampton Place, London WC1a 2EA, UK.

Anopheles arabiensis and An. quadriannulatus species B mosquitoes were collected at sites of human and livestock housing and analysed for blood feeding patterns and infection with malaria sporozoites. A low percentage of human blood meals at some sites suggested that zooprophylaxis could be effective in reducing challenge from Plasmodium falciparum.

Trans R Soc Trop Med Hyg 2001 Nov-Dec;95(6):569-76

Malaria in pregnancy as an indirect cause of infant mortality in sub-Saharan Africa.

Guyatt HL, Snow RW.

Kenya Medical Research Institute/Wellcome Trust Collaborative Programme, P.O. Box 43640, Nairobi, Kenya. 
[email protected]

Although randomized controlled trials of interventions to reduce malaria in pregnancy have demonstrated an increase in the birthweight of the newborn in primigravidae, the subsequent impact on infant mortality in all-parities has not been assessed. The aim of this paper was to model the possible impact of placental malarial infection on infant mortality through reduced birthweight. An extensive literature search was undertaken to define a series of parameters describing the associations between placental infection, birthweight and premature mortality in sub-Saharan Africa. It was shown that a baby is twice as likely to be born of low birthweight if the mother has an infected placenta at the time of delivery (all-parities: 23% vs 11%, primigravidae only: 32% vs 16%), and that the probability of premature mortality of African newborns in the first year of life is 3 times higher in babies of low birthweight than in those of normal birthweight (16% vs 4.6%). Assuming 25% of pregnant women in malaria-endemic areas of Africa harbour placental malarial infection, it is suggested that 5.7% of infant deaths in malarious areas could be an indirect cause of malaria in pregnancy. This would imply that, in 1997, malaria in pregnancy could have been responsible for around 3700 infant deaths under the diverse epidemiological conditions in Kenya. Placental infection with Plasmodium falciparum appears to have a more significant role in infant survival in Africa than has been previously assumed. This may explain the high reduction in infant mortality rates from interventions aimed at reducing transmission, over and above that expected from a decline in direct malaria-specific mortality alone.

Mol Biochem Parasitol 2002 Feb;119(2):273-8

RNA interference (RNAi) inhibits growth of Plasmodium falciparum.

McRobert L, McConkey GA.

School of Biology, University of Leeds, LS2 9JT, Leeds, UK

RNA interference (RNAi) causes degradation of targeted endogenous RNA in many diverse organisms. Erythrocyte-infecting stages of the malaria parasite Plasmodium falciparum were treated with double-stranded RNA (dsRNA) encoding a segment of the gene encoding dihydroorotate dehydrogenase (DHODH). DHODH is an enzyme in pyrimidine biosynthesis, essential for parasite growth. A decrease in parasite growth (P<0.0005) correlated with a decrease in levels of DHODH mRNA. Control treatments with single-stranded RNA, dsRNA encoding the circumsporozoite protein (a stage-specific protein not expressed in the asexual blood stage) and dsRNA encoding a gene from the related organism Toxoplasma gondii did not inhibit growth. As a test for the RNAi assay, parasites were treated with dsRNA encoding chorismate synthase (CS), an enzyme thought to be involved in folate synthesis, to examine the requirement for this enzyme for parasite growth. Growth decreased (P<0.001) though less markedly than by dsRNA encoding DHODH. These results demonstrate the utility of this assay in assessing requirements for gene products, and their potential as chemotherapeutic targets.

Mol Biochem Parasitol 2002 Feb;119(2):249-56

Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins.

Krugliak M, Zhang J, Ginsburg H.

Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

It is generally accepted that intraerythrocytic malaria parasites digest hemoglobin to supply the amino acids needed for the synthesis of their own proteins. This view has never been quantitatively tested. In this investigation we have measured the degradation of hemoglobin and the increase in parasite protein content as a function of parasite maturation in cultures of Plasmodium falciparum. Defined parasite stages were obtained either from tightly synchronized cultures or from asynchronous cultures after density-fractionation. We showed that both hemoglobin digestion and total parasite protein content increased with parasite maturation, from the early trophozoite stage onwards, although the total protein content of the parasite remained significantly lower than that of other eukaryotes. The parasite digested up to 65% of the host cell’s hemoglobin but utilized only up to about 16% of the amino acids derived from hemoglobin digestion. This large discrepancy is profoundly puzzling particularly in view of the need to detoxify the cell from the large quantities of ferriprotoporphyrin IX and iron released during hemoglobin digestion.

SAR QSAR Environ Res 2001;12(6):547-64

Molecular modeling and 3D-QSAR studies in 2-aziridinyl-and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives as potential antimalarial agents.

Pandey SK, Naware NB, Trivedi P, Saxena AK.

Medicinal Chemistry Division, Central Drug Research Institute, (CDRI) Chattar Manzil, Lucknow, India.

Malaria is still continuing to be one of the most dreadful diseases of the tropical countries particularly due to the development of resistance to the existing antimalarials. From observed, antimalarial activity of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives acting through redox cycling mechanism, molecular modeling and three dimensional-quantitative structure activity relationship (3D-QSAR) studies have been carried out on a set of 63 compounds to identify important pharmacophors. Among several 3D-QSAR models generated, three models with correlation coefficient r > 0.82, match > 0.60 and chance = 0.00 have shown two common biophoric sites: one being the oxygen atom at position 1 of the naphthoquinone ring in terms of pi-population, charge and electron donating ability while the second being the center of the phenyl ring in terms of its 6pi-electrons. In addition to these sites, the models also share two common secondary sites: one positively contributing H-acceptor site while the second site contributing negatively in terms of steric refractivity. All these models showed good agreement between the experimental, calculated and predicted antimalarial activities.

Rev Soc Bras Med Trop 2001 Nov-Dec;34(6):591-5

Duffy blood group genotypes among malaria patients in Rondonia, Western Brazilian Amazon.

Cavasini CE, Pereira FJ, Ribeiro WL, Wunderlich G, Ferreira MU.

Laboratorio de Parasitologia Molecular, Faculdade de Medicina de Sao Jose do Rio Preto, Sao Jose do Rio Preto, SP.

We have compared Duffy blood group genotype distribution, as determined by polymerase chain reaction with allele-specific primers, in 68 Plasmodium vivax-infected patients and 59 non-vivax malaria controls from Rondonia, Brazil. Homozygosity for the allele Fy, which abolishes Duffy antigen expression on erythrocytes, was observed in 12% non-vivax controls but in no P. vivax patient. However, no significant association was found between Fy heterozygosity and protection against P. vivax. The Fy x allele, which has recently been associated with very weak erythrocyte expression of Duffy antigen, was not found in local P. vivax patients.

Med Hypotheses 2002 Feb;58(2):148-56

A model of development of acquired immunity to malaria in humans living under endemic conditions.

Taylor-Robinson AW.

School of Biology, University of Leeds, UK

Malaria remains a significant global health problem. Most morbidity and mortality in an endemic setting is in children less than 5 years old, and increasing resistance to infection and disease with age is thought to reflect a slow, gradual acquisition of protective immunity. It is not clear if the semi-immune status of adults, in which parasites are present at below clinical threshold, is the result of cumulative exposure to Plasmodium falciparum or reflects an underlying difference between adult and infant immunity. Immuno-epidemiological studies of people living in malaria-endemic areas have not produced consistent examples of surrogate markers of protection. This gulf in our understanding of immunity to malaria may be addressed by novel application of an established murine model of immune regulation of blood stage infection. This exploits two examples of loss of immunity, selective immunosuppression in pregnancy, and waning of maternally transferred protection in neonates, to distinguish the immunological determinants involved in the radical transition between susceptible and resistant immune status. It is suggested that application of this unique model should significantly advance knowledge of how acquired immunity to malaria develops and is highly relevant to the pathogenesis of malaria in human pregnancy and the design of antimalarial vaccines for use in children. Copyright 2002 Harcourt Publishers Ltd.

Parasitology 2002 Jan;124(Pt 1):9-15

Mathematical modelling of malaria chemotherapy: combining artesunate and mefloquine.

Hoshen MB, Stein WD, Ginsburg H.

MALSAT, Liverpool School of Tropical Medicine, The University of Liverpool, UK.

Clinical data on the use of artesunate combined with mefloquine in a variety of treatment regimens and parasite loads in Thailand were modelled on the basis of experimentally determined pharmacokinetic data. The model assumed no pharmacodynamic interaction between artesunate and mefloquine, but that the parasites were already resistant to mefloquine. Predictions of the model accorded well with the data. In articular, in accordance with clinical observations, the model showed that monotherapy with either drug failed to cure at moderate parasitaemia, yet such patients could be treated effectively with the combination of 3 days of artesunate + mefloquine. For high levels of parasitaemia, 5 days of artesunate + mefloquine were needed. Simulations were also performed for situations of lower resistance to mefloquine and for the immune human populations found in Africa. The importance of mathematical modelling of combination therapy is borne out by this study and suggests its wider application for other drug combinations.

Science 2002 Jan 25;295(5555):677-9

Complete development of mosquito phases of the malaria parasite in vitro.

Al-Olayan EM, Beetsma AL, Butcher GA, Sinden RE, Hurd H.

Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Staffordshire ST5 5BG, UK.

Methods for reproducible in vitro development of the mosquito stages of malaria parasites to produce infective sporozoites have been elusive for over 40 years. We 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. The entire life cycle of P. berghei, a useful model malaria parasite, can now be achieved in vitro.

J Exp Biol 2001 Dec;204(Pt 23):4157-67

A snake venom phospholipase A(2) blocks malaria parasite development in the mosquito midgut by inhibiting ookinete association with the midgut surface.

Zieler H, Keister DB, Dvorak JA, Ribeiro JM.

Medical Entomology Section, Malaria Vaccines Section and. Biophysical Parasitology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0425, USA.

Oocyst formation is a critical stage in the development of the malaria parasite in the mosquito. We have discovered that the phospholipase A(2) (PLA2) from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus) inhibits oocyst formation when added to infected chicken blood and fed to mosquitoes. A similar transmission-blocking activity was demonstrated for PLA2s from the venom of other snakes and from the honeybee. This effect is seen both with the avian malaria parasite Plasmodium gallinaceum and with the human parasite Plasmodium falciparum developing in their respective mosquito hosts. The inhibition occurs even in the presence of an irreversible inhibitor of the active site of PLA2, indicating that the hydrolytic activity of the enzyme is not required for the antiparasitic effect. Inhibition is also seen when the enzyme is fed to mosquitoes together with ookinetes, suggesting that the inhibition occurs after ookinete maturation. PLA2 has no direct effect on the parasite. However, pretreatment of midguts with PLA2 (catalytically active or inactive) dramatically lowers the level of ookinete/midgut association in vitro. It appears, therefore, that PLA2 is acting by associating with the midgut surface and preventing ookinete attachment to this surface. Thus, PLA2 is an excellent candidate for expression in transgenic mosquitoes as a means of inhibiting the transmission of malaria.

J Infect Dis 2002 Feb 1;185(3):380-8

Molecular Markers for Failure of Sulfadoxine-Pyrimethamine and Chlorproguanil-Dapsone Treatment of Plasmodium falciparum Malaria.

Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV.

Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA and Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi. 
[email protected]

Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the “quintuple mutant”) were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.

Blood 2002 Feb 1;99(3):1060-3

Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells.

Glenister FK, Coppel RL, Cowman AF, Mohandas N, Cooke BM.

Department of Microbiology, Monash University, Clayton, Victoria, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and the Life Sciences Division, Lawrence Berkeley Laboratory, CA.

Red blood cells (RBCs) parasitized by Plasmodium falciparum are rigid and poorly deformable and show abnormal circulatory behavior. During parasite development, knob-associated histidine-rich protein (KAHRP) and P falciparum erythrocyte membrane protein 3 (PfEMP3) are exported from the parasite and interact with the RBC membrane skeleton. Using micropipette aspiration, the membrane shear elastic modulus of RBCs infected with transgenic parasites (with kahrp or pfemp3 genes deleted) was measured to determine the contribution of these proteins to the increased rigidity of parasitized RBCs (PRBCs). In the absence of either protein, the level of membrane rigidification was significantly less than that caused by the normal parental parasite clone. KAHRP had a significantly greater effect on rigidification than PfEMP3, contributing approximately 51% of the overall increase that occurs in PRBCs compared to 15% for PfEMP3. This study provides the first quantitative information on the contribution of specific parasite proteins to altered mechanical properties of PRBCs. (Blood. 2002;99:1060-1063)

J Med Chem 2002 Jan 31;45(3):748-51

New Neplanocin Analogues. 12. Alternative Synthesis and Antimalarial Effect of (6’R)-6′-C-Methylneplanocin A, a Potent AdoHcy Hydrolase Inhibitor(1).

Shuto S, Minakawa N, Niizuma S, Kim HS, Wataya Y, Matsuda A.

Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, and Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan.

An improved method for the synthesis of (6’R)-6′-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl(3) to the neplanocin A 6′-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC(50) value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC(50) = 1.8 mg/kg/day).

J Biol Chem 2002 Jan 22; Free full-text article at http://www.jbc.org

PiggyBac-mediated germline transformation of the malaria mosquito Anopheles stephensi using the red fluorescent protein dsRED as a selectable marker.

Nolan T, Bower TM, Brown AE, Crisanti A, Catteruccia F.

Biological Sciences, Imperial College of Science, Technology and Medicine, London SW7 2AZ.

It is estimated that every year malaria infects approximately 300 million people and accounts for the death of 2 million individuals. The Plasmodium parasites that cause malaria in humans are transmitted exclusively by mosquito species belonging to the Anopheles genus. The recent development of a gene transfer technology for Anopheles stephensi mosquitoes, using the Minos transposable element marked with the enhanced green fluorescent protein EGFP(1), provides now a powerful tool to investigate the role of mosquito molecules involved in the interaction with the malaria parasite. Such technology, when further developed with additional markers and transposable elements, will be invaluable for analysing the biology of the vector and for developing malaria resistant mosquitoes to be used as a tool to control malaria transmission in the field. We report here the germline transformation of A. stephensi mosquitoes using a piggyBac-based transposon(2) to drive integration of the gene encoding for the red fluorescent protein dsRED(3). A. stephensi embryos were injected with transformation vector pPBRED, containing the dsRED marker cloned within the arms of piggyBac. Microscopic analysis of G1 larvae revealed the presence of 7 fluorescent phenotypes, whose different molecular origins were confirmed by Southern blotting analysis. Sequencing of the insertion sites in two lines demonstrated that integrations had occurred at TTAA nucleotides, in accordance with piggyBac-mediated transpositions.

J Am Mosq Control Assoc 2001 Dec;17(4):216-20

Epidemiologic investigations of a malaria outbreak in northern Delhi area.

Ansari MA, Sharma YD, Roy A, Biswas S, Sharma PK.

Malaria Research Centre, Vikas Marg, Delhi, India.

Epidemiologic investigations revealed a 56.7 and 13.32% slide positivity rate in febrile and afebrile malaria cases, respectively. In both cases, Plasmodium falciparum was predominant. Anopheles culicifacies resistant to dichlorodiphenyltrichloroethane and benzene hexachloride (hexachlorocyclohexane) was found breeding profusely in pools and ponds created by excavation of earth around brick kiln in the region. Furthermore, children were not found to be producing significant levels of antibodies and a large percentage of patients harbored chloroquine-resistant parasites. Also, more than 1 P. falciparum strain was present in the population. We detected 2 strains, VI and VII, of which type VI was predominant.

Clin Infect Dis 2002 Mar 1;34(5):572-576

Imported Falciparum Malaria in Europe: Sentinel Surveillance Data from the European Network on Surveillance of Imported Infectious Diseases.

Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, Matteelli A, Clerinx J, Corachan M, Puente S, Gjorup I, Harms G, Kollaritsch H, Kotlowski A, Bjorkmann A, Delmont JP, Knobloch J, Nielsen LN, Cuadros J, Hatz C, Beran J, Schmid ML, Schulze M, Lopez-Velez R, Fleischer K, Kapaun A, McWhinney P, Kern P, Atougia J, Fry G, da Cunha S, Boecken G.

Department of Infectious Diseases and Tropical Medicine, University of Munich, 80802 Munich, Germany. 
[email protected]

Malaria continues to have a high morbidity rate associated among European travelers. Thorough recording of epidemiological and clinical aspects of imported malaria has been helpful in the detection of new outbreaks and areas of developing drug resistance. Sentinel surveillance of data collected prospectively since 1999 has begun within TropNetEurop, a European network focusing on imported infectious diseases. TropNetEurop appears to cover [similar]10% of all patients with malaria seen in Europe. Reports of 1659 immigrants and European patients with Plasmodium falciparum malaria were analyzed for epidemiological information and data on clinical features. Regional data were quite diverse, reflecting local patterns of immigration and international travel. By far, the most infections were imported from West Africa. Europeans had more clinical complications; consequently, all deaths occurred in this group. Compared with European standards, the mortality rate was low (0.6% in Europeans). Data from TropNetEurop member sites can contribute to our understanding of the epidemiological and clinical findings regarding imported falciparum malaria.

Vaccine 2002 Jan 15;20(7-8):1039-45

Enhanced CD8 T cell immunogenicity and protective efficacy in a mouse malaria model using a recombinant adenoviral vaccine in heterologous prime-boost immunisation regimes.

Gilbert SC, Schneider J, Hannan CM, Hu JT, Plebanski M, Sinden R, Hill AV.

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN, Oxford, UK

Recombinant replication-defective adenovirus expressing the CS gene from Plasmodium berghei (Ad-PbCS) was found to induce a strong CD8(+) T cell response after intra-dermal or -muscular immunisation. Boosting of an adenovirus-primed immune response with the replication-impaired poxvirus, modified vaccinia virus Ankara (MVA) led to enhanced immunogenicity and substantial protective efficacy. The recombinant adenoviral vaccine was capable of boosting to protective levels a CD8(+) T cell response primed by either a plasmid DNA vaccine, a recombinant Ty virus-like particle vaccine or recombinant MVA each expressing the same epitope or antigen. Complete protective efficacy after intradermal immunisation was observed with the adenovirus prime-MVA boost regime. This study identifies recombinant replication-defective adenovirus as an alternative to recombinant replication-defective poxviruses as boosting agents for the induction of strong protective CD8(+) T cell responses.

Wien Klin Wochenschr 2001 Dec 17;113(23-24):927-9

Atopy and malaria.

Lell B, Borrmann S, Yazdanbakhsh M, Kremsner PG.

Medical Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon. [email protected]

The last decades have seen a dramatic rise in the prevalence of allergic diseases throughout the industrialised world. The “hygiene hypothesis” postulates that this is due to a reduced exposure to infections during childhood. A cohort study in children from Gabon gave us the unique opportunity to examine the relationship between exposure to P. falciparum and atopy. 91 children, who had been closely followed for an average of 5 years and of whom the exact incidence of malaria attacks was known, underwent a skin-prick test with mite antigen. 16 children (18%) had a positive reaction. Gender or age had no effect on the outcome of the test. However, those tested positive had had less infections and a lower incidence of malaria than children tested negative (p = 0.017). Survival analysis shows that children with a high exposure to P. falciparum were at lower risk of an atopic skin reaction (p = 0.001). We postulate that the low exposure to the malaria parasite contributes to the development of an imbalanced immune system with a subsequent higher reactivity to the allergen tested. Immuno-suppression is commonly seen during a malaria attack and this correlates positively with the level of anti-inflammatory cytokines such as interleukin-10. High exposure to parasite antigens might counterbalance pro-inflammatory immune reactions and thus protect against allergic diseases. A better understanding of the relationship between parasitic infection and allergy will help us to develop strategies to prevent allergic disease without being exposed to infectious diseases.

Parasite 2001 Dec;8(4):297-308

Malaria Control in Madagascar

Brutus L, Le Goff G, Rasoloniaina LG, Rajaonarivelo V, Raveloson A, Cot M.

Institut de Recherche pour le Developpement (IRD), Programme Paludisme, BP 434, Antananarivo, Madagascar.

For malaria vector control in Madagascar, the efficacy of lambda-cyhalothrin 10% wettable powder (ICON 10 WP) was compared with DDT 75% WP for house-spraying. This evaluation was conducted from November 1997 to September 1998 in highland villages of Vakinankaratra Region, at the fringe of the malaria epidemic zone, outside the zone covered by routine DDT house-spraying (Operation de pulverisation intro-domiciliaire de DDT: OPID zone). Treatments were compared by house-spraying in four areas: 1) application of DDT 2g ai/m2 and 2) lambda-cyhalothrin 30 mg ai/m2 in previously unsprayed villages; 3) no intervention (control); 4) OPID 5th cycle of DDT 2g ai/m2. The prevalent vector Anopheles funestus almost disappeared from both the DDT and ICON sprayed areas, whereas in the unsprayed (control) area An. funeslus density went up to 60 females per room in April and there were two seasonal peaks of malaria transmission in January and March (see following paper). In the area sprayed with ICON, the parous rate of An. funestus decreased from 47% pre-spray to 39% six months post-spraying, while the parous rate increased in DDT-sprayed area (from 57% pre-spray to 64% six months post-spray). Bioassays of An. funestus on treated walls, six months post-spray, gave mortality rates of 100% on DDT and 90% on ICON. Conversely, ICON appeared to be more effective than DDT on thatched roofs (66% versus 100%, respectively, six months post-spray). In areas sprayed with DDT or ICON the density of An. arabiensis were little affected. This study demonstrated that, under equivalent conditions, both DDT and lambda-cyhalothrin were effective in reducing malaria transmission on the western fringes of the malaria epidemic zone of the malagasy highlands, with a residual effect lasting at least for six months. Lambda-cyhalothrin appeared to be more effective than DDT in reducing the longevity of malaria vectors. In addition to efficacy, the choice of insecticide for malaria vector control should take into account their acceptability by human populations and their toxicity and persistence in the environment.

Ther Drug Monit 2001 Dec;23(6):612-5

Drug monitoring of quinine in men with nonsevere falciparum malaria: study in the Amazon region of Brazil.

Vieira JL, Midio AF.

Departamento de Deontologia e Medicina Legal, Universidade Federal do Para, Para, Brazil.

Quinine sulfate has been the drug of choice for the treatment of the ever-increasing number of cases of falciparum malaria in tropical countries. Because of the spectrum of adverse effects produced by the drug in the so-called cinchona syndrome, the variation in its pharmacokinetics during the episodes of falciparum malaria, and the different therapeutic regimens proposed in different countries, the authors monitored quinine plasma concentrations in daily samples of 20 men of the Amazon region in Brazil with nonsevere falciparum malaria who were administered 1 g quinine sulfate every 12 hours for 7 days. Three blood samples were collected from each patient each day: two immediately before administration of the drug (7 am and 7 pm) and one at 11 am. A total of 440 samples were analyzed by a validated method developed in the authors’ laboratories using the high-performance liquid chromatographic technique. The overall quinine plasma levels obtained varied from 1.52 to 16.89 microg/mL. From the second day of treatment, overall levels varied from 2.33 to 14.29 microg/mL; the peak concentrations showed values from 4.22 to 16.89 microg/mL, showing the efficacy of the therapeutic regimen used. Adverse effects (signs and symptoms of cinchonism) were observed in all patients. However, no cases of hypoglycemia were detected. Intrapatient comparisons of the obtained quinine plasma concentrations were statistically significant. The quinine dose may be reduced on day 4 of treatment when asexual parasitemia is absent. This way, no resistance to the drug is observed, cinchonism can be minimized, and good adherence to the regimen is obtained.

Acta Trop 2002 Feb;81(2):167-73

Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults.

Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H.

Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Kinderspitalgasse 15, A-1095, Vienna, Austria

The frequency and spectrum of adverse events associated with the antimalarial therapeutic regimen of mefloquine (MQ) (750 and 500 mg at an interval of 6 h) was assessed in 22 healthy volunteers who were monitored for 21 days following drug administration. An unexpected high frequency of side effects of any grade were reported by all 22 subjects. The most commonly reported symptoms were vertigo (96%), followed by nausea (82%) and headache (73%). Participants suffering from severe (grade 3) vertigo (73%) required bed rest and specific medication for 1 to 4 days. More females than males reported severe adverse reactions. The majority (77.3%) of the participants (f: 8/12, m: 9/10) showed symptom resolution within 3 weeks (510 h) after drug administration. Biochemical and haematological findings stayed within the normal range of values, but showed nevertheless a significant rise of Na, Cl, Ca, bilirubin, GGT and LDH. The unexpectedly high frequency and severity of adverse reactions after normal therapeutic dosage of MQ in healthy subjects may influence future recommendations regarding the use of MQ for stand-by treatment of suspected malaria in travellers.

J Med Assoc Thai 2001 Sep;84(9):1289-99

Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria pregnant women.

Bounyasong S.

Department of Obstetrics and Gynecology, Srisangwal Hospital, Mae Hong Son, Thailand.

To compare the effectiveness and safety of quinine sulfate and artesunate with mefloquine for treating second trimester pregnancy in women who suffered from Plasmodium falciparum malaria. The prospective study was done in Srisangwal Hospital, Mae Hong Son, Thailand. Sixty, second to third trimester pregnant patients with P. falciparum infection, were recruited at random. They received either quinine sulfate 10 mg/kg/day for at least 7 days, 29 women (group I), or oral artesunate 2 mg/kg as the first dose, 1 mg/kg every 12 hours orally for at least 5 days together with split doses of mefloquine, 15 mg/kg and 6 hours later 10 mg/kg orally 1 day after artesunate was stopped, 28 women (group II). Three cases (5%) were lost to follow-up before delivery, one case in group I and two cases in group II. After treatment, the mean hematocrit of group I was significantly less than group II (p = 0.000). The PCT (parasite clearance time) and FCT (fever clearance time) of group II were significantly shorter than group I (p = 0.000). None of the patients in both groups had recrudescences within 28 days. Group I had more adverse effects than group II. No adverse neurological effects in pregnancy were found in both groups. The calcification of placenta and IUGR (Intrauterine growth retard) were not different between the two groups (p = 0.964, 0.363 respectively). The PCT was not different between the calcified placenta group and normal placenta group (p = 0.058), but the TTPP (Total time of parasite presentation) was (p = 0.000). TTPP related to low birth weight and low apgar score at 1 minute might be the cause (p = 0.000, 0.000 F = 5.261, 21.627 respectively). TTPP and PCT related to neonatal blood pH and caused low neonatal blood pH (p = 0.000, 0.001 F = 24.351, 11.162 respectively). The physical and neurological development of the babies at 2, 4, 6 and 12 months follow-up, were normal and there were no congenital abnormalities in either group. TTPP relating to fetal outcome, the longer the TTPP, the worse the fetal outcome, so we should diagnose early and treat P. falciparum malaria in pregnancy to prevent fetal jeopardy. Artesunate with mefloquine could shorten the PCT more than quinine sulfate in pregnancy, so the fetal outcome was better than that of quinine sulfate. In cases of prolonged infection before treatment, artesunate might be the alternative treatment of P. falciparum malaria in pregnancy. However, its safety should be carefully studied further with a larger sample size.

Bull World Health Organ 2001;79(12):1096-105

Diagnosis and management of febrile children using the WHO/UNICEF guidelines for IMCI in Dhaka, Bangladesh.

Factor SH, Schillinger JA, Kalter HD, Saha S, Begum H, Hossain A, Hossain M, Dewitt V, Hanif M, Khan N, Perkins B, Black RE, Schwartz B.

Respiratory Diseases Branch, Division of Bacterial and Mycotic Disease, NCID, Centers for Disease Control and Prevention, Atlanta, GA, USA.

OBJECTIVE: To determine whether the fever module in the WHO/UNICEF guidelines for the integrated management of childhood illness (IMCI) identifies children with bacterial infections in an area of low malaria prevalence. METHODS: Physicians assessed a systematic sample of 669 sick children aged 2-59 months who presented to the outpatient department of Dhaka Shishu Hospital, Bangladesh. FINDINGS: Had IMCI guidelines been used to evaluate the children, 78% of those with bacterial infections would have received antibiotics: the majority of children with meningitis (100%), pneumonia (95%), otitis media (95%) and urinary tract infection (83%); and 50% or less of children with bacteraemia (50%), dysentery (48%), and skin infections (30%). The current fever module identified only one additional case of meningitis. Children with bacteraemia were more likely to be febrile, feel hot, and have a history of fever than those with dysentery and skin infections. Fever combined with parental perception of fast breathing provided a more sensitive fever module for the detection of bacteraemia than the current IMCI module. CONCLUSIONS: In an area of low malaria prevalence, the IMCI guidelines provide antibiotics to the majority of children with bacterial infections, but improvements in the fever module are possible.

Ann N Y Acad Sci 2001 Dec;954:184-222

Agricultural colonization and malaria on the Amazon frontier.

Singer BH, de Castro MC.

Office of Population Research, Princeton University, New Jersey 08544, USA. [email protected]

The purpose of this paper is to characterize the interrelationships between macropolitical, social and economic policies, human migration, agricultural development, and malaria transmission on the Amazon frontier. We focus our analysis on a recent colonization project, POLONOROESTE, in the state of Rondonia. Employing data from field surveys in 1985-1987 and 1995, we use spatial statistical methodologies linked to a geographical information system (GIS) to describe the patterns of human settlement in the area, the ecological transformations induced by forest clearance practices, and the manner in which these factors determine gradations of malaria risk. Our findings show that land use patterns, linked to social organization of the community and the structure of the physical environment, played a key role in promoting malaria transmission. In addition, the location of each occupied area is itself an important determinant of the pattern of malaria risk. Based on lessons learned from our spatial and temporal characterization of malaria risk, we propose policies for malaria mitigation in the Brazilian Amazon.

Infect Immun 2002 Feb;70(2):692-701

Improved immunogenicity and efficacy of the recombinant 19-kilodalton merozoite surface protein 1 by the addition of oligodeoxynucleotide and aluminum hydroxide gel in a murine malaria vaccine model.

Near KA, Stowers AW, Jankovic D, Kaslow DC.

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425.

Vaccination of mice with yeast-secreted Plasmodium yoelii-derived 19-kilodalton merozoite surface protein 1 (yMSP1(19)) has been shown to afford protection from challenge with a lethal strain of P. yoelii. Sterile immunity can be achieved when MSP1(19) is emulsified in Freund adjuvant but not when it is adsorbed to aluminum hydroxide gel (alum). Because complete Freund adjuvant is not an acceptable adjuvant for use in humans, alternative adjuvants must be identified for formulating MSP1(19) as a vaccine for use in humans. To determine whether oligodeoxynucleotides with CpG motifs (ODN), reported to be a powerful new class of adjuvants, could enhance the immunogenicity of yMSP1(19), C57BL/6 mice were vaccinated either with yMSP1(19) formulated with Freund adjuvant, with alum, or with ODN plus alum and challenged intravenously with P. yoelii 17XL asexual blood-stage parasites. Adsorption of immunogen and adjuvant to alum was optimized by adjusting buffer (phosphate versus acetate) and pH. We found that the adjuvant combination of ODN plus alum with yMSP1(19), injected intraperitoneally (i.p.), increased immunoglobulin G (IgG) yMSP1(19)-specific antibody production 12-fold over Freund adjuvant given i.p., 3-fold over Freund adjuvant given subcutaneously (s.c.), 300-fold over alum given i.p., and 48-fold over alum given s.c. The predominant antibody isotype in the group receiving alum-ODN-yMSP1(19) was IgG1. Increased antibody levels correlated to protection from a challenge with P. yoelii 17XL. Supernatant cytokine levels of gamma interferon in yMSP1(19)-stimulated splenocytes were dramatically elevated in the alum-ODN-yMSP1(19) group. Interleukin-10 (IL-10) levels were also elevated; however, no IL-5 was detected. The cytokine profile, as well as the predominant IgG1 antibody isotype, suggests the protective immune response was a mixed Th1/Th2 response.

Infect Immun 2002 Feb;70(2):655-60

Plasmodium knowlesi Provides a Rapid In Vitro and In Vivo Transfection System That Enables Double-Crossover Gene Knockout Studies.

Kocken CH, Ozwara H, van Der Wel A, Beetsma AL, Mwenda JM, Thomas AW.

Department of Parasitology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands. Departments of Infectious Diseases and Reproductive Biology, Institute of Primate Research, National Museums of Kenya, Karen, Nairobi, Kenya.

Transfection technology for malaria parasites provides a valuable tool for analyzing gene function and correlating genotype with phenotype. Transfection models are even more valuable when appropriate animal models are available in addition to complete in vitro systems to be able to fully analyze parasite-host interactions. Here we describe the development of such a model by using the nonhuman primate malaria Plasmodium knowlesi. Blood-stage parasites were adapted to long-term in vitro culture. In vitro-adapted parasites could readapt to in vivo growth and regain wild-type characteristics after a single passage through an intact rhesus monkey. P. knowlesi parasites, either in vitro adapted or in vivo derived, were successfully transfected to generate circumsporozoite protein (CSP) knockout parasites by double-crossover mechanisms. In vitro-transfected and cloned CSP knockout parasites were derived in a time span of only 18 days. Microscopic evaluation of developing oocysts from mosquitoes that had fed on CSP knockout parasites confirmed the impairment of sporozoite formation observed in P. berghei CSP knockout parasites. The P. knowlesi model currently is the only malaria system that combines rapid and precise double-crossover genetic manipulation procedures with complete in vitro as well as in vivo possibilities. This allows for full analysis of P. knowlesi genotype-phenotype relationships and host-parasite interactions in a system closely related to humans.

Infect Immun 2002 Feb;70(2):512-6

Association of a Determinant on Mouse Chromosome 18 with Experimental Severe Plasmodium berghei Malaria.

Nagayasu E, Nagakura K, Akaki M, Tamiya G, Makino S, Nakano Y, Kimura M, Aikawa M.

Institute of Science and Technology. Division of Molecular Life Science, School of Medicine. Division of Infectious Diseases, Tokai University, Isehara 259-1193, Japan.

Experimental severe malaria (ESM; also known as experimental cerebral malaria) is an acute lethal syndrome caused by infection with Plasmodium berghei ANKA and associated with coma and other neurological manifestations in mice. Various inbred strains of mice exhibit differences in susceptibility to the development of ESM. For example, C57BL/6 mice are highly susceptible and DBA/2 mice are relatively resistant. We report here the results of a genomewide scan for host genomic regions that control resistance to ESM in DBA/2 mice using an F(2) intercross population of susceptible and resistant strains. A region of mid-chromosome 18 was found to be a major determinant of resistance to ESM.

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