4.02.2008
Health Highlights: Method Found to Block Spread of Malaria in the Body [Forbes.com - US ] — (English)
Now, researchers from the Stanford University School of Medicine say they've been able to identify two enzymes that help the malaria parasites spread throughout the body. And they say they've also identified compounds that may be able to block those enzymes...
Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum [Nature Chemical Biology, doi:10.1038/nchembio.70 (subscriprion)] — (English)
Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells...
Gabon: Les femmes catholiques dans la lutte contre le paludisme [Gabonews (Libreville) via allAfrica.com] — (Français)
L'Association des femmes de l'Eglise catholique du Gabon, en collaboration avec le Programme nationale de lutte contre le paludisme et le Programme des Nations unies pour le développement (PNUD) a organisé une campagne de sensibilisation en vue de la lutte contre le paludisme dans la localité d'Essassa à 42 kilomètres de Libreville, a constaté GABONEWS...
1.02.2008
Malaria jab hope over chimp virus [BBC Gardening - UK] — (English)
Scientists believe a chimp virus may hold the clue in the long-running battle to develop a malaria vaccine...
Malaria Vaccine Trials Begin Using 'Chimpanzee Virus' [Science Daily (press release) - USA] — (English)
Trials are underway for a new vaccine to combat the most deadly form of malaria. For the first time ever, researchers will use a virus found in chimpanzees to boost the efficacy of the vaccine...
Malaria-Impfstoff setzt auf Schimpansen-Virus [journal MED - Germany] — (Deutsch)
Wissenschaftler der University of Oxford gehen davon aus, dass ein Schimpansen-Virus den entscheidenden Hinweis im langen Kampf um die Entwicklung eines Malaria-Impfstoffes liefern kann. Die Forscher setzen dieses Virus ein, um eine Immunreaktion in den Zellen auszulösen, wo sich die für Malaria verantwortlichen Parasiten ansammeln. Die ersten Tests laufen derzeit. Sind sie erfolgreich, könnte innerhalb von fünf Jahren ein Impfstoff zur Verfügung stehen. Experten versuchen seit 20 Jahren einen Impfstoff zu entwickeln. Jährlich stirbt laut BBC eine Million Menschen an Malaria...
Buy-a-Net Save-a-Life: Malaria Prevention Benefit Concert [News@Concordia - Montreal,Quebec,Canada] — (English)
All proceeds will be going to a Canadian based charitable organization Buy-A-Net Malaria Prevention Group...
Is DDT Making a Comeback? [AlterNet - San Francisco,CA,USA] — (English)
In Africa, where malaria kills a million children a year, some are advocating the return of DDT. Are they right?...
Net benefits [Economist - UK] — (English)
Giving bed nets and drugs away free may be the way to deal with malaria...
Anti-Malaria Efforts Yield New Success [Washington Post - US] — (English)
Widespread use of insecticide-treated mosquito nets and state-of-the-art drugs has succeeded in cutting malaria deaths in half in two countries most heavily affected by the disease, the World Health Organization is reporting today...
Nets and new drug curb malaria deaths in parts of Africa [IHT] — (English)
Widespread distribution of mosquito nets and a new medicine have sharply reduced malaria deaths in several African countries, World Health Organization researchers reported...
Plasmodium falciparum Regulatory Subunit of cAMP-Dependent PKA and Anion Channel Conductance [PLOS Pahogens] — (English)
Malaria symptoms occur during Plasmodium falciparum development into red blood cells. During this process, the parasites make substantial modifications to the host cell in order to facilitate nutrient uptake and aid in parasite metabolism. One significant alteration that is required for parasite development is the establishment of an anion channel, as part of the establishment of New Permeation Pathways (NPPs) in the red blood cell plasma membrane, and we have shown previously that one channel can be activated in uninfected cells by exogenous protein kinase A. Here, we present evidence that in P. falciparum-infected red blood cells, a cAMP pathway modulates anion conductance of the erythrocyte membrane. In patch-clamp experiments on infected erythrocytes, addition of recombinant PfPKA-R to the pipette in vitro, or overexpression of PfPKA-R in transgenic parasites lead to down-regulation of anion conductance. Moreover, this overexpressing PfPKA-R strain has a growth defect that can be restored by increasing the levels of intracellular cAMP. Our data demonstrate that the anion channel is indeed regulated by a cAMP-dependent pathway in P. falciparum-infected red blood cells. The discovery of a parasite regulatory pathway responsible for modulating anion channel activity in the membranes of P. falciparum-infected red blood cells represents an important insight into how parasites modify host cell permeation pathways. These findings may also provide an avenue for the development of new intervention strategies targeting this important anion channel and its regulation...
Uganda: Lessons from other nations in Malaria fight (opinion) [Afrika - South Africa ] — (English)
The Spraying of DDT to homesteads will soon be extended to new districts. Owing to the application of insecticides on the inside walls of houses, mosquitoes that spread the deadly plasmodium parasite will be repelled from entering houses. In September 2006, the World Health Organisation's Global Malaria Programme director, Dr Arata Kochi, said: "Help save African children as we save our environment"...
31.01.2008
Malaria vaccine enters second stage [SciDev.net - UK] — (English)
A malaria vaccine has performed well in a small clinical trial of adults in Mali, leading to testing being expanded to children...
Donors to bulk-purchase malaria drugs for developing countries [Journal Chrétien - Paris,France] — (English)
Donors are planning to use bulk-purchasing of the new malaria drug called artemether and lumefantrine (ALu) for donation to developing countries with a view to ensure smooth accessibility and availability of the drug to patients in these countries, APA learnt here Thursday...
Angola: Moxico - Malaria Death Cases Drop [Angola Press Agency (Luanda) via allAfrica.com] — (English)
The Provincial Programme of Malaria, in eastern Moxico province, recorded in 2007, 62 deaths of the disease against 285 reported in 2006, characterising a considerable decrease, disclosed Thursday a source close to public health sector...
Madagascar: Recul du palu [L'Express de Madagascar (Antananarivo) via allAfrica.com] — (Français)
Ces quatre dernières années, la province de Toamasina constate une grande amélioration de la santé de sa population...
30.01.2008
Evidence of Blood Stage Efficacy with a Virosomal Malaria Vaccine in a Phase IIa Clinical Trial [PLOS ONE] — (English)
We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this group. One volunteer, who received PEV3A alone, was diagnosed very late, on day 20 compared to an average of 11.8 days in unvaccinated controls. (ii). Morphologically abnormal parasites were present in the blood of all (n = 24) PEV3A vaccinated volunteers, and in only 2/6 controls (p = 0.001). We describe evidence of vaccine-induced blood stage efficacy for the first time in a sporozoite challenge study...
Sénégal: Mbour - vers la distribution de 20.000 moustiquaires imprégnées pour la lutte contre le paludisme [Agence de Presse Sénégalaise (Dakar) via allAfrica.com] — (Français)
20.000 moustiquaires imprégnées seront distribuées prochainement aux populations de la commune de Mbour, dans le cadre de l'exécution du projet Christian Children Found de la cellule d'action contre la malnutrition et la malaria...
Millsaps Global Missions Team Partners with Nothing But Nets [Millsaps College Athletics - Jackson,MS,USA] — (English)
JACKSON – The Millsaps CMT Global Missions team is having a fundraiser for the Nothing But Nets organization at the men's and women's basketball games on Friday, Feb. 8, against visiting Colorado College. Tipoff is set for 6 and 8 p.m....
FINA Announces World Swim Against Malaria [SwimmingWorldMagazine.com - Phoenix,AZ,USA] — (English)
FINA has decided to support the World Swim Against Malaria because malaria is a global problem, and FINA hopes to raise awareness of this through the FINA World Short Course Championships to be held in Manchester...
Malaria in Central Vietnam: analysis of risk factors by multivariate analysis and classification tree models [Malaria Journal 2008, 7:28 (30 January 2008)] — (English)
A combination of two complementary statistical approaches (logistic regression and CART) to classify the malaria risk factors...
Clinical malaria in African pregnant women [Malaria Journal 2008, 7:27 (30 January 2008)] — (English)
It is often considered that pregnant women with a malaria infection are asymptomatic. According to the data reported, this is not the case and several symptoms have a positive predictive value are indicative of malaria in areas of stable transmission...
29.01.2008
Test for P. knowlesi malaria not routine in remote area [SciDev.Net - UK] — (English)
The statement "There is currently no specific diagnostic test for Plasmodium knowlesi" (see Fatal malaria strain 'mistaken for more benign form') is not strictly correct...
Collaborating to Tame the Malaria Scourge [This Days - Nigeria] — (English)
The continuing ravages of malaria in Nigeria in particular and across sub-Saharan Africa in general, has put many interested stakeholders to serious work and brain storming on how best to tame the disease. Since they have realised that it is not a fight that one single body can fight, collaboration has come handy. This is how the ongoing synergy between Esso Exploration and Production Nigeria Limited (EEPNL), an affiliate of ExxonMobil in Nigeria and the Nigerian Red Cross Society (NRCS) to reduce the malaria burden in the country, can be viewed...
Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria [
Malaria Journal 2008, 7:26 (29 January 2008)] — (English)
A study looking at a variety of immunological biomarkers which may be useful in the management of placental malaria...
From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia [Malaria Journal 2008, 7:25 (29 January 2008)] — (English)
This paper describes the historical process and experience of Zambia as it made a major policy change with regard to malaria treatment. It has implications for all malarious countries that sooner or later must change their policies. A drug policy change must be seen as a full health system issue, not just a drug issue. A number of painful experiences are emerging in sub-Saharan Africa, as countries change their policies, and well-documented and successful experiences such as this provide important lessons for others...
Assessment of a treatment guideline to improve home management of malaria in children in rural south-west Nigeria [Malaria Journal 2008, 7:24 (29 January 2008)] — (English)
The use of the guideline with adequate training significantly improved correctness of malaria treatment with chloroquine at home. Adoption of this mode of intervention is recommended to improve compliance with drug use at home. The applicability for deploying artemisinin-based combination therapy at the community level need to be investigated...
In vitro atovaquone/proguanil susceptibility and characterization of the cytochrome b gene of Plasmodium falciparum from different endemic regions of Thailand [Malaria Journal 2008, 7:23 (28 January 2008)] — (English)
In agreement with a recent efficacy study of atovaquone/proguanil, the present information indicates that atovaquone/proguanil can be one of the drugs of choice for the treatment and prophylaxis of multidrug-resistant falciparum malaria in Thailand...
Pilot assessment of the sensitivity of the malaria thin film [Malaria Journal 2008, 7:22 (28 January 2008)] — (English)
The thin film is sensitive enough to be a useful tool to confirm malaria diagnosis in study subjects in some settings. Specificity of the thin film and its utility for confirming thick film or other diagnostic test results should be assessed further...
An interactive model for the assessment of the economic costs and benefits of different rapid diagnostic tests for malaria [Malaria Journal 2008, 7:21 (28 January 2008)] — (English)
Model output demonstrates that which test is preferable varies by location, depending on factors such as malaria transmission intensity and the costs and accuracies of the RDTs under consideration. Despite the uncertainties and complexities involved, adaptable models such as the one presented here can serve as a practical tool to assist policy makers in efficient deployment of new technologies...
Articles requiring subscription
Habitat-Based Larval Interventions: A New Perspective for Malaria Control [Am. J. Trop. Med. Hyg., 78(1), 2008, pp. 2-6] — (English)
Interest in environmental management of mosquito larval habitats has been rekindled due to deterioration of malaria in tropical Africa. Environmental management programs were typically implemented as "all-out" campaigns by treating all potential breeding habitats. In contrast, targeted environmental management is based on a sound understanding of the heterogeneity in mosquito productivity. However, deficiencies in field methodology for measuring productivity hamper our progress in understanding of mosquito productivity. To address these issues, we develop a framework of habitat-based interventions by adoption of a landscape approach to elucidate mechanisms underlying mosquito productivity. The importance of vigorously quantitative estimation of the productivity is highlighted. Spatial models are proposed to examine the interrelationship between mosquito productivity and oviposition of gravid mosquitoes. In our view, environmental management approaches must take into account variability in productivity, in efforts to improve feasibility, cost-effectiveness, and sustainability of such approaches, particularly when implemented along with other malaria control measures...
Patterns of Malaria: Cause-Specific and All-Cause Mortality in a Malaria-Endemic Area of West Africa [Am J Trop Med Hyg 2008 78: 106-113] — (English)
Information on cause-specific mortality is sparse in sub-Saharan Africa. We present seasonal patterns of malaria and all-cause mortality from a longitudinal study with 60,000 individuals in rural northwestern Burkina Faso. The study is based on a demographic surveillance system and covers the period 1999–2003. Overall, 3,492 deaths were observed. Cause of death was ascertained by verbal autopsy. Age-specific death rates by cause and month of death were calculated. Seasonal and temporal trends were modeled with parametric Poisson regression. Infant and children less than 5 years of age mortality was 60.6 (95% CI, 56.2–65.3) and 31.9 (95% CI, 30.4–33.5) per 1,000 for all causes and 23.4 (95% CI, 20.7–26.4) and 13.3 (95% CI, 12.3–14.3) for malaria, respectively. Mortality was significantly higher in the rainy season. It is well described parametrically with a sinusoidal function. In adults, the highest all-cause mortality rates were observed in the dry season. Here, HIV/AIDS has become a leading cause of mortality...
A Filter Paper Method for the Detection of Plasmodium falciparum Gametocytes by Reverse Transcription–Polymerase Chain Reaction [Am J Trop Med Hyg, Jan 2008; 78: 114 - 116] — (English)
Plasmodium falciparum gametocytes are obligate parasite sexual stages required for transmission of malaria from human hosts to the mosquito vector. Assessment of gametocyte carriers in the population is critical in understanding malaria transmission dynamics and in epidemiology studies. We applied a reverse transcription–polymerase chain reaction (RT-PCR)–based approach to detect pfs25 transcripts from blood dried on different filter papers in the laboratory. The detection limit was 1–2 gametocytes/µL. We further validated this assay by analyzing RNA in 10 matched blood samples (liquid blood and blood spotted on filter papers) collected from subjects under field conditions in Zambia. These results thus establish feasibility of detection of Plasmodium falciparum gametocytes by RT-PCR method from dried blood on filter paper. This assay will greatly facilitate bulk analysis of gametocyte RNA transcripts on filter paper, especially in areas where collection and preservation of liquid blood is not feasibl...
Distribution and Chromosomal Characterization of the Anopheles gambiae Complex in Angola [Am J Trop Med Hyg, Jan 2008; 78: 169 - 175] — (English)
Mosquitoes of the Anopheles gambiae complex (N = 1,336) were sampled (2001–2005) across Angola to identify taxa, study inversion polymorphisms, and detect the circumsporozoite protein of Plasmodium falciparum. Anopheles gambiae s.s. was found in all sites; it was characterized as M-form in localities of the tropical dry and semi-desertic belts, whereas the S-form was predominant in comparatively more humid and less anthropized sites. Both forms were characterized by low degrees of chromosomal polymorphism based solely on the 2La inversion, a pattern usually associated with An. gambiae populations from forested, humid, and derived savanna areas. Unexpectedly, this pattern was also observed in M-form populations collected in dry/pre-desertic areas, where this form largely predominates over An. arabiensis, which was also detected in central/inland sites. Anopheles melas was found in northern coastal sites. Three of 534 An. gambiae s.s. were positive for P. falciparum CS-protein, whereas none of the 105 An. melas were positive...
Historical Analysis of a Near Disaster: Anopheles gambiae in Brazil [Am J Trop Med Hyg, Jan 2008; 78: 176 - 178] — (English)
Attributed to human-mediated dispersal, a species of the Anopheles gambiae complex invaded northeastern Brazil in 1930. This event is considered unique among the intercontinental introductions of disease vectors and the most serious one: "Few threats to the future health of the Americas have equalled that inherent in the invasion of Brazil, in 1930, by Anopheles gambiae." Because it was only in the 1960s that An. gambiae was recognized as a species complex now including seven species, the precise species identity of the Brazilian invader remains a mystery. Here we used historical DNA analysis of museum specimens, collected at the time of invasion from Brazil, and aimed at the identification of the Brazilian invader. Our results identify the arid-adapted Anopheles arabiensis as being the actual invading species. Establishing the identity of the species, in addition to being of intrinsic historical interest, can inform future threats of this sort especially in a changing environment. Furthermore, these results highlight the potential danger of human-mediated range expansions of insect disease vectors and the importance of museum collections in retrieving historical information...
What can transgenic parasites tell us about the development of Plasmodium-specific immune responses? [Parasite Immunology, doi:10.1111/j.1365-3024.2007.01011.x ] — (English)
Malaria infects 500 million people and kills an estimated 2·7 million annually, representing one of the most significant diseases in the world. However, efforts to develop effective vaccines have met with limited success. One reason is our lack of basic knowledge of how and where the immune system responds to parasite antigens. This is important as the early events during induction of an immune response influence the acquisition of effector function and development of memory responses. Our knowledge of the interactions of Plasmodia with the host immune system has largely been derived through in vitro study. This is a significant issue as the component parts of the immune system do not work in isolation and their interactions occur in distinct and specialized micro- and macro-anatomical locations that can only be assessed in the physiological context, in vivo. In this context, the availability of transgenic malaria parasites over the last 10 years has greatly enhanced our ability to understand and evaluate factors involved in host–parasite interactions in vivo. In this article, we review the current status of this area and speculate on what parasite transgenesis approaches will tell us about the development of Plasmodium-specific immune responses in the future...
Killer applications: Toward affordable rapid cell-based diagnostics for malaria and tuberculosis [Cytometry B Clin Cytom. 2008 Jan 28] — (English)
In many resource-poor areas, the HIV/AIDS epidemic coexists with epidemics of two much older diseases, malaria and tuberculosis, and the three diseases together kill approximately six million people per year. Although HIV/AIDS is treatable, but not curable, many if not most cases of malaria and tuberculosis (TB) can be cured if diagnosed correctly and promptly. The diagnosis of both malaria and TB is cell-based, typically made by microscopy of stained smears of blood (malaria) and sputum (TB). Cytometry has been shown to be effective for diagnosis of both conditions; however, conventional cytometers have been too complex and costly to be widely applied. It is likely that a newly developed small, simple, robust, inexpensive, energy-efficient low-resolution fluorescence image cytometer, employing a light-emitting diode for excitation and a megapixel digital camera chip for detection, could be used in resource-poor areas for malaria and TB diagnosis and for rapid (24-48 h) determination of antimicrobial susceptibility of Mycobacterium tuberculosis...
Overview: Simplified cytometry for routine monitoring of infectious diseases [Cytometry B Clin Cytom. 2008 Jan 28] — (English)
The interacting epidemics of HIV/AIDS, tuberculosis (TB) and malaria in resource-poor areas of the world have created a critical need for rapid, simple, affordable apparatus and tests that will permit patients with these diseases to be promptly diagnosed and properly managed.As documented in the current issue of Clinical Cytometry, complex flow cytometric analyses used in affluent countries for CD4+ T cell counting in HIV/AIDS have been simplified, introduced, and quality assessed in resource-restricted countries of Africa and the Caribbean, where simple gating protocols such as panleucogating now provide accurate and precise CD4+ T cell counts on a large scale. CD4/CD8 ratios in infants may replace more expensive molecular tests for HIV infection; simplified flow cytometry is also compatible with HIV viral load-associated lymphocyte activation tests and with antigen-specific cellular immune response assays that rapidly diagnose active TB in both HIV-negative and HIV-TB co-infected individuals.In addition, it is becoming evident that smaller, much less expensive fluorescence imaging cytometers can be used for CD4 counting, immunophenotyping, and hematology and for other applications such as diagnosis and drug-susceptibility testing of TB and diagnosis of malaria. With the gradual, organized expansion of the much-needed diagnostic networks in the underprivileged countries, the most cost-effective apparatus may be one capable of performing tests for all the three diseases mentioned. The most sustainable systems will be those that can be assembled and maintained, to the greatest extent possible, in the countries where they will be used....
Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial [Nutr J. 2008 Jan 31] — (English)
At the end of the study we observed a significant decrease in the prevalence of malaria reinfection in the supplemented group (34%) compared to the placebo group (3.5%) (p<0.001). Malaria episodes were lower in the supplemented group (p=0.029), with a 30.2% reduction of malaria cases (p=0.025). Time to first malaria episode was longer in the supplemented group (p=0.015). The supplemented group also had 22% fewer fever episodes than the placebo group (p=0.030)...
Over expression of a Cytochrome P450 (CYP6P9) in a Major African Malaria Vector, Anopheles Funestus, Resistant to Pyrethroids [Insect Molecular Biology, Volume 17 Issue 1 Page 19-25, February 2008] — (English)
Anopheles funestus Giles is one of the major African malaria vectors. It has previously been implicated in a major outbreak of malaria in KwaZulu/Natal, South Africa, during the period 1996 to 2000. The re-emergence of this vector was associated with monooxygenase-based resistance to pyrethroid insecticides. We have identified a gene from the monooxygenase CYP6 family, CYP6P9, which is over expressed in a pyrethroid resistant strain originating from Mozambique. Quantitative Real-Time PCR shows that this gene is highly over expressed in the egg and adult stages of the resistant strain relative to the susceptible strain but the larval stages showed almost no difference in expression between strains. This gene is genetically linked to a major locus associated with pyrethroid resistance in this A. funestus population...
beta-Hematin Interaction with the Hemopexin Domain of Gelatinase B/MMP-9 Provokes Autocatalytic Processing of the Propeptide, Thereby Priming Activation by MMP-3 [Biochemistry. 2008 Feb 1] — (English)
Gelatinase B or matrix metalloproteinase-9 is involved in inflammation and in autoimmune and vascular diseases. In contrast to the constitutive and homeostatic matrix metalloproteinase-2, matrix metalloproteinase-9 is an inducible enzyme. Furthermore, it needs tight regulation, and a major control mechanism of its enzymatic activity is the activation of the latent enzyme by proteolysis of the 87 residue propeptide. Activated matrix metalloproteinase-9 is detected in many vascular or hematological disease states, including in an experimental model for cerebral malaria with Plasmodium berghei ANKA. However, insight into its activation mechanism is incomplete. In view of the association with hemorrhagic and hemolytic diseases, it was studied whether and how hemoglobin and its derivatives might activate pro-matrix metalloproteinase-9. Incubation of matrix metalloproteinase-9 with hemin or -hematin, the core constituent of hemozoin or malaria pigment, leads to differential autocatalysis of the propeptide, mediated by allosteric interaction with the hemopexin domain. The cleavage catalyzed by -hematin coincides with the first cleavage by stromelysin-1/matrix metalloproteinase-3, and preincubation of matrix metalloproteinase-9 with -hematin enhances the activation rate by matrix metalloproteinase-3 at least 6-fold. These findings suggest that reduction of hemorrhage and hemolysis might prevent matrix metalloproteinase-9-mediated inflammatory and vascular damages...
Vitamin B1 and B6 in the malaria parasite: requisite or dispensable? [Brazilian Journal of Medical and Biological Research, 2008 (Review)] — (English)
Vitamins are essential compounds mainly involved in acting as enzyme co-factors or in response to oxidative stress. In the last two years it became apparent that apicomplexan parasites are able to generate B vitamers such as vitamin B1 and B6 de novo. The biosynthesis pathways responsible for vitamin generation are considered as drug targets, since both provide a high degree of selectivity due to their absence in the human host. This report updates the current knowledge about vitamin B1 and B6 biosynthesis in malaria and other apicomplexan parasites. Owing to the urgent need for novel antimalarials, the significance of the biosynthesis and salvage of these vitamins is critically discussed in terms of parasite survival and their exploitation for drug development...
High mobility group box (HMGB) proteins of Plasmodium falciparum: DNA binding proteins with pro-inflammatory activity [Parasitol Int. 2007 Dec 8] — (English)
High mobility group box chromosomal protein 1 (HMGB1), known as an abundant, non-histone architectural chromosomal protein, is highly conserved across different species. Homologues of HMGB1 were identified and cloned from malaria parasite, Plasmodium falciparum. Sequence analyses showed that the P. falciparum HMGB1 (PfHMGB1) exhibits 45, 23 and 18%, while PfHMGB2 shares 42, 21 and 17% homology with Saccharomyces cerevisiae, human and mouse HMG box proteins respectively. Parasite PfHMGB1and PfHMGB2 proteins contain one HMG Box domain similar to B-Box of mammalian HMGB1. Electrophoretic Mobility Shift Assay (EMSA) showed that recombinant PfHMGB1 and PfHMGB2 bind to DNA. Immunofluorescence Assay using specific antibodies revealed that these proteins are expressed abundantly in the ring stage nuclei. Significant levels of PfHMGB1 and PfHMGB2 were also present in the parasite cytosol at trophozoite and schizont stages. Both, PfHMGB1 and PfHMGB2 were found to be potent inducers of pro-inflammatory cytokines such as TNFalpha from mouse peritoneal macrophages as analyzed by both reverse transcription PCR and by ELISA. These results suggest that secreted PfHMGB1 and PfHMGB2 may be responsible for eliciting/ triggering host inflammatory immune responses associated with malaria infection...
What works Interventions for maternal and child undernutrition and survival [The Lancet, Volume 371, Issue 9610, 2 February 2008-8 February 2008, Pages 417-440 ] — (English)
We reviewed interventions that affect maternal and child undernutrition and nutrition-related outcomes. These interventions included promotion of breastfeeding; strategies to promote complementary feeding, with or without provision of food supplements; micronutrient interventions; general supportive strategies to improve family and community nutrition; and reduction of disease burden (promotion of handwashing and strategies to reduce the burden of malaria in pregnancy). We showed that although strategies for breastfeeding promotion have a large effect on survival, their effect on stunting is small. In populations with sufficient food, education about complementary feeding increased height-for-age Z score by 0·25 (95% CI 0·01–0·49), whereas provision of food supplements (with or without education) in populations with insufficient food increased the height-for-age Z score by 0·41 (0·05–0·76). Management of severe acute malnutrition according to WHO guidelines reduced the case-fatality rate by 55% (risk ratio 0·45, 0·32–0·62), and recent studies suggest that newer commodities, such as ready-to-use therapeutic foods, can be used to manage severe acute malnutrition in community settings. Effective micronutrient interventions for pregnant women included supplementation with iron folate (which increased haemoglobin at term by 12 g/L, 2·93–21·07) and micronutrients (which reduced the risk of low birthweight at term by 16% (relative risk 0·84, 0·74–0·95). Recommended micronutrient interventions for children included strategies for supplementation of vitamin A (in the neonatal period and late infancy), preventive zinc supplements, iron supplements for children in areas where malaria is not endemic, and universal promotion of iodised salt. We used a cohort model to assess the potential effect of these interventions on mothers and children in the 36 countries that have 90% of children with stunted linear growth. The model showed that existing interventions that were designed to improve nutrition and prevent related disease could reduce stunting at 36 months by 36%; mortality between birth and 36 months by about 25%; and disability-adjusted life-years associated with stunting, severe wasting, intrauterine growth restriction, and micronutrient deficiencies by about 25%. To eliminate stunting in the longer term, these interventions should be supplemented by improvements in the underlying determinants of undernutrition, such as poverty, poor education, disease burden, and lack of women's empowerment...
On the Delayed Ross-Macdonald Model for Malaria Transmission [Bull Math Biol. 2008 Jan 30] — (English)
The feedback dynamics from mosquito to human and back to mosquito involve considerable time delays due to the incubation periods of the parasites. In this paper, taking explicit account of the incubation periods of parasites within the human and the mosquito, we first propose a delayed Ross-Macdonald model. Then we calculate the basic reproduction number R (0) and carry out some sensitivity analysis of R (0) on the incubation periods, that is, to study the effect of time delays on the basic reproduction number. It is shown that the basic reproduction number is a decreasing function of both time delays. Thus, prolonging the incubation periods in either humans or mosquitos (via medicine or control measures) could reduce the prevalence of infection...
Epidemiological and nutrition transition in developing countries: impact on human health and development [Proceedings of the Nutrition Society (2008), 67: 82-90 Cambridge University Press] — (English)
Whereas common infectious and parasitic diseases such as malaria and the HIV/AIDS pandemic remain major unresolved health problems in many developing countries, emerging non-communicable diseases relating to diet and lifestyle have been increasing over the last two decades, thus creating a double burden of disease and impacting negatively on already over-stretched health services in these countries. Prevalence rates for type 2 diabetes mellitus and CVD in sub-Saharan Africa have seen a 10-fold increase in the last 20 years. In the Arab Gulf current prevalence rates are between 25 and 35% for the adult population, whilst evidence of the metabolic syndrome is emerging in children and adolescents. The present review focuses on the concept of the epidemiological and nutritional transition. It looks at historical trends in socio-economic status and lifestyle and trends in nutrition-related non-communicable diseases over the last two decades, particularly in developing countries with rising income levels, as well as the other extreme of poverty, chronic hunger and coping strategies and metabolic adaptations in fetal life that predispose to non-communicable disease risk in later life. The role of preventable environmental risk factors for obesity and the metabolic syndrome in developing countries is emphasized and also these challenges are related to meeting the millennium development goals. The possible implications of these changing trends for human and economic development in poorly-resourced healthcare settings and the implications for nutrition training are also discussed...
Malaria-Infected Mice Are Cured by Oral Administration of New Artemisinin Derivatives [J Med Chem. 2008 Jan 31] — (English)
In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 × 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6–7 postinfection. At only 3 × 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14–17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7–13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials...
Altered fluid, electrolyte and mineral status in tropical disease, with an emphasis on malaria and leptospirosis [Nat Clin Pract Nephrol. 2008 Feb;4(2):91-101] — (English)
Fluid, electrolyte and mineral perturbations are prevalent features of tropical disease. Hemodynamic alterations, fever, nitrogen wasting, and changes in membrane transport and acid-base balance contribute to these perturbations. Models of malaria and leptospirosis have been used to show that common hemodynamic changes in tropical disease include decreased systemic vascular resistance, increased cardiac output and increased renal vascular resistance. Blood volume is initially increased, but it decreases as disease progresses. Response to fluid loading is decreased. Diabetes insipidus is occasionally observed in malaria. Hyponatremia occurs frequently in tropical diseases, as a result of increased levels of antidiuretic hormone (vasopressin), entry of sodium into cells, sodium loss and resetting of osmoreceptors. Natriuresis and kaliuresis are observed in patients with leptospirosis. Large amounts of sodium and potassium are lost in stool as a result of diarrhea. Hypernatremia is uncommon, whereas hypokalemia caused by hyperventilation is often observed (more frequently in patients with leptospirosis and kaliuresis). During severe tropical infective episodes, hyperkalemia results from intravascular hemolysis or rhabdomyolysis, and occasionally from decreased activity of Na+,K+-ATPase. Hypocalcemia, hypomagnesemia and hypophosphatemia are common features of both malaria and leptospirosis. Loss of magnesium in the urine is uniquely associated with leptospiral nephropathy. Hypozincemia and hypocupremia can also develop during tropical infection, and might interfere with a patient's immune response. These electrolyte and mineral perturbations are transient and quickly resolve when the disease is controlled...
Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease [ Exp Med. 2008 Jan 28] — (English)
From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase–deficient (HDC–/–) mice, which are free of histamine. HDC–/– mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC–/– mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC–/– mice to CM was associated with preserved blood–brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria...
Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation [J Inorg Biochem. 2007 Dec 23] — (English)
The recent literature on hemozoin/β-hematin formation is reviewed, with an emphasis on the mechanism of its formation. Recent findings from unrelated organisms that produce hemozoin, namely the malaria parasite Plasmodium falciparum, the worm Schistosoma mansoni and the kissing bug Rhodnius prolixus all of which consume human hemoglobin show that the formation of this crystalline substance occurs within or at the surface of lipids. Biomimetic experimental models of the lipid–water interface as well as computational studies indicate that these lipid environments are probably extraordinarily efficient at producing hemozoin. A rethink is now needed, with a new emphasis on Fe(III)PPIX in non-aqueous environments that mimic lipids and indeed within the lipid environment itself. These findings are explored and discussed in the context of earlier studies on β-hematin formation...
Blockade of TNF receptor 1 reduces disease severity but increases parasite transmission during Plasmodium chabaudi chabaudi infection [Int J Parasitol. 2007 Dec 23] — (English)
Abstract
Reducing host carriage of transmission-stage malaria parasites (gametocytes) is expected to decrease the population-wide burden of malaria. Some malaria disease severity is attributed to the induction of the pro-inflammatory cytokines TNF-α and lymphotoxin-alpha (LT-α), and we are interested in whether anti-malaria interventions which ameliorate the symptoms induced by those cytokines may have the capacity to alter malaria transmission. As many functions of TNF-α and LT-α are exerted through TNF receptor 1 (TNFR1), we investigated the effect TNFR1 blockade exerted on parasite transmission using the rodent malaria Plasmodium chabaudi chabaudi. We found that blocking TNFR1 simultaneously increased gametocyte density and infectivity to mosquitoes, whilst reducing disease severity (weight loss). These transmission-enhancing and severity-reducing effects of TNFR1 blockade were independent of asexual parasite load and were observed for several P. c. chabaudi genotypes. These results suggest that the effects of candidate malaria interventions on infectivity should be examined alongside effects on disease severity so that the epidemiological consequences of such interventions can be evaluated...
Apical membrane antigen 1: a malaria vaccine candidate in review [Trends Parasitol. 2008 Feb;24(2):74-84] — (English)
Apical membrane antigen 1 (AMA1) is a micronemal protein of apicomplexan parasites that appears to be essential during the invasion of host cells. Immune responses to Plasmodium AMA1 can have profound parasite-inhibitory effects, both as measured in vitro and in animal challenge models, suggesting AMA1 as a potential vaccine component. However, AMA1 is polymorphic, probably as a result of immune selection operating on an important target of naturally occurring immunity. The current understanding of AMA1 will be presented, particularly in relation to the vaccine potential of AMA1 and the approaches being taken towards clinical development...
Extensive microsatellite diversity in the human malaria parasite Plasmodium vivax [Gene. 2008 Jan 14] — (English)
The population structure of Plasmodium vivax remains elusive. The markers of choice for large-scale population genetic studies of eukaryotes, short tandem repeats known as microsatellites, have been recently reported to be less polymorphic in P. vivax. Here we investigate the microsatellite diversity and geographic structure in P. vivax, at both local and global levels, using 14 new markers consisting of tri- or tetranucleotide repeats. The local-level analysis, which involved 50 field isolates from Sri Lanka, revealed unexpectedly high diversity (average virtual heterozygosity [HE], 0.807) and significant multilocus linkage disequilibrium in this region of low malaria endemicity. Multiple-clone infections occurred in 60% of isolates sampled in 2005. The global-level analysis of field isolates or monkey-adapted strains identified 150 unique haplotypes among 164 parasites from four continents. Individual P. vivax isolates could not be unambiguously assigned to geographic populations. For example, we found relatively low divergence among parasites from Central America, Africa, Southeast Asia and Oceania, but substantial differentiation between parasites from the same continent (South Asia and Southeast Asia) or even from the same country (Brazil). Parasite relapses, which may extend the duration of P. vivax carriage in humans, are suggested to facilitate the spread of strains across continents, breaking down any pre-existing geographic structure...
Inhibitory Properties of the Antibody Response to Plasmodium vivax Duffy Binding Protein in an Area with Unstable Malaria Transmission [Scandinavian Journal of Immunology, Volume 67 Issue 3 Page 270-278, March 2008] — (English)
The function of the Plasmodium vivax Duffy binding protein (DBP) during the erythrocyte invasion process is critical for successful parasite growth and pathogenesis in human infections. Although DBP is the subject of intensive malaria vaccine research, investigations on the functional proprieties of anti-DBP antibodies in the human population have been limited [Infect Immun68 (2000) 3164]. In the present study, we examined the ability of sera from different populations of the Brazilian Amazon – an area of markedly unstable malaria transmission – to inhibit the erythrocyte-binding function of the DBP ligand domain (region II, DBPII). We found that long-term exposure to malaria in the Amazon area elicits DBP-specific antibodies that inhibit the binding of different DBPII variants to erythrocytes. Despite the great variability of inhibitory antibody responses observed among study participants, we observed a positive correlation between erythrocyte binding-inhibitory activity and enzyme-linked immunosorbent assay anti-DBP antibodies. Of importance, there was a non-significant tendency towards increased levels of anti-DBP antibodies among individuals with asymptomatic P. vivax infections...
Naturally Acquired Immunity and Reduced Susceptibility to falciparum Malaria in Two Subpopulations of Endemic Eastern India [Scandinavian Journal of Immunology, Volume 67 Issue 2 Page 177-184, February 2008 ] — (English)
This study was aimed to assess the prevalence of naturally acquired humoral immune responses and their association with reduced susceptibility to malaria in children and adults with differential clinical conditions from an Indian zone where malaria is endemic. The study was undertaken in an eastern province of India (Keonjhar, Orissa) in a group of 341 children (both younger and older) and 98 adults living in two different areas, Town area and Forest area. They were studied for their parasitological and immunological profiles. Sera from different age-matched groups were screened by ELISA to measure IgG reactivities for characterizing humoral immune responses to the B-cell epitopes of Plasmodium falciparum MSP1, AMA1, RAP1 and EBA175 peptides and P. falciparum-infected erythrocyte lysate. In Town area, overall P. falciparum cases were 5.5%, whereas those in Forest area were 26.7%. We observed an age-wise increasing trend of immunity in these two populations. It was also noticed that the frequency of responders to stage-specific antigens was higher in individuals from the Town area where the frequency of malaria was lower. The naturally acquired humoral immune responses to different stage-specific antigens of P. falciparum reflect the reduced risk of malaria in the study groups. The higher frequency of seroresponders showed correlation with lower risk of developing malaria...
Polymorphism of Antimalaria Drug Metabolizing, Nuclear Receptor, and Drug Transport Genes among Malaria Patients in Zanzibar, East Africa [Therapeutic Drug Monitoring. 30(1):10-15, February 2008] — (English)
Artemisinin-based combination therapy is a main strategy for malaria control in Africa. Zanzibar introduced this new treatment policy in 2003. The authors have studied the prevalence of a number of functional single nucleotide polymorphisms (SNPs) in genes associated with the elimination of the artemisinin-based combination therapy compounds in use in Zanzibar to investigate the frequencies of subgroups potentially at higher drug exposure and therefore possible higher risk of toxicity.One hundred three unrelated children with uncomplicated malaria from the Unguja and Pemba islands of Zanzibar were enrolled. With use of polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR-based allele discrimination methods, the CYP2B6 (G15631T), CYP3A4 (A-392G), CYP3A5 (A6986G, G14690A, 27131-132 insT, C3699T) SNPs and MDR1 SNPs C3435T, G2677T/A, and T-129C were analyzed. PCR product sequencing was applied to regulatory regions of MDR1, the CYP3A4 proximal promoter, and to exons 2 and 5 of PXR, a gene coding for a nuclear factor activated by artemisinin antimalarials and associated with the transcription induction of most of the studied genes.Homozygous subjects for alleles coding for low activity proteins were found at the following frequencies: 1) MDR1: 2.9%; 2) CYP2B6: 9.7%; 3) CYP3A5: 14.1%; and 4) CYP3A4: 49.5%. No functionally relevant allele was found in the analyzed regions of PXR. A new MDR1 SNP was found (T-158C), located in a putative antigen recognition element.Ten (10.1%) subjects were predicted to be low metabolizers simultaneously for CYP3A4 and CYP3A5. This fraction of the population is suggested to be under higher exposure to certain antimalarials, including lumefantrine and quinine...
Biochemical characterization of Plasmodium falciparum Sir2, a NAD(+)-dependent deacetylase [Molecular and Biochemical Parasitology, 2007 Dec 15] — (English)
In Plasmodium falciparum, the causative agent of cerebral malaria, silent information regulator 2 (Sir2) has been implicated in pathogenesis through its role in var gene silencing. P. falciparum Sir2 (PfSir2) in addition to the catalytic core, has a 13 residue N-terminal and 4 residue C-terminal extension over the shorter Archaeoglobus fulgidus Sir2. In this paper, we highlight our studies aimed at understanding the kinetic mechanism of PfSir2 and the role of N- and C-terminal extensions in protein function and oligomerization. Bisubstrate kinetic analysis showed that PfSir2 exhibits a rapid equilibrium ordered sequential mechanism, with peptide binding preceding NAD+. This study also reports on surfactin as a novel Sir2 inhibitor exhibiting competitive inhibition with respect to NAD+ and uncompetitive inhibition with acetylated peptide. This inhibition pattern with surfactin provides further support for ordered binding of substrates. Surfactin was also found to be a potent inhibitor of intra-erythrocytic growth of P. falciparum with 50% inhibitory concentration in the low micromolar range. PfSir2, like the yeast homologs (yHst2 and Sir2p), is a trimer in solution. However, dissociation of trimer to monomers in the presence of NAD+ is characteristic of the parasite enzyme. Oligomerization studies on N- and/or C-terminal deletion constructs of PfSir2 highlight the role of C-terminus of the protein in mediating homotrimerization. N-terminal deletion resulted in reduced catalytic efficiency although substrate affinity was not altered in the constructs. Interestingly, deletion of both the ends relaxed NAD+ specificity...
Ovipositional periodicity of caged Anopheles gambiae individuals [ J Circadian Rhythms. 2008 Jan 25;6(1):2] — (English)
On equatorial time, caged laboratory strain A. gambiae groups deposited 65% of their total eggs between 1800 and 0 h, and the remaining 35% were spread between 0 and 1000 h. Caged house-collected A. gambiae groups deposited 74% of their total eggs between 1800 and 200 h, ceased oviposition for 3 h, and then spread the remaining 26% of their eggs near or after dawn. Ninety-six percent of individual A. gambiae females spread their eggs over a continuous 2-4 h period without interruption. In tests of capacity for mid afternoon oviposition, females given evening access to an ovipositional resource deposited 2% of their total eggs between 1200 and 1700 h. A. gambiae females given only access to an ovipositional resource between 1200 and 1700 h deposited 3 times more eggs during that time period than did females previously given evening access...
Protein structure based strategies for antigen discovery and vaccine development against malaria and other pathogens [Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):259-65] — (English)
The review surveys potential "structural antigens" which represent small protein domains that can be chemically synthesized and, isolated from the context of the whole protein, can fold in the same native structure. They include natively unfolded protein regions, small globular domains, alpha-helical coiled coils and regions with tandem repeats forming structures ranging from the collagen triple helices to solenoid-like arrangements. We also describe and compare new strategies for development of vaccine that use the concept of structural epitopes. One type of approach is based on engineering artificial mini-proteins able to mimic structural epitopes of natural proteins. The review compares the "engineering" methodologies with "bioinformatics" approaches that became possible recently, after the sequencing of the genomes of many pathogens, and involve genome-wide bioinformatics searches for "structural antigens". In particular, based on the known P. falciparum genome, we identified putative alpha-helical coiled coil regions, 30-40 amino acids long, in proteins presented in asexual malaria blood stages. Peptides of such regions frequently fold into the "native" structure. A hundred such peptides were synthesized and all of them were recognized at various degrees (5-80%) by a panel of sera from donors living in malaria-endemic areas. The results obtained demonstrate that a bioinformatics/chemical synthesis strategy can rapidly lead to the identification of new proteins that can be targets of potential vaccines and/or drugs against malaria and other infectious organisms...
The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs [Curr Med Chem. 2008;15(2):161-71] — (English)
Malaria, one of the major reemerging parasitic diseases, is caused by protozoal parasites belonging to the genus plasmodia. Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The current line of therapy against malaria is faced with the hurdles of a low or total lack of efficacy due to the evolution of drug-resistant strains of the malarial parasites. Preventive vaccination against malaria is an ideal solution to this problem but is not expected to arrive for at least a decade. Development of antimalarial drugs involving novel mechanisms of action is therefore of imminent importance. Several novel drug candidates of synthetic and natural products origin as well as their combination therapies are currently being evaluated for their efficacy against the drug-resistant strains of the parasites. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway as well as the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This review provides an overview of the latest developments in terms of drugs, combination therapies and novel plasmodial targets being carried out to counter the menace of drug-resistant malaria....
Insecticide-treated bednets and child survival in rural Kenya [The Lancet, Volume 371, Issue 9607, 12 January 2008-18 January 2008, Pages 115-116] — (English)
Greg Fegan and colleagues (Sept 22, p 1035)1 seem to show that the recent upward leap in coverage of Kenyan children with insecticide-treated nets (ITNs) has had the hoped-for effect of reducing child mortality. However, the average reduction in mortality of 44% among net users compared with non-users is of only borderline significance (95% CI 4–67, p=0·04)...
Methods of Microarray Data Analysis V [Springer US] — (English)
Oxidative Stress Genes in Plasmodium falciparum as Indicated by Temporal Gene Expression: Construction of Malaria Gene Expression Network Using Partial Correlations ...
Prepared in cooperation with WHO ANGOLA INFO.
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