Role In Malaria Research Articles

Malaria Eradication in the Americas: A Retrospective Analysis of Childhood Exposure.

This study uses the malaria-eradication campaigns in the United States (circa 1920), and in Brazil, Colombia and Mexico (circa 1955) to measure how much childhood exposure to malaria depresses labor productivity. The campaigns began because of advances in health technology, which mitigates concerns about reverse causality. Malarious areas saw large drops in the disease thereafter. Relative to non-malarious areas, cohorts born after eradication had higher income as adults than the preceding generation. These cross-cohort changes coincided with childhood exposure to the campaigns rather than to pre-existing trends. Estimates suggest a substantial, though not predominant, role for malaria in explaining cross-region differences in income.

Elevated Levels of Vascular Endothelial Growth Factor (VEGF) and Soluble Vascular Endothelial Growth Factor Receptor (VEGFR)-2 in Human Malaria

In cerebral malaria, the binding of parasitized erythrocytes to the cerebral endothelium and the consequent angiogenic dysregulation play a key role in pathogenesis. Because vascular endothelial growth factor (VEGF) is widely regarded as a potent stimulator of angiogenesis, edema, inflammation, and vascular remodeling, the plasma levels of VEGF and the soluble form of the VEGF receptor (sVEGFR)-1 and -2 in uncomplicated malaria patients and healthy adults were measured by enzyme-linked immunosorbent assay (ELISA) to examine their roles in malaria. The results showed that VEGF and sVEGFR-2 levels were significantly elevated in malaria patients compared with healthy adults. Moreover, it was confirmed that malarial parasite antigens induced VEGF secretion from the human mast cell lines HMC-1 or KU812 cell. This is the first report to suggest that the interaction of VEGF and sVEGFR-2 is involved in the host immune response to malarial infection and that malarial parasites induce VEGF secretion from human mast cells.

Endoglin in African Children withPlasmodium falciparumMalaria: A Novel Player in Severe Malaria Pathogenesis?

Molecular mechanisms involved in the pathogenesis of severe Plasmodium falciparum malaria-specifically, cerebral malaria-are still unclear. Transforming growth factor beta (TGF-beta) family members are important regulators of inflammation that influence malaria pathogenesis. The soluble form of the auxiliary receptor endoglin (sEng) may play a role in malaria pathogenesis. Serum levels of sEng were measured using enzyme-linked immunosorbent-assay in Gabonese children with cerebral malaria (n = 7) severe malaria (n = 43), or uncomplicated malaria (n = 43) and were compared with levels in healthy control subjects (n = 25) and in another infectious disease group (n = 8). Serum sEng levels were higher in patients with cerebral malaria and all patients with severe malaria when compared with levels in patients in the other infection group and the healthy control group. Furthermore, sEng correlated significantly with disease severity. Only 7% of patients with uncomplicated malaria and none of the control patients (patients in the other infection group or the healthy control group) had serum levels higher than 12 ng/mL, whereas this was found in 85.7% of patients with cerebral malaria and 46.5% of patients with severe malaria. High sEng levels may attenuate anti-inflammatory response resulting in clinical deterioration of patients with P. falciparum malaria. Our results further corroborate the role of the vascular compartment, especially the endothelium, in severe malaria pathogenesis.

Low frequency of the TIRAPS180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy

BackgroundThe Toll-like receptors (TLRs) mediate innate immunity to various pathogens. A mutation (S180L) in the TLR downstream signal transducer TIRAP has recently been reported to be common in Europeans and Africans and to roughly half the risks of heterogeneous infectious diseases including malaria, tuberculosis, bacteremia, and invasive pneumococal disease in heterozygous mutation carriers.MethodsWe assessed the TIRAP S180L variant by melting curve and RFLP analysis in 1095 delivering women from malaria-endemic Ghana, as well as in a further 1114 individuals participating in case control studies on sepsis and leprosy in Germany, Turkey and Bangladesh.ResultsIn Ghana, the TIRAP S180L polymorphism was virtually absent. In contrast, the mutation was observed among 26.6%, 32.9% and 12% of German, Bangladesh and Turkish controls, respectively. No significant association of the heterozygous genotype with sepsis or leprosy was observed. Remarkably, homozygous TIRAP 180L tend to increase the risk of sepsis in the German study (P = 0.04).ConclusionA broad protective effect of TIRAP S180L against infectious diseases per se is not discernible.

Malaria and Agricultural Production: Are There Bidirectional Effects? The Case of Coffee and Cocoa in Côte d'Ivoire

The sectors of coffee and cocoa in Cote d’Ivoire represented, before the political crisis, approximately 15% of the GDP and 40% of exports. The production zone of these two crops is the forest, which is a malaria endemic area. The cultivation of these crops is less constraining than that of the food crops such as rice or yam, which need to be replanted each year. However, the maintenance of the ground and trees and pest management are major tasks contributing to high yields. But, by increasing the work time in fields, they also expose farmers to mosquito bites and, as a consequence, to the risk of malaria. Farmers in this area also grow food crops, and more specifically rice, as rain cultivation crops, but some also cultivate these crops in irrigated lowland. The aim of this paper is twofold: first of all, to evaluate the role of malaria in coffee and cocoa production; secondly, to assess the role of the rice production scheme on malaria transmission. Three functions are therefore estimated: the production of coffee, the production of cocoa, and the production of health. Data were collected during a survey carried out on 750 households (21 villages) in the forest area. The main results show that malaria has no effect on coffee and cocoa production and that lowland irrigated rice cultivation does not constitute a risk factor for malaria transmission.JEL Classification: I12, O13.

Overproduction, purification and crystallization of a chondroitin sulfate A-binding DBL domain from a Plasmodium falciparum var2csa-encoded PfEMP1 protein.

The PfEMP1 proteins of the malaria parasite Plasmodium falciparum are inserted into the membrane of infected red blood cells, where they mediate adhesion to a variety of human receptors. The DBL domains of the var2csa-encoded PfEMP1 protein play a critical role in malaria of pregnancy, tethering infected cells to the surface of the placenta through interactions with the glycosaminoglycan carbohydrate chondroitin sulfate A (CSA). A CSA-binding DBL domain has been overproduced in a bacterial expression system, purified and crystallized. Native data sets extending to 1.9 A resolution have been collected and phasing is under way.

Reply to comment on: Co-infection with subclinical HIV and Wuchereria bancrofti, and the role of malaria and hookworms, in adult Tanzanians: infection intensities, CD4/CD8 counts and cytokine responses

We appreciate Dr Eisenhut's interest in our paper (Nielsen et al., 2007), which evolved from a previous cross-sectional study (Nielsen et al., 2006) in which a negative association between hookworm and HIV infection was found. As we pointed out, this association may reflect a cause—effect relationship but may also be caused by confounding. If the relationship is causal, the direction cannot be determined owing to the cross-sectional nature of the study. In our recent study (Nielsen et al., 2007), we presented a higher CD4% and CD4/CD8 ratio in HIV-positive individuals with hookworm co-infection than in HIV-positives without hookworm infection, which may be due to a cause–effect relationship or a result of confounding effects. Among other suggestions, we introduced immunological hyporesponsiveness and thereby reduced replication of HIV virus induced by chronic hookworm infection (Borkow and Bentwich, 2004) as a possible underlying mechanism of a negative association between HIV and hookworm infection. Dr Eisenhut questions the plausibility of our explanation and made the point that hyporesponsiveness would lead to an on average smaller number of white cells, including CD4 lymphocytes, in response to infection. We acknowledge this point, but find that it does not exclude the possibility of reduced HIV virus replication (due to a hookworm-induced general immunological hyporesponsiveness) in the remaining CD4 cells and thereby a reduced rate of CD4 cell destruction in hookworm-infected individuals. This is to be compared with HIV-positive individuals without hookworms with a then relatively higher number of CD4 cells but, owing to the lack of hookworm-induced hyporesponsiveness, also a higher level of virus replication and CD4 cell destruction. Based on this hypothesis, it is difficult to predict which of the two groups would have the highest CD4 count, but at some point the negative effect of the hyporesponsiveness (decrease in CD4 cells) might be exceeded by a positive effect (reduced destruction of CD4 cells) in co-infected individuals, resulting in a higher number of CD4 cells in hookworm-infected HIV-positive individuals than in HIV-positives without hookworms. The level of CD4 count in the two groups at a given point would obviously depend on the stage of the HIV infection and perhaps also on the intensity of the hookworm infection. Thus, we concur with Dr Eisenhut's suggestion of including data on infection history in future studies aimed at elucidating HIV and helminth interactions. The possibility that the better immune status in hookworm-infected HIV-positive individuals reflects the fact that these individuals have been infected with HIV more recently is plausible and should have been discussed in our paper (Nielsen et al., 2007). It is well established that HIV infection impairs nutritional status and that low nutritional status may affect the course of HIV infection (Fawzi et al., 2004). We therefore support the suggestion of including indicators of malnutrition whenever possible in studies involving HIV-infected individuals.

Patterns of co-association of C-reactive protein and nitric oxide in malaria in endemic areas of Iran

In addition to numerous immune factors, C-reactive protein (CRP) and nitric oxide (NO) are believed to be molecules of malaria immunopathology. The objective of this study was to detect CRP and NO inductions by agglutination latex test and Griess microassay respectively in both control and malaria groups from endemic areas of Iran, including Southeastern (SE) (Sistan & Balouchestan, Hormozgan, Kerman) and Northwestern (NW) provinces (Ardabil). The results indicated that CRP and NO are produced in all malaria endemic areas of Iran. In addition, more CRP and NO positive cases were observed amongst malaria patients in comparison with those in control group. A variable co-association of CRP/NO production were detected between control and malaria groups, which depended upon the malaria endemic areas and the type of plasmodia infection. The percentage of CRP/NO positive cases was observed to be lower in NW compare to SE region, which may be due to the different type of plasmodium in the NW (Plasmodium vivax) with SE area (P. vivax, Plasmodium falciparum, mixed infection). The fluctuations in CRP/NO induction may be consistent with genetic background of patients. Although, CRP/NO may play important role in malaria, their actual function and interaction in clinical forms of disease remains unclear.

Co-infection with subclinical HIV and Wuchereria bancrofti, and the role of malaria and hookworms, in adult Tanzanians: infection intensities, CD4/CD8 counts and cytokine responses

The association between HIV and Wuchereria bancrofti, and the role of malaria and hookworms, were analysed by comparing three groups of individuals with: (1) HIV (HIV+; n=16); (2) W. bancrofti (circulating filarial antigen (CFA)+; n=25); and (3) HIV and W. bancrofti (HIV+/CFA+; n=18). A slightly higher HIV load and lower CD4% was observed in the HIV+/CFA+ group compared with the HIV+ group, and a slightly higher W. bancrofti CFA intensity was observed in the CFA+ group compared with the HIV+/CFA+ group, but none of these differences were statistically significant. Specific and non-specific IL-4, IL-10, IFNgamma and TNF levels were measured. Only specific IL-4 was significantly higher in the CFA+ group compared with the HIV+/CFA+ group. Thus, there was no clear evidence for an interaction between HIV and W. bancrofti infection. A multiple linear regression model showed that the presence of CFA was strongly positively associated with specific TNF response and, similarly, that HIV-positive individuals had higher TNF responses than HIV-negative individuals. Interestingly, the CD4% and CD4/CD8 ratio were higher in HIV-positive individuals with hookworms than in those without hookworm co-infection. Malaria was not associated with any of the other infections, or with CD4/CD8 counts or cytokine responses.

Seasonal variations in maternal mortality in Maputo, Mozambique: the role of malaria

To evaluate the impact of malaria on maternal death through the analysis of the seasonal variations of crude and malaria-specific maternal mortality rates. All maternal deaths and live births occurring at Maputo Central Hospital, located in an urban area, between January 2001 and December 2003, were retrospectively recorded. Clinical diagnoses of the causes of death and period of the year were analysed. Two hundred and seventy-eight deaths were recorded. The overall crude maternal mortality rate was 995/100 000 live births. Malaria was the most frequent cause of maternal death, accounting for 23%. Crude and malaria-specific maternal mortality rates showed a similar pattern of seasonal variation, with peaks at the beginning and the end of the malaria transmission season. The malaria-specific maternal mortality rate was significantly higher during the rainy seasons (rate ratio 1.919; 95% CI 1.061, 3.470; P = 0.031). Malaria may contribute to maternal mortality in highly endemic countries in sub-Saharan Africa, at least in urban areas. Efforts to improve malaria control in pregnancy may have an impact on maternal mortality in sub-Saharan Africa.

Protective Roles of Mast Cells and Mast Cell-Derived TNF in Murine Malaria

TNF plays important roles in the protection and onset of malaria. Although mast cells are known as a source of TNF, little is known about the relationship between mast cells and pathogenesis of malaria. In this study, mast cell-deficient WBB6F1-W/W(v) (W/W(v)) and the control littermate WBB6F1+/+ (+/+) mice were infected with 1 x 10(5) of Plasmodium berghei ANKA. +/+ mice had lower parasitemia with higher TNF levels, as compared with W/W(v) mice. Diminished resistance in W/W(v) mice was considered to be due to mast cells and TNF. This fact was confirmed by experiments in W/W(v) mice reconstituted with bone marrow-derived mast cells (BMMCs) of +/+ mice or of TNF-/- mice. W/W(v) mice with BMMCs of +/+ mice exhibit lower parasitemia and mortality accompanying significantly higher TNF levels than those of W/W(v) mice. Parasitemia in W/W(v) mice with BMMCs of TNF-/- mice was higher than that in +/+ mice. Activation of mast cells by anti-IgE or compound 48/80 resulted in release of TNF and decrease of parasitemia. In addition, splenic hypertrophy and increased number of mast cells in the spleen were observed after infection in +/+ mice and W/W(v) mice reconstituted with BMMCs of +/+ mice as compared with W/W(v) mice. These findings propose a novel mechanism that mast cells and mast cell-derived TNF play protective roles in malaria.

Comment on: Co-infection with subclinical HIV and Wuchereria bancrofti, and the role of malaria and hookworms, in adult Tanzanians: infection intensities, CD4/CD8 counts and cytokine responses

Summary The association between HIV and Wuchereria bancrofti, and the role of malaria and hookworms, were analysed by comparing three groups of individuals with: (1) HIV (HIV+; n = 16); (2) W. bancrofti (circulating filarial antigen (CFA)+; n = 25); and (3) HIV and W. bancrofti (HIV+/CFA+; n = 18). A slightly higher HIV load and lower CD4% was observed in the HIV+/CFA+ group compared with the HIV+ group, and a slightly higher W. bancrofti CFA intensity was observed in the CFA+ group compared with the HIV+/CFA+ group, but none of these differences were statistically significant. Specific and non-specific IL-4, IL-10, IFNγ and TNF levels were measured. Only specific IL-4 was significantly higher in the CFA+ group compared with the HIV+/CFA+ group. Thus, there was no clear evidence for an interaction between HIV and W. bancrofti infection. A multiple linear regression model showed that the presence of CFA was strongly positively associated with specific TNF response and, similarly, that HIV-positive individuals had higher TNF responses than HIV-negative individuals. Interestingly, the CD4% and CD4/CD8 ratio were higher in HIV-positive individuals with hookworms than in those without hookworm co-infection. Malaria was not associated with any of the other infections, or with CD4/CD8 counts or cytokine responses.

WITHDRAWN: Co-infection with sub-clinical HIV and Wuchereria bancrofti, and the role of malaria and hookworms, in adult Tanzanians: infection intensities, CD4/CD8 counts and cytokine responses

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Is malaria a predisposing factor for third molar pericoronitis in the tropics?

Malaria is an important disease in the tropics, and its role as a predisposing factor or co morbidity has been investigated in many diseases including HIV infection and tuberculosis. There are very few studies, which have investigated its role in oral and dental diseases. Our study aimed to demonstrate the possible role of malaria in predisposing to pericoronitis, an infection affecting impacted third molars predominantly. Thirty-eight patients presenting with pericoronitis were tested for malaria parasites and results compared with that obtained from controls that were equally susceptible to pericoronitis but did not have the infection. 19.7% of the study group compared to 6.6% of control group had malaria parasite in their blood. This difference was statistically significant, P=0.018 (Fisher's exact). The odds ratio was 4.3 (95% CI=1.2-17.0). Malaria appears to be a predisposing factor to pericoronitis in this study. There is a need for further studies on the possible role of malaria in oral and dental diseases.

Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region

Interferon-gamma, encoded by IFNG, is a key immunological mediator that is believed to play both a protective and a pathological role in malaria. Here, we investigate the relationship between IFNG variation and susceptibility to malaria. We began by analysing West African and European haplotype structure and patterns of linkage disequilibrium across a 100 kb genomic region encompassing IFNG and its immediate neighbours IL22 and IL26. A large case-control study of severe malaria in a West Africa population identified several weak associations with individual single-nucleotide polymorphisms in the IFNG and IL22 genes, and defined two IL22 haplotypes that are, respectively, associated with resistance and susceptibility. These data provide a starting point for functional and genetic analysis of the IFNG genomic region in malaria and other infectious and inflammatory conditions affecting African populations.

Malaria in Pregnancy

Recently, there has been a resurgence of malaria in densely populated areas of the United States secondary to human migration from endemic areas where factors such as cessation of vector control, vector resistance to insecticides, disease resistance to drugs, environmental changes, political instability, and indifference, have played a role for malaria becoming an overwhelming infection of these tropical underdeveloped countries. It is important for health care providers of gravida to be alert of the disease and its effects on pregnancy.

MOTHER-TO-CHILD TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 IN RELATION TO THE SEASON IN YAOUNDE, CAMEROON

A public health program to prevent mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) by treatment with nevirapine has been ongoing in Yaounde, Cameroon since January 2000. After 24 months, plasma samples from 119 children born to HIV-1-positive mothers were tested for HIV-1 RNA between six and eight weeks after birth. Thirteen (10.9%) tested positive (95% confidence interval = 5.2-16.7%). Risk factors associated with MTCT in this study were maternal viral load (P < 0.05), low birth weight (chi2 for trend = 8.78, P = 0.01), and birth during the second half of the year. A high correlation was repeatedly observed between rainfall in a given month and the risk of MTCT of HIV-1 in children born three months later (r = 0.634, P < 0.001). Although we cannot rule out other tropical infections related to the rainy season, the role of malaria is highly suspected since the interval of three months we observed between the peaks of rainfall and the rate of transmission is consistent with the Plasmodium life cycle.

Reduced prevalence of Plasmodium falciparum infection and of concomitant anaemia in pregnant women with heterozygous G6PD deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency confers protection against malaria in children, yet its role in malaria in pregnancy is unknown. In a cross-sectional study among 529 pregnant Ghanaian women, Plasmodium falciparum infection, anaemia and G6PD genotypes were assessed. Of these, 30.4% were heterozygous and 2.6% were homozygous for G6PD deficiency. The prevalence of P. falciparum infection decreased from 66% in G6PD-normal women to 58% in heterozygotes, and to 50% in individuals with homozygous G6PD deficiency (Chi2(trend) = 4.4, P = 0.04). Multivariate analysis revealed that in multigravid women but not in primigravidae, heterozygous G6PD deficiency was associated with a reduced risk of P. falciparum infection (Odds ratio (OR), 0.6; 95% confidence interval (95% CI), [0.4-0.9]). This protection against infection was limited to the third trimenon of pregnancy. In addition, heterozygous G6PD deficiency was associated with a reduced risk of anaemia among infected multigravidae (OR, 0.5 [0.3-1.0]). Pregnancy is a period of high vulnerability to malaria. The results of this study provide evidence for protection against malaria in pregnancy caused by heterozygous G6PD deficiency. This advantage, even if confined to multigravid women, may contribute to the selection of G6PD variants in malaria-endemic regions.

Understanding the Knops blood group and its role in malaria.

The antibodies that once were referred to as "HTLAs" have now help to define an entire blood group system with a well characterized genetic basis. Although not "clinically significant" in transfusion medicine, the Knops blood group has gained importance in the field of infectious disease. Its further role in protein (CR1) function and autoimmune diseases remains unknown but may provide interesting work for years to come.

Poor serologic responses five to seven years after immunization with high and standard titer measles vaccines.

Few data exist on the persistence of measles antibodies after vaccination of West African infants. Therefore we examined measles antibody titers 5 to 7 years after children in rural Senegal had received high titer Edmonston-Zagreb (EZ-HT), high titer Schwarz (SW-HT) or standard titer Schwarz (SW-STD) measles vaccines in infancy. Children had received either high titer vaccines at 5 months of age or standard titer at 10 months of age. Finger prick blood samples were tested for measles antibody 5 to 7 years later by the hemagglutinin inhibition test. Persistence of antibody after high titer vaccines was poor with the result that 39 and 50% of the EZ-HT and the SW-HT groups had low titers of hemagglutinin inhibition measles antibodies (< or =125 mIU/ml). Nineteen percent of the children in the SW-STD group had low titers which is a lower prevalence than in the high titer groups [relative risk (95% confidence intervals), 0.05 (0.28 to 0.88) vs. EZ-HT; relative risk, 0.38 (0.22 to 0.66) vs. SW-HT]. Geometric mean (95% confidence interval) antibody titers in children with detectable values were 616 (435 to 871) in the EZ-HT, 1106 (616 to 1866) in the SW-HT and 1271 (871 to 1741) mIU/ml in the SW-STD groups, respectively. Multivariant regression analysis showed that mean titers were 2.00 (1.03 to 3.89) times higher for children with low prevaccination antibody titers (< or =125 mIU/ml) and 3.06 (1.90 to 4.94) times higher if blood was collected in the rainy season. Given the rapid decline in antibody titers over a 5- to 6-year period in an area where measles vaccine coverage was high, it seems likely that multiple dose immunization schedules will be needed in the future to maintain protective antibody concentrations (>125 mIU/ml) in West Africa. The role of subclinical boosting by exposure to natural measles and the possible role of malaria, which increases immunoglobulin turnover, in influencing long term antibody persistence after vaccination deserve further investigation.