Malaria Susceptibility Research Articles

Impact of Co-Infections and BCG Immunisation on Immune Responses among Household Contacts of Tuberculosis Patients in a Ugandan Cohort

BackgroundTuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.MethodsAdults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.ResultsWe enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.ConclusionsWe found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.

Correction: Human Candidate Polymorphisms in Sympatric Ethnic Groups Differing in Malaria Susceptibility in Mali

Correction: Human Candidate Polymorphisms in Sympatric Ethnic Groups Differing in Malaria Susceptibility in Mali

Neuroauditory toxicity of artemisinin combination therapies-have safety concerns been addressed?

Although artemisinin-based combination therapies (ACTs) are widely viewed as safe drugs with a wide therapeutic dose range, concerns about neuroauditory safety of artemisinins arose during their development. A decade ago, reviews of human data suggested a potential neuro-ototoxic effect, but the validity of these findings was questioned. With 5–10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria. Fifteen studies reported a neurological or auditory assessment. The large heterogeneity of neuro-ototoxic end points and assessment methodologies and the descriptive nature of assessments hampered a formal meta-analysis and definitive conclusions, but they highlight the persistent lack of data from young children. This subgroup is potentially most vulnerable to any neuroauditory toxicity because of their development stage, increased malaria susceptibility, and repeated ACT exposure in settings lacking robust safety monitoring.

Association between Fc-gamma receptor IIa (CD32) gene polymorphism and malaria susceptibility: A meta-analysis based on 6928 subjects

BackgroundPrevious studies about the association between the -131R/H polymorphism in the Fc-gamma receptor IIa (FcγRIIa) gene and malaria susceptibility have yielded conflicting results. The aim of this meta-analysis was to clarify more accurately the association of this polymorphism with malaria risk. MethodsA systematic literature search of the associated studies up to August 1, 2013, was conducted using the following electronic databases: PubMed, Embase, Medline, and the China National Knowledge Infrastructure (CNKI). Statistical analyses were performed by STATA12.0 software, with odds ratios (ORs) and their 95% confidence intervals (CIs). ResultsSix eligible studies including 4111 malaria cases and 2817 controls were identified. A pooled analysis of these studies pointed to a significant association between the variant H allele and reduced susceptibility to malaria or possible protection against malaria: H vs. R (OR=0.691, POR=0.009); HH vs. RR (OR=0.523, POR=0.013); RH vs. RR (OR=0.770, POR=0.037); RH+HH vs. RR (OR=0.664, POR=0.019); and HH vs. RH+RR (OR=0.649, POR=0.037). In subgroup analysis, similar significant associations were also found in Asia (HH vs. RR: OR=0.137, POR=0.009; HH vs. RH+RR: OR=0.267, POR=0.000) and in Africa (RH vs. RR: OR=0.842, POR=0.002; RH+HH vs. RR: OR=0.859, POR=0.004). ConclusionsThis meta-analysis suggests that the variant H allele of the FcγRIIa-131R/H polymorphism may be a protective factor against blood-stages of malaria infection, both in Asians and Africans. The finding may aid the development of effective immune protection strategies against malaria that focus on antibody responses and enrich current knowledge of gene polymorphism in the malaria. Further large and well-designed studies are needed to confirm this association.

Using the information value method in a geographic information system and remote sensing for malaria mapping: a case study from India

This paper explores the scope of malaria-susceptibility modelling to predict malaria occurrence in an area. An attempt has been made in Varanasi district, India, to evaluate the status of malaria disease and to develop a model by which malaria-prone zones could be predicted using five classes of relative malaria susceptibility, i.e.very low, low, moderate, high and very high categories. The information value (Info Val) method was used to assess malaria occurrence and various time-were used as the independent variables. A geographical information system (GIS) is employed to investigate associations between such variables and distribution of different mosquitoes responsible for malaria transmission. Accurate prediction of risk depends on a number of variables, such as land use, NDVI, climatic factors, population, distance to health centres, ponds, streams and roads etc., all of which have an influence on malaria transmission or reporting. Climatic factors, particularly rainfall, temperature and relative humidity, are known to have a major influence on the biology of mosquitoes. To produce a malaria-susceptibility map using this method, weightings are calculated for various classes in each group. The groups are then superimposed to prepare a Malaria Susceptibility Index (MSI) map. We found that 3.87% of the malaria cases were found in areas with a low malaria-susceptibility level predicted from the model, whereas 39.86% and 26.29% of malaria cases were found in predicted high and very high susceptibility level areas, respectively. Malaria susceptibility modelled using a GIS may have a role in predicting the risks of malaria and enable public health interventions to be better targeted.

NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria

Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes.

Fc gamma Receptor IIa‐H131R Polymorphism and Malaria Susceptibility in Sympatric Ethnic Groups, Fulani and Dogon of Mali

It has been previously shown that there are some interethnic differences in susceptibility to malaria between two sympatric ethnic groups of Mali, the Fulani and the Dogon. The lower susceptibility to Plasmodium falciparum malaria seen in the Fulani has not been fully explained by genetic polymorphisms previously known to be associated with malaria resistance, including haemoglobin S (HbS), haemoglobin C (HbC), alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Given the observed differences in the distribution of FcγRIIa allotypes among different ethnic groups and with malaria susceptibility that have been reported, we analysed the rs1801274-R131H polymorphism in the FcγRIIa gene in a study of Dogon and Fulani in Mali (n = 939). We confirm that the Fulani have less parasite densities, less parasite prevalence, more spleen enlargement and higher levels of total IgG antibodies (anti-CSP, anti-AMA1, anti-MSP1 and anti-MSP2) and more total IgE (P < 0.05) compared with the Dogon ethnic group. Furthermore, the Fulani exhibit higher frequencies of the blood group O (56.5%) compared with the Dogon (43.5%) (P < 0.001). With regard to the FcγRIIa polymorphism and allele frequency, the Fulani group have a higher frequency of the H allele (Fulani 0.474, Dogon 0.341, P < 0.0001), which was associated with greater total IgE production (P = 0.004). Our findings show that the FcγRIIa polymorphism might have an implication in the relative protection seen in the Fulani tribe, with confirmatory studies required in other malaria endemic settings.

Dynamics of malaria transmission and susceptibility to clinical malaria episodes following treatment of Plasmodium falciparum asymptomatic carriers: results of a cluster-randomized study of community-wide screening and treatment, and a parallel entomology study

BackgroundIn malaria-endemic countries, large proportions of individuals infected with Plasmodium falciparum are asymptomatic and constitute a reservoir of parasites for infection of newly hatched mosquitoes.MethodsTwo studies were run in parallel in Burkina Faso to evaluate the impact of systematic identification and treatment of asymptomatic carriers of P. falciparum, detected by rapid diagnostic test, on disease transmission and susceptibility to clinical malaria episodes. A clinical study assessed the incidence of symptomatic malaria episodes with a parasite density >5,000/μL after three screening and treatment campaigns ~1 month apart before the rainy season; and an entomological study determined the effect of these campaigns on malaria transmission as measured by entomological inoculation rate.ResultsThe intervention arm had lower prevalence of asymptomatic carriers of asexual parasites and lower prevalence of gametocyte carriers during campaigns 2 and 3 as compared to the control arm. During the entire follow-up period, out of 13,767 at-risk subjects, 2,516 subjects (intervention arm 1,332; control arm 1,184) had symptomatic malaria. Kaplan-Meier analysis of the incidence of first symptomatic malaria episode with a parasite density >5,000/μL showed that, in the total population, the two treatment arms were similar until Week 11–12 after campaign 3, corresponding with the beginning of the malaria transmission season, after which the probability of being free of symptomatic malaria was lower in the intervention arm (logrank p < 0.0001). Similar trends were observed in infants and children <5 years and in individuals ≥5 years of age. In infants and children <5 years old who experienced symptomatic malaria episodes, the geometric mean P. falciparum density was lower in the intervention arm than the control arm. This trend was not seen in those individuals aged ≥5 years. Over the year, monthly variation in mosquito density and entomological inoculation rate was comparable in both arms, with September peaks in both indices.ConclusionCommunity screening and targeted treatment of asymptomatic carriers of P. falciparum had no effect on the dynamics of malaria transmission, but seemed to be associated with an increase in the treated community’s susceptibility to symptomatic malaria episodes after the screening campaigns had finished. These results highlight the importance of further exploratory studies to better understand the dynamics of disease transmission in the context of malaria elimination.

MBL2Variations and Malaria Susceptibility in Indian Populations

Human mannose-binding lectin (MBL) encoded by the MBL2 gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2 gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2 -221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, corrected P value [P(Corr)] = 0.0036; severe malaria OR = 1.6, P(Corr) = 0.02). The exon1 variants MBL2*B (severe malaria OR = 2.1, P(Corr) = 0.036; mild versus severe malaria OR = 2.5, P(Corr) = 0.039) and MBL2*C (mild versus severe malaria OR = 5.4, P(Corr) = 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR = 3.4, P(Corr) = 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPA increases the malaria risk. Our findings in Indian populations demonstrate that MBL2 functional variants are strongly associated with malaria and infection severity.

Human candidate polymorphisms in sympatric ethnic groups differing in malaria susceptibility in Mali.

Malaria still remains a major public health problem in Mali, although disease susceptibility varies between ethnic groups, particularly between the Fulani and Dogon. These two sympatric groups share similar socio-cultural factors and malaria transmission rates, but Fulani individuals tend to show significantly higher spleen enlargement scores, lower parasite prevalence, and seem less affected by the disease than their Dogon neighbours. We have used genetic polymorphisms from malaria-associated genes to investigate associations with various malaria metrics between the Fulanai and Dogon groups. Two cross sectional surveys (transmission season 2006, dry season 2007) were performed. Healthy volunteers from the both ethnic groups (n=939) were recruited in a rural setting. In each survey, clinical (spleen enlargement, axillary temperature, weight) and parasitological data (malaria parasite densities and species) were collected, as well as blood samples. One hundred and sixty six SNPs were genotyped and 5 immunoassays (AMA1, CSP, MSP1, MSP2, total IgE) were performed on the DNA and serum samples respectively. The data confirm the reduced malaria susceptibility in the Fulani, with a higher level of the protective O-blood group, and increased circulating antibody levels to several malaria antigens (p<10-15). We identified SNP allele frequency differences between the 2 ethnic groups in CD36, IL4, RTN3 and ADCY9. Moreover, polymorphisms in FCER1A, RAD50, TNF, SLC22A4, and IL13 genes were correlated with antibody production (p-value<0.003). Further work is required to understand the mechanisms underpinning these genetic factors.

Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations

BackgroundThere are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis.MethodsIn this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5′ and 3′ region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome.ResultsIt is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk.ConclusionsThese findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.

Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP–based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.

Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure

Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have re-sequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 (Kilifi) allele, that are correlated with malaria endemicity. We show that the ICAM-1 (Kilifi) allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.

Association of HLA-G 3′UTR polymorphisms with response to malaria infection: A first insight

Malaria represents one of the most important causes of mortality and morbidity in Africa. Variability in clinical presentation is partly due to host genetic polymorphisms. Among them, human leukocyte antigen (HLA) class I and class II alleles may be responsible for malaria susceptibility; however less is known about the possible role of non classical HLA molecules. Among them, HLA-G is a tolerogenic molecule with immunomodulatory properties, which differs from classical HLA class I molecules by its lower genetic diversity, tissue expression and function. Although primarily associated with maternal-fetal tolerance, HLA-G is now known to be involved in a wide range of physiopathological conditions, such as tumor, autoimmunity, transplantation, inflammation and viral infection by suppressing the function of various immune cells. In this work, we present the first evidence of an association between HLA-G 3′UTR polymorphisms and malaria infection. More precisely, we showed that HLA-G polymorphisms are associated with asymptomatic infection through two parasitological phenotypes, the intensity of Plasmodium falciparum infection and the mean level of parasite density. The allele+3187G and its haplotype (UTR-1, 14bp-Del/3001C/3003T/3010G/3035C/3052C/3142C/3187G/3196C) was associated with lower level of infection under a dominant model, and the haplotype UTR-3 (Del/3001C/3003T/3010C/3035C/3152C/3142G/3187A/3196C) was associated with high levels of infection under a recessive model. In conclusion, although further investigations are on the way to better address the possible involvement of the HLA-G molecule in the control of P. falciparum infection, this work presents the first evidence of an association between HLA-G polymorphisms and malaria infection. Further investigations are on the way to take into account the particularities of African populations.

IL1B, IL4R, IL12RB1 and TNF gene polymorphisms are associated with Plasmodium vivax malaria in Brazil

BackgroundMalaria is among the most prevalent parasitic diseases worldwide. In Brazil, malaria is concentrated in the northern region, where Plasmodium vivax accounts for 85% disease incidence. The role of genetic factors in host immune system conferring resistance/susceptibility against P. vivax infections is still poorly understood.MethodsThe present study investigates the influence of polymorphisms in 18 genes related to the immune system in patients with malaria caused by P. vivax. A total of 263 healthy individuals (control group) and 216 individuals infected by P. vivax (malaria group) were genotyped for 33 single nucleotide polymorphisms (SNPs) in IL1B, IL2, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, IL12RB1, SP110, TNF, TNFRSF1A, IFNG, IFNGR1, VDR, PTPN22 and P2X7 genes. All subjects were genotyped with 48 ancestry informative insertion-deletion polymorphisms to determine the proportion of African, European and Amerindian ancestry. Only 13 SNPs in 10 genes with differences lower than 20% between cases and controls in a Poisson Regression model with age as covariate were further investigated with a structured population association test.ResultsThe IL1B gene -5839C > T and IL4R 1902A > G polymorphisms and IL12RB1 -1094A/-641C and TNF -1031 T/-863A/-857 T/-308 G/-238 G haplotypes were associated with malaria susceptibility after population structure correction (p = 0.04, p = 0.02, p = 0.01 and p = 0.01, respectively).ConclusionPlasmodium vivax malaria pathophysiology is still poorly understood. The present findings reinforce and increase our understanding about the role of the immune system in malaria susceptibility.

Vector ecology and susceptibility in a malariaendemic focus in southern Islamic Republic of Iran

This study aimed to carry out a malaria situation analysis, species composition and susceptibility levels of the main malaria vector, Anopheles stephensi, to different insecticides in Bashagard. A longitudinal survey was conducted in 2 randomly selected villages in Bashagard. Malaria vectors were sampled by dipping method for the larvae and hand catch, night-biting catch, total catch, and shelter pit collection for the adults. Standard WHO susceptibility tests were used for a variety of insecticides on F1 progeny of An. stephensi reared from wild-caught females. In total, 693 adult anopheline mosquitoes and 839 third and fourth-instar larvae were collected and identified. They comprised 7 species; the most abundant adult and larvae anopheline mosquito was An. dthali (40.7% and 30.5% respectively). An. culicifacies (24.2%) and An. stephensi (16.7%) were the next most common species for adult mosquitoes. An. stephensi was fully susceptible to malathion and pyrethroid insecticides but resistant to DDT and tolerant to dieldrin.

Zinc erythrocyte protoporphyrin as marker of malaria risk in pregnancy - a retrospective cross-sectional and longitudinal study.

BackgroundThe effects of iron interventions and host iron status on infection risk have been a recurrent clinical concern, although there has been little research on this interaction in pregnant women.MethodsCross-sectional and longitudinal analyses were undertaken to determine the association of whole blood zinc erythrocyte protoporphyrin (ZPP) with malaria parasitaemia in pregnant women attending antenatal and delivery care at Montfort and Chikwawa Hospitals, Shire Valley, Malawi. Prevalence of antenatal, delivery and placental malaria was assessed in relation to maternal ZPP levels. The main outcome measures were prevalence of peripheral and placental Plasmodium falciparum parasitaemia and odds ratios of malaria risk.ResultsA total of 4,103 women were evaluated at first antenatal visit, of whom at delivery 1327 were screened for peripheral and 1285 for placental parasitaemia. Risk of malaria at delivery (peripheral or placental) was higher in primigravidae (p < 0.001), and lower (peripheral) with use of intermittent preventive anti-malarials during pregnancy (p < 0.001). HIV infection was associated with increased malaria parasitaemia (p < 0.02, peripheral or placental). Parasitaemia prevalence was lower in women with normal ZPP levels compared to those with raised concentrations at both first antenatal visit (all gravidae, p = 0.048, and at delivery (all gravidae, p < 0.001; primigravidae, p = 0.056). Between first antenatal visit and delivery women who transitioned from raised (at first antenatal visit) to normal ZPP values (at delivery) had lower peripheral parasitaemia prevalence at delivery compared to those who maintained normal ZPP values at both these visits (all gravidae: 0.70, 95%CI 0.4-1.1; primigravidae: 0.3, 0.1-0.8). In regression analysis this difference was lost with inclusion of HIV infection in the model.ConclusionsRaised ZPP concentrations in pregnancy were positively associated with P. falciparum parasitaemia and were probably secondary to malaria inflammation, rather than indicating an increased malaria risk with iron deficiency. It was not possible from ZPP measurements alone to determine whether iron deficiency or repletion alters malaria susceptibility in pregnancy.

Role of polymorphisms of toll-like receptor (TLR) 4, TLR9, toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A genes in malaria susceptibility and severity in Burundian children

BackgroundMalaria caused by Plasmodium falciparum is one of the leading causes of human morbidity and mortality from infectious diseases, predominantly in tropical and sub-tropical countries. As genetic variations in the toll-like receptors (TLRs)-signalling pathway have been associated with either susceptibility or resistance to several infectious and inflammatory diseases, the supposition is that single nucleotide polymorphisms (SNPs) of TLR2, TLR4, TLR9, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A could modulate malaria susceptibility and severity.MethodsThis study was planned to make a further contribution to solving the problem of the real role of the most common polymorphisms of TLR4, TLR9, TIRAP and FCGR2A genes in modulating the risk of malaria and disease severity in children from Burundi, Central Africa. All the paediatric patients aged six months to 10 years admitted to the hospital of Kiremba, Burundi, between February 2011 and September 2011, for fever and suspicion of acute malaria were screened for malaria parasitaemia by light microscopy of thick and thin blood smears. In children with malaria and in uninfected controls enrolled during the study period in the same hospital, blood samples were obtained on filter paper and TLR4 Asp299Gly rs4986790, TLR9 G1174A rs352139, T-1486 C rs187084 TLR9 T-1237 C rs5743836, TIRAP Ser180Leu rs8177374 and the FCGR2A His131Arg rs1801274 polymorphisms were studied using an ABI PRISM 7900 HT Fast Real-time instrument.ResultsA total of 602 patients and 337 controls were enrolled. Among the malaria cases, 553 (91.9 %) were considered as suffering from uncomplicated and 49 (8.1 %) from severe malaria. TLR9 T1237C rs5743836CC was associated with an increased risk of developing malaria (p = 0.03), although it was found with the same frequency in uncomplicated and severe malaria cases. No other differences were found in all alleles studied and in genotype frequencies between malaria cases and uninfected controls as well as between uncomplicated and severe malaria cases.ConclusionsTLR9 T1237C seems to condition susceptibility to malaria in Burundian children but not its severity, whereas none of the assessed SNPs of TLR4, TIRAP and FCGR2A seem to influence susceptibility to malaria and disease severity in this population.

HIV and malaria interactions: where do we stand?

Reversing the spread of HIV infection and the incidence of malaria constitute two of the Millenium Development Goals. However, despite recent achievements, both diseases still entail global heath problems. Furthermore, their overlapping geographical distribution raises concerns and challenges for potential immunological, clinical and therapeutic interactions. It has been reported that HIV infection increases malaria susceptibility and reduces the efficacy of antimalarial drugs. On the other hand, the effect of malaria on HIV-infected individuals has also been explored, with the parasitic infection increasing the risk of HIV disease progression and mother-to-child transmission of HIV. The spread of malaria and parasite resistance to antimalarials could also be accelerated by HIV-associated immunosuppresion. Current knowledge of the epidemiological, clinical, immunological and therapeutic interactions of the two diseases is reviewed in this article. We focus on the latest available data, pointing out key future research areas and challenges of the field.

Intermittent preventive treatment with sulfadoxine-pyrimethamine does not modify plasma cytokines and chemokines or intracellular cytokine responses to Plasmodium falciparum in Mozambican Children

BackgroundCytokines and chemokines are key mediators of anti-malarial immunity. We evaluated whether Intermittent Preventive Treatment in infants with Sulfadoxine-Pyrimethamine (IPTi-SP) had an effect on the acquisition of these cellular immune responses in Mozambican children. Multiple cytokines and chemokines were quantified in plasma by luminex, and antigen-specific cytokine production in whole blood was determined by intracellular cytokine staining and flow cytometry, at ages 5, 9, 12 and 24 months.ResultsIPTi-SP did not significantly affect the proportion of CD3+ cells producing IFN-γ, IL-4 or IL-10. Overall, plasma cytokine or chemokine concentrations did not differ between treatment groups. Th1 and pro-inflammatory responses were higher than Th2 and anti-inflammatory responses, respectively, and IFN-γ:IL-4 ratios were higher for placebo than for SP recipients. Levels of cytokines and chemokines varied according to age, declining from 5 to 9 months. Plasma concentrations of IL-10, IL-12 and IL-13 were associated with current infection or prior malaria episodes. Higher frequencies of IFN-γ and IL-10 producing CD3+ cells and elevated IL-10, IFN-γ, MCP-1 and IL-13 in plasma were individually associated with increased malaria incidence, at different time points. When all markers were analyzed together, only higher IL-17 at 12 months was associated with lower incidence of malaria up to 24 months.ConclusionsOur work has confirmed that IPTi-SP does not negatively affect the development of cellular immune response during early childhood. This study has also provided new insights as to how these cytokine responses are acquired upon age and exposure to P. falciparum, as well as their associations with malaria susceptibility.Trial RegistrationClinicalTrials.gov: NCT00209795