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Background The use of herbs for malaria treatment is common among pregnant women in Nigeria. This study through a survey documented three most commonly used herbs in the management of pregnancy-associated malaria in Abeokuta, Nigeria. This study also evaluated the efficacy and abortifacient properties of the selected herbs against established Plasmodium berghei NK65 infection in 110 experimental pregnant mice randomly distributed into 22 groups and treated with extracts of Morinda lucida (L.) Benth. (Rubiaceae), Enantia chlorantha (oliv.) (Annonaceae), and Cymbopogon citatrus (Stapf) (Poaceae) at a graded dose of 100, 200, and 300 mg/kg and Sulphadoxine-pyrimethamine (Fansidar) at 10 mg/kg. Results From the survey, Cymbopogon citratus (Leaf), Morinda lucida (Leaf), and Enanthia chlorantha (Bark) were the most frequently mentioned to be useful in management of malaria during pregnancy. Both M. lucida and E. chlorantha produced up to 70% P. gerghei chemosuppression in a dose dependent manner. Chemosupression was less than 50% in mice treated with C. citratus extracts. E. chlorantha induced abortion, while extracts of C. citratus and M. lucida caused miscarriage in pregnant mice. Progesterone titters were reduced in mice treated with plant extracts compared with those administered with Fansidar and untreated groups (p < 0.05). Conclusion This study showed that M. lucida and E. chlorantha had anti-malarial properties, which are promising in reducing problems with pregnancy associated malaria in the face of growing resistance to currently available drugs. However, they are capable of inducing abortion by impairing the production of progesterone. In order to reduce the risk of danger posed by use of herbs in pregnancy on mothers and the developing fetus, there is need for proper awareness on the possible abortifacient and teratogenic properties of herbs used in management of malaria during pregnancy.

Pregnancy Associated Malaria (PAM) threatens more than one million pregnant women and their infants in endemic regions due to poor outcomes, such as maternal anemia, stillbirth, infant death, etc. VAR2CSA, a 350 kDa transmembrane protein encoded by Plasmodium falciparum (P.falciparum), plays a vital role in the cytoadherence of infected erythrocytes (IEs) to placenta. Chondroitin sulfate A (CSA), displayed mostly on the surface of placental or tumor cells, has been recognized as the specific ligand for VAR2CSA. However, the architecture and CSA binding mechanism of VAR2CSA remain elusive. In this study, we determined the cryo-EM structures of P. falciparum VAR2CSA ectodomain and its complex with CSA at a resolution of 3.6 A and 3.4 A, respectively. Most importantly, it was revealed that CSA binding induces significant conformational change to close the binding pocket by turning DBL2X and DBL1X closer to DBL4e, and meanwhile enlarge the inner binding pocket via slightly moving a CSA-binding helix of DBL2X outward. Impressively, the structural analysis indicated that 9 key residues with positive charge in DBL2X might be mainly responsible for CSA binding, which is further validated by multidisciplinary methods, i.e., sequence alignment, site mutagenesis, CSA binding tests, and cytoadherence assays using confocal fluorescence microscopy. In summary, we elucidated the detailed molecular mechanism of cytoadherence to placenta or tumor cells through VAR2CSA, which may facilitate antigen design for PAM vaccine, and improve the drug delivery systems targeting both placenta and tumors.

Background Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual “blood-stage” parasites in the placenta, the major virulence mechanism. Methods The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. Results All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. Conclusions PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. Clinical Trials Registration EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489., The pregnancy-associated malaria-vaccine candidate PAMVAC is safe and well tolerated with all three tested formulations and induces functional binding-inhibitory antibodies. The vaccine with glucopyranosyl lipid adjuvant (GLA) in stable emulsion is superior to Alhydrogel and a GLA/QS21 liposomal formulation.

Background: The consequences of malaria during pregnancy are different regarding local conditions of malaria transmission. In stable malaria areas, the main complications are maternal anaemia and fetal growth restriction. This study aims to determine if pregnancy-associated malaria is associated with the risk of the above-mentioned complications and to determine if IPTp-sp reduces them in Kisangani. Methods: It is a cross-sectional analytical study conducted in parturients, in 6 medical facilities of Kisangani, from January 1st to September 30th, 2017. At delivery we measured their hemoglobin, we performed the thick blood smear of their peripheral blood and placental apposition; and we weighed their newborns at birth. Results: Risk of anaemia at delivery increased with malaria access during pregnancy (p = 0.0056; OR: 1.4221, 95% CI: 1.0851 - 1.8638) and peripheral parasitaemia at delivery (p = 0.0000; OR: 6.3855, 95% CI: 4.5552 - 8.9512). LBW increased with peripheral parasitaemia at delivery (p = 0.0000; OR: 3.5299, 95% CI: 2.4424 - 5.1015) and placental parasitaemia (p = 0.0000; OR: 18.3247, 95% CI: 12.5141 - 26.8332). IPTp-sp did not have effect on maternal hemoglobin at delivery (p = 0.1546; OR: 0.7553, IC a 95%: 0.4414 - 1.2923) and the birth weight (p = 0.1225; OR: 0.6638, IC a 95%: 0.3375 - 1.3056). Conclusion: In Kisangani, pregnancy-associated malaria is associated with maternal anaemia at delivery and LBW. IPTp-sp does not reduce the risk of these complications. Therefore, studies evaluating IPTp alternatives are required in malaria endemic areas.

Malaria in pregnancy poses a serious public health issues especially in developing countries. This study was to determine the Prevalence and risk factors of Malaria among Pregnant women attending antenatal clinic in Aboh Mbaise General Hospital. A total of 284 pregnant women participated in this study. A structured interviewer-administered questionnaire was used to obtain some socio-demographic characteristics of patients. Thick and thin films were made from blood collected from each pregnant woman. The films were stained using the gold standard staining technique, Giemsa staining for detecting malaria parasites in blood. Data generated was analyzed using SPSS 23.0 statistical package. A p-value0.05). Malaria prevalence followed the trend of 1st trimester 80(28.2%) to 2nd trimester 66(23.2%) to 3rd trimester 45(15.8%) in that order but the differences were not statistically significant (p>0.05). The lowest frequency occurred in the month of February 9(3.2%) while the highest frequency occurred in the month of July 62(21.8%) but the difference was not statistically significant (p>0.05). Patients who had bushes around their compound, and who didn’t use mosquito bed net (MBN) and insecticide treated nets (ITNs); those patients surrounded by mosquito breeding sites and who didn’t use Intermittent Preventive Treatment (IPT) were significantly associated with malaria parasite infection (p< 0.05). The prevalence of malaria parasite among the pregnant women in was 70.8%. Lack of education and employment; and risk factors like non-compliance to use of ITNs/MBN; and non-usage of IPT during pregnancy, presence of mosquito breeding sites and bushes around the premises of the study participants were risk factors contributing to prevalence of malaria among pregnant women in Aboh Mbaise General Hospital in Imo State.

Malaria is a leading cause of morbidity and mortality in the world. In general, malaria is easily treated but in a subset of cases it develops to severe disease. Severe malaria has a high rate of mortality even with the best available care. This creates the need for intensive research to fully characterise the pathogenesis of the disease in order to create future novel therapies. One of the hallmarks of malaria infections is its ability to adhere to specific sites in the body leading to severe disease syndromes such as cerebral malaria and pregnancy associated malaria. In this review, the platelet-mediated clumping adhesion phenotypes of malaria-infected erythrocytes were discussed in the context of infected erythrocyte adhesion phenotypes such as cytoadhesion and rosetting. Platelet-mediated clumping refers to a phenomenon of P. falciparum-infected erythrocytes whereby they agglutinate to form large aggregates held together by activated platelets. This unique phenotype is important because it has been associated with severe malaria in both children and adults in diverse geographical and transmission settings. The precise mechanisms by which platelet-mediated clumping occurs are yet to be precisely described. The platelet receptors implicated in this phenotype include CD36, P-Selectin and gC1qR. The parasite derived ligands that mediate this phenotype are yet to be described. Key words: Malaria, platelets, platelet-mediated clumping, infections.

Background Pregnancy-associated malaria (PAM) has been associated with adverse pregnancy outcomes like preterm birth (PTB) and low birthweight (LBW), which are among the leading causes of infant mortality globally. Rates of PTB and LBW are high in countries with a high burden of malaria. PAM may be a contributing factor to PTB and LBW, but is not well understood. Methods We conducted a systematic review and meta-analysis of studies examining the relationship between PAM and PTB or LBW using PubMed. The title and abstract of all studies were screened by two reviewers, and the full text of selected studies was reviewed to ensure they met inclusion criteria. Information regarding study characteristics and of PTB and LBW births among women with and without PAM was abstracted for included studies. Results Our search terms yielded 2237 articles, of which 18 met our final inclusion criteria. Eight studies examined associations between PAM and PTB, and 10 examined associations between PAM and LBW (population size ranging from 35 to 9956 women). The overall risk of LBW was 63% higher among women with PAM compared with women without PAM (95% CI = 1.48–1.80) and the risk of PTB was 23% higher among women with PAM compared with women without PAM (95% CI = 1.07–1.41). Conclusions These results indicate that infection with PAM is associated with PTB and LBW. Further understanding of the pathogenesis of disease and the immunologic changes that occur during pregnancy is essential for reducing the disproportional effects this disease has on this vulnerable population.

International audience; Background. Sickle cell trait (HbAS) confers partial protection against malaria by reducing the adhesion of Plasmodium falciparum-infected erythrocytes to host receptors, but little is known about its potential protection against placental malaria. Methods. Using flow cytometry, we assessed the recognition of HbAA and HbAS VAR2CSA-expressing infected erythrocytes, by plasma from 159 Beninese pregnant women with either HbAA (normal) or HbAS. Using multivariate linear models adjusted for gravidity, parasite infection at delivery, glucose-6-phosphate dehydrogenase deficiency, and α-thalassemia carriage, we observed significantly reduced cell surface antibody binding of HbAS-infected erythrocytes by plasma from HbAS compared with HbAA women (P < 10-3). Results. The difference in cell surface antibody binding was only observed when infected erythrocytes and plasma were associated according to the same hemoglobin genotype. Similar levels of VAR2CSA-specific antibody were measured by enzyme-linked immunosorbent assay in the 2 groups, suggesting that the altered interaction between VAR2CSA and HbAS women's antibodies could reflect abnormal display of VAR2CSA on HbAS erythrocytes. Conclusions. Our data stress the need for assessments of erythrocyte disorders such as the sickle cell trait in a population group when studying immunological responses to P falciparum.

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development, and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push toward malaria vaccines.

SUMMARYMalaria is one of the most serious infectious diseases with most of the severe disease caused byPlasmodium falciparum(Pf). Naturally acquired immunity develops over time after repeated infections and the development of antimalarial antibodies is thought to play a crucial role. Neonates and young infants are relatively protected from symptomatic malaria through mechanisms that are poorly understood. The prevailing paradigm is that maternal antimalarial antibodies transferred to the fetus in the last trimester of pregnancy protect the infant from early infections. These antimalarial antibodies wane by approximately 6 months of age leaving the infant vulnerable to malaria, however direct evidence supporting this epidemiologically based paradigm is lacking. As infants are the target population for future malaria vaccines, understanding how they begin to develop immunity to malaria and the gaps in their responses is key. This review summarizes the antimalarial antibody responses detected in infants and how they change over time. We focus primarily on Pf antibody responses and will briefly mentionPlasmodium vivaxresponses in infants.

Background Using indicators of disease severity, clinicians can predict which Plasmodium falciparum (Pf) malaria patients being treated with artesunate or quinine are likely to die despite these drugs. Effective “rescue adjuncts” are needed when drugs alone are inadequate. “Therapeutically-rational exchange” (T-REX) of special malaria-resistant red blood cells (RBCs) has been proposed to optimize adjunctive exchange transfusion. Methods Studies were reviewed that (1) quantified how group-O status and “sickle-trait” (HbAS) and “C-trait” (HbAC) hemoglobins affect Pf mortality, risk of thrombosis, or birth outcomes for women with pregnancy associated malaria (PAM), (2) reported prevalences of “dual-gene” malaria-resistant RBCs, or (3) reflected the level of exchange-transfusion and malaria-related expertise in Benin and Nigeria. Results Data show that the malaria- and thrombosis-resistance of RBCs depend on specific genes and the patient’s clinical status and medical history. In malaria-endemic Benin and Nigeria, prevalences of “dual-gene” malaria-resistant group-O HbAS and group-O HbAC RBCs are substantial, and both malaria- and exchange-related expertise are outstanding. Conclusions T-REX of “dual-gene” malaria-resistant RBCs is feasible in Benin and Nigeria and warrants evaluation as a rescue adjunct for 3 subsets of Pf-malaria patients. For therapeutic use, group-O HbAS RBCs are likely to be more effective than non-O HbAS RBCs for Pf-infected patients who (1) have a history of thrombosis or (2) are taking birth-control hormones while group-O HbAC RBCs may substantially improve birth outcomes for women with PAM. Studies suggest it is prudent to assume – until proven otherwise – that T-REX of “dual-gene” malaria-resistant RBCs can improve (“personalize”) rescue of these patient subsets.

Background Pregnant women are more susceptible to Plasmodium falciparum than before pregnancy, and infection has consequences for both mother and offspring. The World Health Organization recommends that pregnant woman in areas of transmission receive intermittent preventive treatment (IPTp) starting in the second trimester. Consequently, women are not protected during the first trimester, although P. falciparum infections are both frequent and harmful. Methods A cohort of nulligravid women was followed up during subsequent pregnancy. Malaria was diagnosed by means of microscopy and polymerase chain reaction. Parasites were genotyped at polymorphic loci. Results Among 275 nulligravidae enrolled, 68 women became pregnant and were followed up during pregnancy. Before pregnancy, P. falciparum prevalence rates were 15% by microscopy and 66% by polymerase chain reaction. Microscopic infection rates increased to 29% until IPTp administration, and their density increased by 20-fold. Conversely, submicroscopic infection rates decreased. After IPTp administration, all types of infections decreased, but they increased again late in pregnancy. The risk of infection during pregnancy was higher in women with a microscopic (odds ratio, 6.5; P = .047) or submicroscopic (3.06; P = .05) infection before pregnancy and was not related to the season of occurrence. Most infections during pregnancy were persistent infections acquired before pregnancy. Conclusions Microscopic and submicroscopic malaria infections were frequent in nulligravid women from south Benin. During the first trimester of pregnancy, microscopic infections were more frequent, with a higher parasite density, and mainly derived from parasites infecting the woman before conception. Preventive strategies targeting nonpregnant women with a desire for conception need to be designed.

Okezie Caleb Okamgba,1 Martin O Ifeanyichukwu,1 Ayodele O Ilesanmi,2 Lawrence N Chigbu3 1Department of Medical Laboratory Science, Faculty of Health Sciences and Technology, Nnamdi Azikwe University, Nnewi Campus, Nnewi, Anambra State, 2Department of Medical Laboratory Science, Kwara State University, Malete, Kwara State, 3Department of Microbiology, College of Medicine, Abia State University, Uturu, Abia State, Nigeria Background: Activation of immune cells by malaria infection induces the secretion of cytokines and the synthesis of other inflammatory mediators. This study compared the cytokine levels and leukocyte count between malaria-infected peripheral and placental blood of pregnant women before delivery and postpartum. The cytokines assessed include interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), interleukin-6 (IL-6) and interleukin-10 (IL-10). Materials and methods: The subjects comprised 144 malaria-infected pregnant women and 60 malaria-infected women at post-partum stage (for placental blood collection). Others were 60 malaria-uninfected pregnant women and 40 malaria-uninfected women at postpartum stage (for placental blood collection). Forty malaria-infected and 40 malaria-uninfected nonpregnant women served as control subjects. The test groups were asymptomatic, and the control groups were apparently healthy subjects. All were aged between 17 and 44 years. Ethical approval for the study was obtained at Abia State University Teaching Hospital and Living Word Mission Hospital, Aba. Informed consent was obtained from the participants. Blood samples were aseptically collected initially from the maternal peripheral circulation and from the placenta on delivery, and tested for HIV and malaria using standard methods. IFN-γ, TNF-α, IL-4, IL-6 and IL-10 were measured by enzyme-linked immunosorbent assay technique. Kruskal–Wallis test was used for comparison of the groups. Results: IFN-γ was significantly higher in the peripheral than in placental blood (P=0.001). IL-4 and IL-10 were significantly lower in the peripheral than in placental blood (P=0.001 and P=0.004, respectively). The total leukocytes, neutrophils and lymphocyte counts were significantly higher in the placenta than in peripheral blood (P=0.001), and the mixed differential count was significantly higher in the placenta than in peripheral blood (P=0.012). Conclusion: This study has shown that the cytokine levels and leukocyte counts may differ between the peripheral and placental blood of the same women. Therefore, measurement of parameters in the peripheral circulation may not always reflect the levels in the placental blood for the assessment of immune cellular response at the materno–fetal interface. Keywords: malaria parasite density, cytokines, peripheral blood, placental blood, leukocyte

Malaria infection in pregnancy is a major public health problem which poses serious life threats to pregnant mothers and foetuses. Accurate diagnosis and prompt treatment of pregnancy associated malaria (PAM) are important in preventing adverse pregnancy outcomes. This study compared the diagnostic performance of two rapid diagnostic tests (RDTs), parasite lactate dehydrogenase (PLDH) based Optimal IT and parasite aldolase base Dr. Grey’s with the gold standard microscopy in pregnant women. Blood samples of 113 pregnant women were collected from two hospitals in Lagos and screened for malaria parasite by Giemsa stained smear and two malaria rapid diagnostic tests, Optimal IT parasite lactate dehydrogenase and Dr. Grey aldolase. The results showed that, out of 113 blood samples screened, 23 (20.4%), 51 (45.1%) and 14 (12.4%) were positive by microscopy, Aldolase and PLDH respectively. 17 (33.3%) and 34 (66.7%) of the aldolase positive samples were positive and negative by microscopy respectively. 11 (21.6%) of the aldolase positive samples were positive for both microscopy and PLDH. Of the positive samples, 34 (66.7%) were negative for both microscopy and PLDH. 3 (13.0%) were positive by microscopy but negative by aldolase and PLDH (RDTs). There was no statistically significant difference between the performances of the different RDTs. This study revealed that microscopy, the gold standard underestimated the real burden of malaria during pregnancy and aldolase (RDT) performed better than microscopy and PLDH, the other RDT in diagnosing pregnant-associated malaria.

Pregnancy-associated malaria remains a major risk to the pregnant woman, her foetus and infants in sub- Saharan Africa. Infection by Plasmodium falciparum significantly affects maternal, foetal and neonatal wellbeing. Maternal anaemia, low birth weight, preterm labour, spontaneous abortion, and maternal and neonatal mortalities are some of its consequences. It complicates maternal immunological response and possibly also selfishly pre-empt foetal immunological response by transplacental communications. Therefore, the impacts may extend well beyond the duration of pregnancy and the immediate period post-delivery. Effective case management and prevention continue to yield positive results, but challenges still remains especially in sub-Saharan Africa. The challenges of antenatal service provision, compliance with intermittent preventive treatment at pregnancy by sulfadoxinepyrimethamine (IPTp-SP), widespread SP resistance, and resistance to insecticide treated nets (ITNs) and insecticides continue to complicate efforts at PAM control in sub-Saharan Africa. Hopefully, the Global Technical Strategy for Malaria 2016–2030 will comprehensively consider these challenges and improve the prospect of every pregnant woman in sub-Saharan Africa.

Background: The study was conducted to investigate malaria prevalence among a group of women in the Democratic Republic of Congo (DRC) who received intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). Methods: A total of 250 women from Bandundu city who received two doses of IPTp-SP were enrolled in the survey. Blood samples were collected at the time of delivery and malaria prevalence was determined using microscopy, rapid diagnostic test (RDT), and nested polymerase chain reaction (PCR). Results: Malaria infection was detected in 81 (32.4%), 93 (37.2%), and 92 (36.8%) samples by microscopy, RDT, and PCR, respectively. Among 92 samples, P. falciparum mono-infection (n=87; 94.5%), P. falciparum+P. vivax (n=2; 2.2%) and P. falciparum+P. malariae (n=1; 1.1%) mixed infections, and P. vivax mono-infection (n=2; 2.2%) were detected. Prevalence of malaria was not affected by age and number of pregnancies (p

ObjectivesTo investigate whether high-dosed folate supplements might diminish the efficacy of malaria intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) in a cohort of pregnant women in Benin, where malaria is holoendemic. MethodsWe followed 318 women during the entire pregnancy and analysed haematological and Plasmodium falciparum indicators in the context of an intermittent preventive treatment trial in Benin. During the follow-up, women received two-dose IPTp (1500/75 mg of SP per dose) at the maternity clinic and 600 mg of albendazole, 200 mg ferrous sulphate and 5 mg folic acid per day for home treatment. ResultsHigh folate levels were not associated with increased malaria risk (adjusted OR (aOR) = 0.51 (95% CI: 0.17; 1.56, P-value = 0.24)), nor with increased P. falciparum density (beta coefficient = -0.26 (95% CI: -0.53; 0.02), P-value = 0.07) in a randomised trial of IPTp in Benin. On the contrary, higher iron levels were statistically associated with increased odds of a positive blood smear (aOR = 1.7 95% CI (1.2; 2.3), P-value < 0.001) and P. falciparum parasite density (beta coefficient = 0.2 95% CI (0.1; 0.3), P-value < 0.001). High folate levels were statistically associated with decreased odds of anaemia (aOR = -0.30 95% CI (0.10; 0.88), P-value = 0.03). ConclusionsHigh folate levels are not associated with increased malarial risk in a prospective longitudinal cohort in the context of both iron and high-dosed folate supplements and IPTp. They are associated with reduced risk of anaemia, which is particularly important because iron, also given to treat anaemia, might be associated with increased malaria risk. Abstract ObjectifsExaminer si des supplements de folates a forte dose pourraient diminuer l'efficacite du traitement preventif intermittent du paludisme pendant la grossesse (TPIg) par la sulfadoxine- pyrimethamine (SP) dans une cohorte de femmes enceintes au Benin, oU le paludisme est holoendemique. MethodesNous avons suivi 318 femmes pendant toute la grossesse et analyse les indicateurs hematologiques et de P. falciparum dans le cadre d'un essai de traitement preventif intermittent au Benin. Durant le suivi, les femmes ont recu deux doses de TPIg (1500/75 mg de SP par dose) a la clinique de maternite et 600 mg d'albendazole, 200 mg de sulfate ferreux et 5 mg d'acide folique par jour pour le traitement a domicile. ResultatsDes taux eleves de folates n'etaient pas associes a un risque accru de paludisme (OR ajuste (ORa) = 0,51; IC95%: 0,17; 1,56; p = 0,24), ni a une augmentation de la densite de P. falciparum (coefficient beta = -0,26; IC95%: -0,53; 0,02; p = 0,07) dans un essai randomise de TPIg au Benin. Par contre, des niveaux de fer plus eleves etaient statistiquement associes a une augmentation de la probabilite d'un frottis sanguin positif (ORa = 1,7; IC95%: 1,2- 2,3; p

Plasmodium falciparum, the causative agent of the deadliest form of human malaria, alternates expression of variable antigens, encoded by members of a multi-copy gene family named var. In var2csa, the var gene implicated in pregnancy-associated malaria, translational repression is regulated by a unique upstream open reading frame (uORF) found only in its 5′ UTR. Here, we report that this translated uORF significantly alters both transcription and posttranslational protein trafficking. The parasite can alter a protein's destination without any modifications to the protein itself, but instead by an element within the 5′ UTR of the transcript. This uORF-dependent localization was confirmed by single molecule STORM imaging, followed by fusion of the uORF to a reporter gene which changes its cellular localization from cytoplasmic to ER-associated. These data point towards a novel regulatory role of uORF in protein trafficking, with important implications for the pathology of pregnancy-associated malaria.

Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA’s ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: −267.99 g; 95% Confidence Interval [CI]: −466.43 g,−69.55 g) and higher odds of low birthweight (

Pregnancy-associated malaria (PAM) poses a threat to both the mother and fetus, increasing the risk of severe maternal anemia, fetal growth restriction and low birth weight infants. Two vaccines are currently in development to protect women from Plasmodium falciparum in pregnancy. Both vaccine constructs target the ID1-DBL2X domain of VAR2CSA, a protein expressed on the surface of infected erythrocytes (IEs) that mediates parasite sequestration in the placenta. Although development of an effective vaccine may be hampered by ID1-DBL2X polymorphisms expressed by field isolates, a recent study showed that genetic variation of this domain in South American parasite populations is much lower than in other geographical locations. This suggests that a recombinant vaccine designed to be efficacious in Africa and Asia is likely to be efficacious in South America. However, these studies did not include Colombian parasite populations in their analyses, which are known to be genetically distinct from other South American parasite populations due to their independent introduction from Africa. Therefore, we sought to determine the genetic variation of the ID1-DBL2X domain in Colombian parasites to assess the potential efficacy of the vaccine against PAM in this region. Through sequence analysis and population genetics, we show that there is a low degree of genetic variation amongst Colombian parasite populations and that a vaccine containing conserved antigen variants for worldwide populations is likely to be protective against PAM in Colombia. Our analysis also points towards an African origin for Colombian parasite populations, and suggests that their introduction into Colombia was a recurrent process encompassing multiple introduction events.

Pregnancy-associated malaria (PAM) is a severe form of the disease caused by sequestration of Plasmodium falciparum-infected red blood cells (iRBCs) in the developing placenta. Pathogenesis of PAM is partially based on immunopathology, with frequent monocyte infiltration into the placenta. Neutrophils are abundant blood cells that are essential for immune defence but may also cause inflammatory pathology. Their role in PAM remains unclear. We analysed neutrophil alterations in the context of PAM to better understand their contribution to disease development. Pregnant women exposed to Plasmodium falciparum had decreased numbers of circulating neutrophils. Placental-like BeWo cells stimulated with malaria parasites produced the neutrophil chemoattractant IL-8 and recruited neutrophils in a trans-well assay. Finally, immunostaining of a PAM placenta confirmed neutrophil accumulation in the intervillous space. Our data indicate neutrophils may play a role in placental malaria and should be more closely examined as an etiological agent in the pathophysiology of disease.

The existence of asymptomatically parasitemic individuals in malaria-endemic areas has long been recognised to signify naturally acquired immunity to malaria disease, resulting from control of the parasite’s asexual blood-stage. This has for many years been viewed as a ‘proof-of-concept’ encouraging the development of blood-stage vaccines (BSVs). Results of clinical trials of candidate subunit BSVs have mostly, however, not lived up to early expectations and the field is currently experiencing a challenging period.

Clinical immunity to pregnancy associated-malaria (PAM) in multigravida women has been attributed to antibodies that recognize VAR2CSA on the infected erythrocyte (IE) surface. The size and complexity of VAR2CSA have focused efforts on selecting one or more of its six Duffy binding-like (DBL) domains for vaccine development. Presently, however, there is no consensus as to which DBL domain(s) would be most effective in eliciting immunity. This is because antibodies to a number of the DBL domains have been found to block the adhesion of VAR2CSA-expressing erythrocytes to chondroitin sulfate A (CSA)—a major criterion for evaluating vaccine candidacy. Opsonization of IEs by cytophilic antibodies that recognize VAR2CSA represents an important yet understudied effector mechanism in acquired immunity to PAM. To date, no studies have sought to determine the targets of those antibodies. In this study, we found that IgGs from multigravida Malian women showed (i) higher reactivity to recombinant DBL domains by enzyme-linked immunosorbent assay (ELISA), (ii) more binding to VAR2CSA-expressing IEs, and (iii) greater opsonization of these IEs by human monocytic cells than IgGs from malaria-exposed Malian men and malaria-naive American adults. Preincubation of IgGs from multigravida women with recombinant DBL2χ, DBL3χ, or DBL5ε domains significantly diminished opsonization of VAR2CSA-expressing IEs by human monocytes. These data identify the DBL2χ, DBL3χ, and DBL5ε domains as the primary targets of opsonizing IgGs for the first time. Our study introduces a new approach to determining the antigenic targets of opsonizing IgGs in phagocytosis assays.

Parasites with increased resistance to sulfadoxine might undermine malaria control measures., Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance.

Pregnant women have an increased risk of malaria infection, independent of previously acquired immunity. Women in their first pregnancy and children under the age of five are the primary victims of malaria worldwide. Pregnant women develop antibodies against placenta-adhesive parasites in a parity-dependent manner. Various efforts to understand the targets, quality, and quantity of this antibody response could aid the design of an effective vaccine against placental malaria. This review focuses on the research that has led to the current understanding of the antibody response that primigravidae (PG) acquire to Plasmodium falciparum malaria and draws from this knowledge to suggest serology and PG as sentinels for malaria transmission.