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Background. It is unknown whether iron supplementation in human immunodeficiency virus (HIV)–infected children living in regions with high infection pressure is safe or beneficial. A 2-arm, double-blind, randomized, controlled trial was conducted to examine the effects of iron supplementation on hemoglobin, HIV disease progression, and morbidity. Methods. HIV-infected Malawian children aged 6–59 months with moderate anemia (hemoglobin level, 7.09.9 g/dL) were randomly assigned to receive 3 mg/kg/day of elemental iron and multivitamins (vitamins A, C, and D) or multivitamins alone for 3 months. Participants were followed for 6 months. Results. A total of 209 children were randomly assigned to treatment, and 196 (93.8%) completed 6 months of follow-up. Iron supplementation was associated with greater increases in hemoglobin concentrations (adjusted mean difference [aMD], 0.60; 95% confidence interval [CI], .06-1.13; P= .03) and reduced the risk of anemia persisting for up to 6 months follow-up (adjusted prevalence ratio, 0.59; 95% CI, .38-.92; P = .02). Children who received iron had a better CD4 percentage response at 3 months (aMD, 6.00; 95% CI, 1.84-10.16; P= .005) but an increased incidence of malaria at 6 months (incidence rate, 120.2 vs 71.7; adjusted incidence rate ratio [aIRR], 1.81 [95% CI, 1.04-3.16]; P = .04), especially during the first 3 months (incidence rate, 78.1 vs 36.0; aIRR, 2.68 [95% CI, 1.08-6.63]; P = .03). Conclusions. Iron supplementation in anemic HIV-infected children has beneficial effects on hemoglobin, anemia, and immunity but increases the risk of malaria. Thus, iron supplementation in HIV-infected children living in malaria-endemic areas should only be provided in combination with adequate protection from malaria. Clinical Trials Registration. ISRCTN-62947977.

BackgroundIntermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) decreases placental malaria parasitemia and associated maternal anemia, premature delivery, and low birth weight. However, the optimal regimen in the setting of a high prevalence of human immunodeficiency virus (HIV) infection remains unclear MethodsIn Malawi, where the efficacy of SP for the treatment of malaria in children is decreasing, we conducted a randomized, nonblinded study to compare the efficacy of monthly SP IPTp with a 2-dose regimen for the prevention of placental parasitemia in HIV-positive and -negative primigravid and secundigravid women ResultsOf HIV-positive women, 7.8% who received monthly SP had placental malaria, compared with 21.5% of those who received 2-dose SP (relative risk [RR], 0.36 [95% confidence interval {CI}, 0.17–0.79]). Of HIV-negative women, 2.3% who received monthly SP and 6.3% who received 2-dose SP had placental malaria (RR, 0.37 [95% CI, 0.11–1.19]). Less than 1% of women reported adverse drug reactions, with no increase in HIV-positive women or those who received monthly SP ConclusionsIn HIV-positive pregnant women, monthly SP IPTp is more efficacious than a 2-dose regimen in preventing placental malaria. The study also demonstrates the continued efficacy of SP for the prevention of placental malaria, even in the face of its decreasing efficacy for the treatment of malaria in children. In areas with intense transmission of falciparum malaria and a high prevalence of HIV infection, monthly SP IPTp should be adopted

Abstract Background To better understand transmission dynamics, we characterized Plasmodium falciparum genetic diversity in Eswatini, where transmission is low and sustained by importation. Methods Twenty-six P. falciparum microsatellites were genotyped in 66% of confirmed cases (2014–2016; N = 582). Population and within-host diversity were used to characterize differences between imported and locally acquired infections. Logistic regression was used to assess the added value of diversity metrics to classify imported and local infections beyond epidemiology data alone. Results Parasite population in Eswatini was highly diverse (expected heterozygosity [HE] = 0.75) and complex: 67% polyclonal infections, mean multiplicity of infection (MOI) 2.2, and mean within-host infection fixation index (FWS) 0.84. Imported cases had comparable diversity to local cases but exhibited higher MOI (2.4 vs 2.0; P = .004) and lower mean FWS (0.82 vs 0.85; P = .03). Addition of MOI and FWS to multivariate analyses did not increase discrimination between imported and local infections. Conclusions In contrast to the common perception that P. falciparum diversity declines with decreasing transmission intensity, Eswatini isolates exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission. Estimates of malaria transmission intensity from genetic data need to consider the effect of importation, especially as countries near elimination. In contrast to the commonly held perception that P. falciparum diversity declines with decreasing transmission intensity, infections from Eswatini exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission.

ABSTRACT Plasmodium falciparum infection-mediated Epstein–Barr virus (EBV) reactivation is well established in malaria-endemic countries. We hypothesize that, during malaria onset, the reactivated EBV can infect human brain microvascular endothelial cells (HBECs). This may cause severe cerebral manifestations. We infected HBECs with EBV in vitro. The subsequent gene expression pattern of EBV, inflammatory and endothelial markers was analysed using qRT-PCR. Further, a wound-healing assay for cells maintaining blood–brain barrier (BBB) integrity was performed to investigate the effect of EBV-infected HBECs secretions. The RBC adhesion assay was conducted to assess RBC attachment onto HBECs during EBV and P. falciparum mono- and co-infection. Our experiments revealed that EBV infection of HBECs significantly elevated several inflammatory (TNFα, CCL2) and endothelial (integrin β3, PECAM, VEGFA, VWF, claudin-5, cx37) markers. The EBV-infected HBECs secretion significantly reduced migration of HBECs, glial and neuronal cells. Additionally, EBV–P. falciparum co-infection significantly (P < 0.05) enhanced RBC adhesion to HBECs compared to mono-infection scenarios. Conclusively, the EBV infection of HBECs led to endothelial activation and modulated the BBB microenvironment. The EBV-P. falciparum co-infection scenario increased RBC adhesion on ECs which is a hallmark of cerebral malaria. Together with malaria, EBV infection can aid in exacerbation of cerebral malaria pathology. EBV infection of HBECs affects the microenvironment of blood–brain barrier and EBV–Plasmodium falciparum co-infection enhances RBC adhesion to HBECs.

Clinical trials monitoring malaria drug resistance require genotyping of recurrent Plasmodium falciparum parasites to distinguish between treatment failure and new infection occurring during the trial follow up period. Because trial participants usually harbour multi-clonal P. falciparum infections, deep amplicon sequencing (AmpSeq) was employed to improve sensitivity and reliability of minority clone detection. Paired samples from 32 drug trial participants were Illumina deep-sequenced for five molecular markers. Reads were analysed by custom-made software HaplotypR and trial outcomes compared to results from the previous standard genotyping method based on length-polymorphic markers. Diversity of AmpSeq markers in pre-treatment samples was comparable or higher than length-polymorphic markers. AmpSeq was highly reproducible with consistent quantification of co-infecting parasite clones within a host. Outcomes of the three best-performing markers, cpmp, cpp and ama1-D3 , agreed in 26/32 (81%) of patients. Discordance between the three markers performed per sample was much lower by AmpSeq (six patients) compared to length-polymorphic markers (eleven patients). Using AmpSeq for discrimination of recrudescence and new infection in antimalarial drug trials provides highly reproducible and robust characterization of clone dynamics during trial follow-up. AmpSeq overcomes limitations inherent to length-polymorphic markers. Regulatory clinical trials of antimalarial drugs will greatly benefit from this unbiased typing method.

Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC). P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC) and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP) we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START) domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host) phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites.

Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.

Epstein-Barr virus is notorious for causing multiple kinds of cancer. It has also been increasingly linked to multiple sclerosis. What evidence now supports or can be sought potentially to strengthen this linkage?

Scientific evidence strongly suggests that parasites are directly or indirectly associated with carcinogenesis in humans. However, studies have also indicated that parasites or their products might confer resistance to tumour growth. Plasmodium protozoa, the causative agents of malaria, exemplify the ambivalent link between parasites and cancer. Positive relationships between malaria and virus-associated cancers are relatively well-documented; for example, malaria can reactivate the Epstein-Barr Virus, which is the known cause of endemic Burkitt lymphoma. Nevertheless, possible anti-tumour properties of malaria have also been reported and, interestingly, this disease has long been thought to be beneficial to patients suffering from cancers. Current knowledge of the potential pro- and anti-cancer roles of malaria suggests that, contrary to other eukaryotic parasites affecting humans, Plasmodium-related cancers are principally lymphoproliferative disorders and attributable to virus reactivation, whereas, similar to other eukaryotic parasites, the anti-tumour effects of malaria are primarily associated with carcinomas and certain sarcomas. Moreover, malarial infection significantly suppresses murine cancer growth by inducing both innate and specific adaptive anti-tumour responses. This review aims to present an update regarding the ambivalent association between malaria and cancer, and further studies may open future pathways to develop novel strategies for anti-cancer therapies.

Raised HIV viral load in blood has been associated with accelerated disease progression and increased transmission of infection. To assess the effect of Plasmodium falciparum malaria on concentrations of HIV in blood, we did a prospective cohort study in Malawi. We recruited 367 HIV-1-infected adults. Among 334 people aparasitaemic at baseline, 148 had at least one malaria episode during follow-up and received antimalarial treatment. Of these, 77 had HIV-1-RNA measurements at baseline, during malaria, and post-malaria. We used linear regression with generalised estimating equations to assess effect of four definitions of malaria (any parasitaemia, parasite density ⩾2000/μL, febrile parasitaemia, and febrile parasitaemia with parasite density ⩾2000/μl) on changes in log HIV-1 RNA, overall and by baseline CD4 count. With malaria defined as any parasitaemia, HIV-1-RNA concentration almost doubled between baseline (median 96 215 copies per mL) and malaria (168 901 copies per mL), a 0·25 (95% CI 0·11–0·39) log increase in mean RNA concentration. HIV-1-RNA concentration fell to median 82 058 copies per mL by about 8–9 weeks post-malaria. Increases in HIV-1-RNA were greatest for people with fever, parasite density 2000/μL or greater, and CD4 count more than 300 cells per μL, in whom concentrations rose from median 38 483 copies per mL at baseline to 196 098 copies per mL during malaria, a mean log increase of 0·82 (95% CI 0·55–1·10, p<0·0001), and fell to median 75 331 copies per mL post-malaria. People who remained aparasitaemic showed no changes in HIV-1-RNA concentration. HIV-infected individuals with malaria have a significantly increased viral load, which might enhance HIV transmission and accelerate disease progression.