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Cloning and expression of the FCR3.varCSA gene. (A) Overlapping clones of the varCSA gene were isolated from genomic FCR3-CSA parasites and were sequenced. Regions amplified by reverse transcription-PCR from FCR3-CSA trophozoites mRNA confirm that the genomic varCSA gene sequence is contiguous with the exception of the intron region. (B) Schematic domain organization of the FCR3.varCSA gene. An unusually small intron of 230 bp separates exon I and exon II of the varCSA gene. The amino acid boundaries of the different DBL and CIDR-1 domains are indicated. (C) Domain regions that have been expressed on the surface of CHO-745 cells with their amino acid boundaries.
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Malaria during the first pregnancy causes a high rate of fetal and neonatal death. The decreasing susceptibility during subsequent pregnancies correlates with acquisition of antibodies that block binding of infected red cells to chondroitin sulfate A (CSA), a receptor for parasites in the placenta. Here we identify a domain within a particular Plas...
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Context 1
... Phenotype of Parasites Selected for CSA Binding. The binding characteristics of the CSA-selected PRBCs (Table 1) resemble the adhesive phenotype observed in PRBCs isolated from placentas of malaria-infected women, i.e., binding to CSA but not to CD36 (2). These adhesion properties are very different from those of CD36-selected PRBCs, which bound to several receptors but not to CSA (Table 1). Furthermore, sera from multigravid women from Cameroon and Senegal efficiently block adhesion of FCR3-CSA PRBCs to CSA (J.G. and A.S., unpublished data). DBL-1 of a previous publication (7) was used to extend the gene sequence in the 5 and 3 directions. We obtained 10,628 bp that contain the entire extracellular region encoded by exon I (9,931 bp) and 698 bp of exon II, the intracellular domain (Fig. 1). An unusually short intron of 230 bp separates the two exons. The DNA sequence predicts an ORF of 3,542 amino acids and an overall structure homologous to the published var sequences, with seven DBL domains and a CIDR1 domain found after DBL1 (Fig. 1B). FCR3.varCSA sequence probes corresponding to DBL-1, DBL34, and DBL67 hybridize to a large transcript of 13 kilobases in total RNA of FCR3-CSA trophozoites (Fig. 2 A; data not shown). Reverse transcription-PCR of mRNA and PCR of genomic DNA proved that the sequence was contiguous (Fig. 1 ...
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... Phenotype of Parasites Selected for CSA Binding. The binding characteristics of the CSA-selected PRBCs (Table 1) resemble the adhesive phenotype observed in PRBCs isolated from placentas of malaria-infected women, i.e., binding to CSA but not to CD36 (2). These adhesion properties are very different from those of CD36-selected PRBCs, which bound to several receptors but not to CSA (Table 1). Furthermore, sera from multigravid women from Cameroon and Senegal efficiently block adhesion of FCR3-CSA PRBCs to CSA (J.G. and A.S., unpublished data). DBL-1 of a previous publication (7) was used to extend the gene sequence in the 5 and 3 directions. We obtained 10,628 bp that contain the entire extracellular region encoded by exon I (9,931 bp) and 698 bp of exon II, the intracellular domain (Fig. 1). An unusually short intron of 230 bp separates the two exons. The DNA sequence predicts an ORF of 3,542 amino acids and an overall structure homologous to the published var sequences, with seven DBL domains and a CIDR1 domain found after DBL1 (Fig. 1B). FCR3.varCSA sequence probes corresponding to DBL-1, DBL34, and DBL67 hybridize to a large transcript of 13 kilobases in total RNA of FCR3-CSA trophozoites (Fig. 2 A; data not shown). Reverse transcription-PCR of mRNA and PCR of genomic DNA proved that the sequence was contiguous (Fig. 1 ...
Context 3
... Phenotype of Parasites Selected for CSA Binding. The binding characteristics of the CSA-selected PRBCs (Table 1) resemble the adhesive phenotype observed in PRBCs isolated from placentas of malaria-infected women, i.e., binding to CSA but not to CD36 (2). These adhesion properties are very different from those of CD36-selected PRBCs, which bound to several receptors but not to CSA (Table 1). Furthermore, sera from multigravid women from Cameroon and Senegal efficiently block adhesion of FCR3-CSA PRBCs to CSA (J.G. and A.S., unpublished data). DBL-1 of a previous publication (7) was used to extend the gene sequence in the 5 and 3 directions. We obtained 10,628 bp that contain the entire extracellular region encoded by exon I (9,931 bp) and 698 bp of exon II, the intracellular domain (Fig. 1). An unusually short intron of 230 bp separates the two exons. The DNA sequence predicts an ORF of 3,542 amino acids and an overall structure homologous to the published var sequences, with seven DBL domains and a CIDR1 domain found after DBL1 (Fig. 1B). FCR3.varCSA sequence probes corresponding to DBL-1, DBL34, and DBL67 hybridize to a large transcript of 13 kilobases in total RNA of FCR3-CSA trophozoites (Fig. 2 A; data not shown). Reverse transcription-PCR of mRNA and PCR of genomic DNA proved that the sequence was contiguous (Fig. 1 ...
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... That Binds to CSA. Surface iodination of FCR3-CSA trophozoite-infected RBCs identified a single molecule of 400 kDa ( Fig. 2B) with the characteristics of the var gene product PfEMP-1 (21). First, it was degraded by trypsin treatment of intact PRBCs (Fig. 2B). Second, it was efficiently extracted only in denaturing detergent (2% SDS). Third, it was variant [absent in CD36-selected PRBCs (FCR3-CD36), which instead express an iodinated molecule of 250 kDa] (Fig. 2B). The mild trypsinization removed the iodinated part of the molecule but did not ablat binding to CSA. Adhesion was interrupted only at very high concentrations of trypsin (data not shown). This is in agreement with the trypsin-resistant phenotype of PfEMP1 from other CSA-adherent PRBCs (12). Surface-iodinated PfEMP-1 extracted from FCR3-CSA PRBCs before trypsinization bound to human thrombomodulin- coated Dynabeads (Fig. 2C) whereas the FCR3-CD36 PfEMP-1 did not bind thrombomodulin (Fig. 2C). Thus, the CSA- containing thrombomodulin that bound FCR3-CSA PRBCs (Table 1) affinity-purified a red cell surface molecule with the characteristics of PfEMP-1. DBL-3 of the FCR3.varCSA Gene Binds Specifically to CSA. Biot-CSA and Biot-CSC were developed as specific reagents to measure CSA binding to the FCR3.varCSA domains. The activity of the biotinylated compounds was identical to that of the nonbiotin- ylated material (Table 1), with PRBCs binding only to Biot-CSA. Of the eight receptor-like domains expressed on the surface of CHO-745 cells (mutants not expressing CSA) (Fig. 1C), only DBL3 and DBL7 transfectants bound Biot-CSA (Fig. 3 A and B). No binding was observed if cells were incubated with biotin alone or if the cells were treated with chondroitinase ABC after incubation with Biot-CSA (data not shown). Addition of CSA blocked the binding of Biot-CSA to both DBLs; however, addition of CSC, a molecule that does not block CSA-mediated PRBC adhesion (12,24), had no effect on binding to DBL3 but blocked binding to DBL7 (Fig. 3C). In addition, only DBL7 expressed on CHO cells bound Biot-CSC, and this binding was inhibited by addition of CSA or CSC (Fig. 3C). Thus, the binding properties of DBL3, but not of DBL7, are compatible with the adhesion properties of CSA-adherent PRBCs (Table ...
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... Other studies have shown a decreased prevalence of antibodies against the variant surface antigen (VSA) among HIV-positive pregnant women, which helps to prevent parasite attachment to chondroitin surface A (CSA), which is more concentrated in the placenta [68][69][70][71]. This decrease was found in all gravidities, irrespective of the malaria infection status. ...
Malaria and HIV are geographically in the tropics and subtropics of the world, including sub-Saharan Africa. Understanding the overlapping effect of both infections, especially among pregnant women, is crucial in managing pregnant women during antenatal care visits, and postpartum babies. It was realized that the prevalence of malaria among HIV-positive pregnant women ranges between 31–61%, while for non-HIV infected pregnant women the prevalence still stands between 10 and 36%. Co-infection is between 0.52 and 56.3%. Even though the rate of mother-to-child transmission of HIV has dropped, MTCT of malaria still remains a problem. MTCT is associated with low birth-weight, anemia, and even immune dysregulation. The adoption of the Option B+ plan has proven to be effective in the fight against the MTCT of HIV. However, malaria in pregnancy still remains a problem. Concurrent administration of both antimalarial drugs and Cotrimozaxole to pregnant women is not recommended, because of the toxic effect of the interaction of both drugs. Nevertheless, studies looking at the effect of the current ART regimens on mothers and their children need to be carried out. Studies looking at exposed children over a longer period of time, to determine their susceptibility to malaria infection and also to monitor their immune response to malaria over time, are needed.
... CS/DS chains are modified by sulfation at various hydroxy groups, which gives rise to structural diversity, thereby playing an important role in a variety of biological processes including interactions with various growth factors, cytokines, and morphogens, cell proliferation, tissue morphogenesis, and infections iD, and iE ( Figure 1). The A, iA, D, and E units are involved in infection of malaria, binding with heparin cofactor II, neurite outgrowth, and infection of herpes simplex virus, respectively (Maimone and Tollefsen 1991;Clement et al., 1998;Buffet et al., 1999;Bergefall et al., 2005). However, the functional domain in CS/DS does not appear to be composed of a single distinct saccharide sequence, but rather several heterogeneous sulfation patterns, the "wobble CS-DS motifs" (Purushothaman et al., 2012). ...
Chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) are covalently attached to specific core proteins to form proteoglycans in their biosynthetic pathways. They are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases as well as sulfotransferases. Structural diversities of CS/DS and HS are essential for their various biological activities including cell signaling, cell proliferation, tissue morphogenesis, and interactions with a variety of growth factors as well as cytokines. Studies using mice deficient in enzymes responsible for the biosynthesis of the CS/DS and HS chains of proteoglycans have demonstrated their essential functions. Chondroitin synthase 1-deficient mice are viable, but exhibit chondrodysplasia, progression of the bifurcation of digits, delayed endochondral ossification, and reduced bone density. DS-epimerase 1-deficient mice show thicker collagen fibrils in the dermis and hypodermis, and spina bifida. These observations suggest that CS/DS are essential for skeletal development as well as the assembly of collagen fibrils in the skin, and that their respective knockout mice can be utilized as models for human genetic disorders with mutations in chondroitin synthase 1 and DS-epimerase 1. This review provides a comprehensive overview of mice deficient in CS/DS biosyntheses.
... In falciparum malaria, the severity of cerebral and placental malaria is in part attributed to the adhesive potential of the infected red blood cells [14,15]. Cytoadherence is primarily observed in adhesion of infected red blood cell (iRBC) to endothelial cells [16][17][18], placental tissues [19][20][21][22], and to uninfected red blood cells (uRBCs) [23,24]. Although cytoadhesion is better described in P. falciparum infections, it also occurs with P. vivax. ...
Purpose of Review
Information about rosettes in Plasmodium vivax infection is scarce. However, the understanding of this phenomenon is important for elucidating the pathobiology of Plasmodium spp. This review summarizes the advances in the knowledge of rosetting phenomenon in P. vivax malaria.
Recent Findings
In vitro and ex vivo studies seek to shed light on some aspects of rosetting in vivax malaria. The major efforts are to determine the purpose of this phenomenon and the elements involved in rosetting. Recent data reveal a receptor and suggest that specific components are involved in rosetting. Moreover, there is strong evidence supporting the role of rosettes as an immune evasion strategy.
Summary
Although there are many unknown aspects behind rosetting, recent findings have contributed to elucidating rosette formation mechanisms and have clarified its role and biological hallmarks. These findings reinforce that rosetting is important and understanding the underlying biology may help develop new strategies for malaria control.
... This can be followed by a second DBLδ-CIDR tandem domain or additional other types of DBL domains in larger proteins. Notably, however, the VAR2CSA PfEMP1 variants do not contain typical CIDR domains and bind placental chondroitin sulfate A via specialized DBL domains (14,15). PfEMP1 has diversified to bind the endothelial protein C receptor (EPCR) (10), the scavenger receptor CD36 (16), or yet undermined receptors via head structure CIDR domains. ...
Background:
Malaria pathogenicity is determined, in part, by the adherence of Plasmodium falciparum infected erythrocytes to the microvasculature mediated via specific interactions between PfEMP1 variant domains to host endothelial receptors. Naturally acquired antibodies against specific PfEMP1 variants can play an important role in clinical protection against malaria.
Methods:
We evaluated IgG responses against a repertoire of PfEMP1 CIDR domain variants to determine the rate and order of variant-specific antibody acquisition and their association with protection against febrile malaria in a prospective cohort study conducted in an area of intense, seasonal malaria transmission.
Results:
Using longitudinal data, we found that IgG to the pathogenic domain variants CIDRα1.7 and CIDRα1.8 were acquired the earliest. Furthermore, IgG to CIDRγ3 was associated with reduced prospective risk of febrile malaria and recurrent malaria episodes.
Conclusion:
This study provides evidence that acquisition of IgG antibodies to PfEMP1 variants is ordered and demonstrates that antibodies to CIDRα1 domains are acquired the earliest in children residing in an area of intense, seasonal malaria transmission. Future studies will need to validate these findings in other transmission settings and determine the functional activity of these naturally acquired CIDR variant-specific antibodies.
Funding:
Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.
... Malaria-infected erythrocytes (IEs) evade host immune surveillance through adhesion to CS in the placenta (Fried and Duffy 1996). Placental sequestration of IEs is mediated by the VAR2CSA protein, a member of the PfEMP1 protein family produced by the malaria pathogen Plasmodium falciparum (Buffet et al. 1999;Reeder et al. 1999;Magistrado et al. 2008). Upon erythrocyte infection, VAR2CSA is expressed at the plasma membranes of IEs, facilitating cytoadherence to distinct subsets of CS chains on CSPGs at the plasma membrane of the placental syncytiotrophoblasts (Ayres . ...
Chondroitin sulfate (CS) is the placental receptor for the VAR2CSA malaria protein, expressed at the surface of infected erythrocytes during Plasmodium falciparum infection. Infected cells adhere to syncytiotrophoblasts or get trapped within the intervillous space by binding to a determinant in a 4-O-sulfated CS chains. However, the exact structure of these glycan sequences remains unclear. VAR2CSA-reactive CS is also expressed by tumor cells, making it an attractive target for cancer diagnosis and therapeutics. The identities of the proteoglycans carrying these modifications in placental and cancer tissues remains poorly characterized. This information is clinically relevant since presentation of the glycan chains may be mediated by novel core proteins or by a limited subset of established proteoglycans. To address this question, VAR2CSA-binding proteoglycans were affinity-purified from human placenta, tumor tissue, and cancer cells, and analyzed through a specialized glycoproteomics workflow. We show that VAR2CSA-reactive CS chains associate with a heterogenous group of proteoglycans, including novel core proteins. Additionally, this work demonstrates how affinity purification in combination with glycoproteomics analysis can facilitate the characterization of CSPGs with distinct CS epitopes. A similar workflow can be applied to investigate the interaction of CSPGs with other CS binding lectins as well.
... In earlier studies, var2csa and other var genes, such as var1csa and varcs2, have been associated with the adhesion of infected erythrocytes in addition to var2csa, but this could not be confirmed in more recent studies (171,(177)(178)(179)(180). However, studies investigating the genome and protein synthesis of placental parasites have revealed other highly regulated genes and proteins that might be indirectly involved in the pathogenesis of placental malaria (181)(182)(183)(184)(185). While the disruption of the var2csa gene leads to the loss of CSA binding capacity (179,186), no other highly regulated var genes are directly related to placental adhesion (187). ...
Malaria in pregnancy still constitutes a particular medical challenge in tropical and subtropical regions. Of the five Plasmodium species that are pathogenic to humans, infection with Plasmodium falciparum leads to fulminant progression of the disease with massive impact on pregnancy. Severe anemia of the mother, miscarriage, stillbirth, preterm delivery and intrauterine growth restriction (IUGR) with reduced birth weight are frequent complications that lead to more than 10,000 maternal and 200,000 perinatal deaths annually in sub-Saharan Africa alone. P. falciparum can adhere to the placenta via the expression of the surface antigen VAR2CSA, which leads to sequestration of infected erythrocytes in the intervillous space. This process induces a placental inflammation with involvement of immune cells and humoral factors. Especially, monocytes get activated and change the release of soluble mediators, including a variety of cytokines. This proinflammatory environment contributes to disorders of angiogenesis, blood flow, autophagy, and nutrient transport in the placenta and erythropoiesis. Collectively, they impair placental functions and, consequently, fetal growth. The discovery that women in endemic regions develop a certain immunity against VAR2CSA-expressing parasites with increasing number of pregnancies has redefined the understanding of malaria in pregnancy and offers strategies for the development of vaccines. The following review gives an overview of molecular processes in P. falciparum infection in pregnancy which may be involved in the development of IUGR.
... Antigenic variation is advantageous for the parasite because it prolongs the length of infection within the host and thus increases the chances of transmission to new hosts[68]. The infection would be cleared once the host immune response detects and controls all variants The features of PfEMP-1 structure include the extracellular exposed Nterminal composed of the NTS followed by a variable number of polymorphic DBL domains and CIDR domains, and the TM region, encoded by the highly variable exon I. Adhesion of some DBL and CIDR domains to host receptors such as CD36 by CIDR1α domain[70][71][72][73], ICAM-1 by DBLβC2[74], CSA by DBLγ[75] ...
To avoid clearance by the spleen, P. falciparum-infected erythrocytes adhere to the microvascular endothelial cells lining the blood vessels and sequester in the microvasculature of vital organs. Cytoadhesion results in reduced blood perfusion and inflammatory endothelial cell activation. While the parasite matures during the intraerythrocytic cycle, the infected erythrocyte undergoes a series of modifications including altered morphology, reduced deformability and increased adhesiveness. These properties govern the cytoadherence process and determine the dynamic adhesion behavior under physiological flow conditions. Several red blood cell polymorphisms, including sickle hemoglobin and hemoglobin C, have been associated with protection against severe malaria and malaria-related death. The mechanisms underlying this protection are poorly understood but it might be conferred, in part, by the reduced binding capability of infected erythrocytes to microvascular endothelial cells. Here, we quantitatively compared the adhesion dynamics of infected wild-type and sickle cell trait erythrocytes, at different parasite developmental stages, using flow chamber assays. Differences in the dynamic adhesion behavior were observed for trophozoite and schizont-stages. While a discoid shape in early stage caused flipping of the infected cell, an almost spherical cell at the late stage of the intraerythrocytic cycle results in a regular rolling motion. We further showed that changes in mechanical and adhesive properties of infected sickle cell trait erythrocytes resulted in substantial differences in the flipping and rolling dynamics, relative to infected wild-type erythrocytes, which led to a reduced contact time and predicted contact area to the endothelial cells as well as a reduced firm adherence. As a consequence of the differential firm and dynamic adhesion behavior, infected sickle trait-erythrocytes were less likely to activate microvascular endothelial cells, which in turn, might reduce the pathology observed in sickle cell trait individuals infected with P. falciparum. Overall, our findings improve the understanding of the protection mechanism against severe malaria conferred by sickle hemoglobin.
... Adhesion assay of parasitized RBC to CSA bound on plastic Petri dish was carried out as previously described (Beeson et al., 1999;Buffet et al., 1999;Viebig et al., 2005). Briefly, circles of approximately 0.5 cm diameter were marked on the underside of a plastic Petri dish for each receptor, all in triplicates. ...
Although the molecular mechanisms by which haemoglobinopathic erythrocytes protect their carriers against life-threatening complications of severe malaria have yet to be elucidated, one of the contributing factors is believed to be reduced cytoadhesion in the microvasculatures of vital organs. Previous studies have described perturbations in host actin remodelling, reduced surface levels of PfEMP1 adhesin, abnormal knob sizes and distributions as well as malformed Maurer’s clefts in infected haemoglobinopathic erythrocytes, relative to those seen in infected HbAA erythrocytes. We attempted to establish super-resolution imaging with direct stochastic optical reconstruction microscopy (dSTORM) as an intermediate throughput method of visualising host actin remodelling in infected erythrocytes. Unfortunately, individual F-actin and spectrin filaments could not be resolved and no significant differences in the actin and spectrin labelling of uninfected versus infected erythrocytes were distinguishable. We also further explored the kinetics of adhesion phenotype and protein transport in haemaglobinopathic erythrocytes. We found that infected HbAS erythrocytes exhibited slower temporal increase in number of adherent cells as well as a lower total number of adherent cell relative to infected HbAA erythrocytes. A delay in the establishment of new permeability pathway (NPP) was also observed in infected haemoglobinopathic erythrocytes. We tested the hypothesis that the inherent redox imbalance found in uninfected haemoglobinopathic erythrocytes is the beginning of a cascade of events which precipitates in the reduced cytoadhesive phonotype associated with protection against severe malaria. By exposing uninfected HbAA erythrocytes to transient oxidative stress, we were able to mimic various phenotypes associated with the protective traits, including reduced cytoadhesion and surface PfEMP1 levels, malformed and dispersed knobs, aberrant Maurer’s cleft morphologies and inability to remodel host actin cytoskeleton. Taken together, our findings describe a cascade of events which begins with the redox imbalance inherent to uninfected haemoglobinopathic erythrocytes. This oxidative milieu interferes with parasitic protein export, host actin remodelling and knobs and Maurer’s cleft formation, which leads to aberrant display of PfEMP1 on the cell surface and a reduced level of cytoadhesion. This helps to alleviate the life-threatening consequences of severe malaria.
... Parasites were synchronized with repeated treatments of 5% sorbitol for 10 min, and kept in a shaking incubator for all described experiments. Parasites were selected to express the PfEMP1 variant VAR2CSA, by repeated panning using chondroitin sulphate A, as previously described (67). Peptide spectrum matches for individual spectra were automatically designated as confidently assigned using the Spectrum Mill autovalidation module to apply targetdecoy based false-discovery rate (FDR) scoring threshold criteria via a three-step auto threshold strategy at the peptide and protein levels. ...
Despite recent efforts towards control and elimination, malaria remains a major public health problem worldwide. Plasmodium falciparum resistance against artemisinin, used in front line combination drugs, is on the rise, and the only approved vaccine shows limited efficacy. Combinations of novel and tailored drug and vaccine interventions are required to maintain the momentum of the current malaria elimination program. Current evidence suggests that strain-transcendent protection against malaria infection can be achieved using whole organism vaccination or with a polyvalent vaccine covering multiple antigens or epitopes. These approaches have been successfully applied to the human-infective sporozoite stage. Both systemic and tissue-specific pathology during infection with the human malaria parasite P. falciparum is caused by asexual blood stages. Tissue tropism and vascular sequestration are the result of specific binding interactions between antigens on the parasite-infected red blood cell (pRBC) surface and endothelial receptors. The major surface antigen and parasite ligand binding to endothelial receptors, PfEMP1 is encoded by about 60 variants per genome and shows high sequence diversity across strains. Apart from PfEMP1 and three additional variant surface antigen families RIFIN, STEVOR and SURFIN, systematic analysis of the infected red blood cell surface is lacking. Here we present the most comprehensive proteomic investigation of the parasitized red blood cell surface so far. Apart from the known variant surface antigens, we identified a set of putative single copy surface antigens with low sequence diversity, several of which are validated in a series of complementary experiments. Further functional and immunological investigation is underway to test these novel P. falciparum blood stage proteins as possible vaccine candidates.
... Adhesion assay. Static adhesion assays were used to determine the adhesive behaviour of trophozoite-stage P. falciparum FCR3 CSA -infected erythrocytes to CSA (20-30 h post infection) 25,63 . Plastic Petri dishes were prepared by pre-coating several areas of 20 mm 2 overnight with 1 mg ml À 1 purified CSA or 1% BSA as a negative control. ...
Plasmodium falciparum infections can cause severe malaria, but not every infected person develops life-threatening complications. In particular, carriers of the structural haemoglobinopathies S and C and infants are protected from severe disease. Protection is associated with impaired parasite-induced host actin reorganization, required for vesicular trafficking of parasite-encoded adhesins, and reduced cytoadherence of parasitized erythrocytes in the microvasculature. Here we show that aberrant host actin remodelling and the ensuing reduced cytoadherence result from a redox imbalance inherent to haemoglobinopathic and fetal erythrocytes. We further show that a transient oxidative insult to wild-type erythrocytes before infection with P. falciparum induces the phenotypic features associated with the protective trait of haemoglobinopathic and fetal erythrocytes. Moreover, pretreatment of mice with the pro-oxidative nutritional supplement menadione mitigate the development of experimental cerebral malaria. Our results identify redox imbalance as a causative principle of protection from severe malaria, which might inspire host-directed intervention strategies.
