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In , the NATs identified in P. The involvement of distinct types of transcriptional machinery and different mechanisms, such as transcriptional run-through, bidirectional and antisense-specific promoters, produces a varied landscape of differential regulation observed for P. However, an increasing number of studies have described a role of host miRNAs in host-parasite interactions reviewed by Judice et al. The incorporation of RNA sequencing data will be extremely important to further work on annotated genes and continue the curation and further characterization of putative genes sets that are being identified in new P.

On the other hand, transcript data will indicate the significance of SNPs and increase of copy number variation CNV during the hypothesized recent population expansion in P. Furthermore, genome-wide transcriptome analysis already contributes to a better understanding of the dynamics of P. Most importantly, it gives an understanding of the role of the transcriptional regulatory machinery and fine-tuned mechanisms that promote the large and diverse population upkeep of P.

Even though only few studies into P. For example, early gametogenesis Bousema and Drakeley, along with the asexual cycle seems to be achieved by transcriptional repression of an AP2 transcription factor Yuda et al. Another example is the biological process underlying hypnozoite latent stage formation and activation, suggested to be under epigenetic regulation.

Studies using simian hepatocyte cultures report an acceleration of hypnozoite activation when histone methylation is inhibited. Thus, methylation of histones promotes suppression of transcription, and ultimately, maintain hypnozoite dormancy Barnwell and Galinski, ; Dembele et al. Other example of P. In spite of all advances mentioned above, the functions of half of the predicted proteins in P. Unsurprisingly, P. The apicoplast proteome plays an important role in several major parasite metabolic processes, including some described for P.

The localization of several other central pathways is being clarified. For example, it was confirmed that the glyoxalase pathway occurs in the apicoplast, although in P. Although P. Thus, alternative invasion and host escape pathways still remain largely unknown.

Stage-specific analysis of P. In order to overcome the low parasitemia data challenge, some studies have pooled samples from different patients. However, such procedures can potentially increase the assortment of proteins detected, render their identification and association with disease pathogenesis more difficult, and affect the reproducibility of vivax proteomic data and follow up validation studies.

Proteome studies are expected to contribute greatly by disclosing proteins expressed in clinical isolates and reveal new unique parasite pathways involved in malaria pathophysiology, leading to identification of new targets for drug and vaccine development. Efforts are being made to identify potential vivax malaria biomarkers to understand host responses.

The earliest proteome study, published in Acharya et al. In , the same authors were the first to examine the P. That same year Roobsoong et al. Such proteins could be P. More recently, trophozoite proteins were identified in P. The in-depth analysis of two P. High-throughput screening has been used to study P. Furthermore, differences between P. Most of these highly immunoreactive proteins are hypothetical, but there have been suggestions of their importance for P.

Figure 5. Slices of the P. Humoral immunity of vivax malaria patients has also been interrogated. Chen and co-authors cloned and expressed 89 proteins that were screened against sera from vivax malaria patients using protein arrays to show 18 highly immunogenic of which 7 had been already characterized as vaccine candidates and the remaining were uncharacterized Chen et al. Later, Ray and colleagues Ray et al. Collectively, these results indicate that several physiologically important host pathways have been modulated during parasitic infection including vitamin D metabolism, hemostasis and the coagulation cascade, acute phase response and interleukin signaling, and the complement pathway Ray et al.

To uncover pathway modulation occurring during uncomplicated Ray et al. Recently, human serum proteome comparative studies were published Ray et al. The involvement of the acute phase response was confirmed, including acute phase reactants or proteins, cytokine signaling, oxidative stress and anti-oxidative pathways, muscle contraction and cytoskeletal regulation, lipid metabolism and transport, complement cascades, and several coagulation and hemostasis associated proteins in malaria pathophysiology Ray et al.

However, alterations in the blood coagulation cascade, as reported for severe falciparum malaria, were not identified for severe vivax malaria Ray et al. Moreover, these proteomic studies allowed the identification of prospective new host markers, such as the differentially expressed proteins superoxide dismutase, ceruloplasmin, vitronectin, titin, and nebulin.

Furthermore, they confirmed the already investigated apolipoprotein A1 and E, serum amyloid A and haptoglobin markers. Those are important for future improved diagnosis, discrimination of other infections, as well as disease progression and shift toward severe clinical manifestations, response to new therapies and outcome prediction Ray et al. Analysis of a recent longitudinal cohort of vivax malaria patients revealed that some serum levels of proteins such as haptoglobin, apolipoprotein E, apolipoprotein A1, carbonic anhydrase 1, and hemoglobin subunit alpha, revert to baseline levels under treatment, but others did not show the same behavior in the convalescent phase of the infection Ray et al.

Serum proteome results also prompt the malaria community for a clearer definition of severity parameters for P. The panorama emerging from all malaria proteome studies is that a great fraction of proteins identified until now are uncharacterized and of unknown functions, alongside with several housekeeping proteins. However, other proteins of major metabolic pathways for parasite survival show us that we are in a good position to better understand immune evasion and host cell invasion mechanisms within the pathophysiology of vivax malaria. These pathways comprise metabolism glycolysis, hemoglobin digestion, nucleic acid synthesis and cellular invasion binding proteins, protein synthesis, modification, and degradation Figure 5A.

Intracellular transport, translocation and presentation of variable antigen proteins Figure 5B , which promote erythrocyte modification Figure 5C , have been carefully analyzed, in particular proteins directly related to drug resistance. All chaperonin complexes, some involved in heat shock, oxidative stress and other counteractive responses, have been identified Acharya et al.

Although there was evidence of transcription for genes encoding almost all P. Integrating genomic and transcriptomic information is paving the way for systems biology approaches. For instance, chokepoint analysis has the potential to uncover enzymes predicted to have only one substrate or product, thus pushing the way to new drug target discoveries. Analysis of the hypnozoites proteome faces great experimental hurdles. A list of candidate genes includes all homologs of other dormancy genes previously discovered in other organisms Carlton et al.

An in vitro system for culturing liver stages of this parasite Mazier et al. Taken together, blood proteome studies shed light on vivax malaria pathogenesis and pave the way for future integrated multi-omics investigations. Ex vivo specific functional assays may provide further insights. Researchers relied on the amplification of a small set of polymorphic antigens to assess the genetic diversity of P. Feng et al. Thus, coding regions are more conserved than intergenic ones, and central chromosomal regions more than sub telomeric, indicative of a purifying selection.

This implies an ancient evolutionary history shaped by distinct selection pressures Feng et al. The genetic variability seen for P. Several studies have highlighted the great degree of diversity, which is shared between P. Compared to P. While microsatellite marker analysis has revealed the genetic diversity of P. Therefore, P. Whole genome analysis of genetic diversity between five P. Genomic and transcriptomic sequencing of several patient P. Genomics data suggest that evolutionary pressures acted upon and currently shape several P.

The detection of pvdbp gene duplication Menard et al. More recently, Auburn and colleagues reported amplification breakpoints for the multidrug resistance 1 gene pvmdr1 Auburn et al. Thus, P. Multi-species WTS data suggests that variability in non-coding sequences of genes but other features such as transcription factors, upstream bidirectional promoter regions, post-transcriptional control including epigenetic regulation, chromatin remodeling events or ncRNAs may have a greater impact on transcription modulation across the Plasmodium spp. Hoo et al.

With few exceptions verified in small-scale studies Winter et al. However, some haplotype reconstruction studies have reported that 2—4 strains account for the majority of P. For instance, deep genome sequencing of more than clinical Asian-Pacific samples confirmed the complex genetic structure of P. Still, this remarkable polyclonality can have several origins: parasite infection could originate from a single meiosis event, from multiple infections with unrelated parasites as a consequence of several mosquito bites, or from a combination of a relapse and a new infection event, all of them having implications on parasite population diversity Lin et al.

Microsatellite marker identification and WGS have allowed the characterization of relapse infections as the result of heterologous hypnozoite activation Imwong et al. Furthermore, hypnozoites present hidden in the hosts function as a reservoir and a dynamic and continuous source and flow of genetic diversity in the present P. The tailored and more affordable P.

Additionally, they are helping to characterize and discern between recrudescence, relapses Lin et al. As for P. In addition, the production of an effective vivax malaria vaccine is hampered by the existence of such huge diversity of antigens concentrated in invasion and immune evasion related genes Neafsey et al. During the last 10 years, several P.

The lack of a P. Nevertheless, we are living in times of rapid development, expansion and application of high-throughput and highly sensitive technology tools that were absurdly expensive only a few years ago. Exciting progress is being made in single-cell Nair et al. The application of such tools to in vitro cell or animal experimental models may help us explore further some aspects of P. Specifically, the development, establishment and validation of in vitro cell culture and animal experimental models as the published Mazier et al.

Clearly, this would positively impact on our understanding of several molecular mechanisms taking place in the parasite during cell invasion, development, stage transition, host immune system evasion and environmental stress responses Table 3. Table 2. Plasmodium vivax omics achievements and ongoing research efforts. Table 3. Plasmodium vivax omics challenges and future progress in a systems biology setting.

The extensive and detailed omics datasets that are continuously made available by several research groups, under which technical and experimental progress has and is being achieved brings forward an old problem: how to analyze and integrate large and complex information within and between datasets in a standard and easy-to-share platform, accessible by all.

Several initiatives, such as the comparative databases PlasmoDB Bahl et al. Such platforms should be continuously developed with the most recent powerful bioinformatics tools and information combined with suitable mathematical modeling and epidemiologic analysis. Mainstream bioinformatics institutes around the world are providing expert support to the Plasmodium research community, critically needed given the extraordinary challenges posed by the complex nature of the P. Worldwide, major efforts must be taken by the entire community in order to establish some criteria for dealing with data collection, analysis and annotation, so that it can be easily accessed and fully explored in order to design adequate interventions to ever changing conditions, focusing on the control, elimination and prevention of malaria.

CB and LA contributed to literature review and writing of the manuscript. CB and AK were responsible for the original figure concept and design. All authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acharya, P. A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax.

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Microbiology of Medically Important Viruses

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Pulmonary manifestations of uncomplicated falciparum and vivax malaria: cough, small airways obstruction, impaired gas transfer, and increased pulmonary phagocytic activity. The pathophysiology of vivax malaria. Trends Parasitol. Aresha, M. Genotyping of Plasmodium vivax infections in Sri Lanka using Pvmsp-3alpha and Pvcs genes as markers: a preliminary report. PubMed Abstract Google Scholar. Auburn, S. Dissecting malaria biology and epidemiology using population genetics and genomics.

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Barnwell, J. Malarial liver parasites awaken in culture. Plasmodium vivax : malarial proteins associated with the membrane-bound caveola-vesicle complexes and cytoplasmic cleft structures of infected erythrocytes. Barry, A. Uncovering the transmission dynamics of Plasmodium vivax using population genetics. Health , — Battle, K.

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Bautista, J. Malaria proteomics: insights into the parasite-host interactions in the pathogenic space. Proteomics 97, — Beeson, J. Towards a vaccine against Plasmodium vivax malaria. PLoS Med. Beutler, E. Glucosephosphate dehydrogenase deficiency and antimalarial drug development. Bitoh, T. Risk analysis of the re-emergence of Plasmodium vivax malaria in Japan using a stochastic transmission model. Health Prev. Boopathi, P. Revealing natural antisense transcripts from Plasmodium vivax isolates: evidence of genome regulation in complicated malaria.

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On the infectiousness of patients infected with Plasmodium vivax and Plasmodium falciparum. Bozdech, Z. The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. The transcriptome of Plasmodium vivax reveals divergence and diversity of transcriptional regulation in malaria parasites. Brazeau, N. Longitudinal pooled deep sequencing of the Plasmodium vivax K12 kelch gene in cambodia reveals a lack of selection by artemisinin. Bright, A. A high resolution case study of a patient with recurrent Plasmodium vivax infections shows that relapses were caused by meiotic siblings.

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Cheeseman, I. Population structure shapes copy number variation in malaria parasites. Chen, J. Immunoproteomics profiling of blood stage Plasmodium vivax infection by high-throughput screening assays. Proteome Res. Chung, B. Predictors of Plasmodium vivax malaria-induced nephropathy in young Korean men. Nephron Clin. Cole-Tobian, J. Diversity and natural selection in Plasmodium vivax Duffy binding protein gene.

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The neglected Plasmodium vivax : are researchers from endemic areas really concerned about new treatment options? Plasmodium vivax : cloning and expression of a major blood-stage surface antigen. Variant genes and the spleen in Plasmodium vivax malaria.

Dembele, L. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures.

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While some become severely ill, others recover without any complications. Human genetic factors account partly for these variations. Several susceptibility and resistance determinants involving polymorphisms of erythrocytes, endothelial receptors or the immune system have already been defined. In many studies red blood cell polymorphisms e. ABO blood group, sickle cell trait, G6PD deficiency, ovalocytosis have been proposed as protective factors against severe malaria for reviews, see [ , ]. However, these explanations are not established facts and the underlying mechanisms for the observed associations require further in-depth investigations.

The genetic polymorphism of human immune systems is believed to be directly associated with susceptibility to malaria infections for review, see [ , ]. In a recent study, it was found that the genotype of the NK cell receptor the killer Ig-like receptor, KIR was at least one of the determinants involved in the interaction between NK cell and P.

However, the study on the genetic variation of KIR receptor in malaria endemic areas requires further investigation. Discovering the immunogenetic factors associated with malaria disease is important for understanding the pathogenesis and for rational design of malaria vaccines with higher affinity to MHC molecules. The polymorphism of endothelial receptors associated with increased susceptibility to severe malaria has recently been described. A high-frequency coding polymorphism in the N-terminal domain of ICAM-1 was found to be associated with susceptibility to cerebral malaria in Kenya but not in the Gambia [ , ].

Malaria has played a major role in selecting and maintaining protective polymorphism in endemic regions. Since cytoadhesion of pRBCs have been associated with severe disease and ICAM-1 has been implicated as one of the important receptors involved in these interactions one would assume that protective mutations in the N-terminal domain of ICAM-1, which also contains the binding site for pRBCs, could occur in malaria-endemic regions.

However this was not the case in the Kenyan study, where individuals with the mutation ICAM-1 Kilifi were more at risk for cerebral malaria. In order to understand how such polymorphism can be maintained and why it has differential effect on malaria susceptibility in different African populations Craig et al. Although simplified, one could hypothesize that this allele was originally selected for as a protective polymorphism via reduced binding of pRBCs to ICAM-1, thus reducing the risk for cerebral malaria.

However, due to evolutionary process between the host and the parasite some compensatory mutations in PfEMP-1 could have been selected in parasites for high avidity ICAM-1 binding in high transmission areas, such as Kenya. But, in low transmission areas, such as The Gambia, the allele may still be protective. However, ICAM-1 was analysed as a single receptor in those studies.

The parasites might be able to bind to other receptors as well. The genetic determimants in this aspect are far from clear. Furthermore, reports on malaria susceptibility in different ethnic groups in Burkina Faso, West Africa have revealed that the Fulani population is less susceptible and more immunologically responsive to malaria than their neighbouring ethnic groups [—].

According to former reports this is not due to malaria exposure or socio-cultural circumstances [ , ]. Neither does it seem to involve other known genetic determinants. Recently, Luoni et al. To date, many genetic factors have been defined and it is likely that many more have yet to be discovered. Efforts at present are aimed at understanding the functional basis of known associations. For optimal design of any drug or vaccine, disease associated host genetic factors have to be taken into consideration. It is thus important to further elucidate the importance of these factors in disease and health and to understand the underlying mechanisms.

Disease severity in P. The severe symptoms of malaria are manifested in the erythrocytic stage of the parasite life cycle through the process of sequestration. Instrumental in this process is the expression of parasite-derived proteins on the pRBC surface which promote cytoadhesion and rosetting. Disruption of these adhesive events should therefore prevent the pathology of severe disease. Thus, identifying the proteins involved in these events is fruitful in the development of anti-severe malaria interventions. The most challenging obstacle is, however, the antigenic diversity of malaria antigens.

As discussed earlier, all the surface exposed antigens including antigens on the free sporozoite and merozoite surface display certain degree of polymorphism. In terms of vaccine development, sterile immunity is an unachievable goal. However, the molecule types which cause both placental and cerebral malaria are rare. Hence development of anti-severe disease interventions could be possible if there only exist a few PfEMP1 types, which are truly associated with the diseases.

Currently, we have no optimal strategy to sustainably reduce or eliminate the burden of malarial disease. There is no vaccine and with a worrisome ever-increasing drug resistance our chances to win the battle against malaria are diminishing. Nevertheless, we should be optimistic. We have now access to genome sequences, bioinformatic tools and high-throughput technologies which will ultimately provide an integrated picture of parasite biology and malaria pathogenesis and hopefully facilitate the target identification for therapeutic interventions.

Analysis of the genome and the assessment of expression profiles at different stages of parasite life cycle have already amassed a great body of information. However, expression profiles at the mRNA level only will not provide a comprehensive picture. Immune responses recognize proteins not mRNA, and in many instances, such as alternative splice sites or post-translational modifications, mRNA transcription data are not adequate. Thus a confirmation of the gene expression profiles at the protein level is fundamental. Advances in proteomics together with recent developments in gene-targeting technologies will therefore be crucial for the final identification of the most promising drug targets and vaccine candidates.

Ultimately it is important that these technologies are, apart from in vitro adapted cultures, also applied on field isolates in order to identify the true PfEMP1s or other proteins involved in malaria pathogenesis. Oxford University Press is a department of the University of Oxford.

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Volume Article Contents. Molecular aspects of malaria pathogenesis Niloofar Rasti. Oxford Academic. Google Scholar. Mats Wahlgren. Qijun Chen. Cite Citation. Permissions Icon Permissions. Abstract Plasmodium falciparum being the most lethal plasmodiae is still a major cause of the disease burden and mortality in malaria endemic areas.

Malaria , Infection , Adhesion , Antigenic variation , Genome. Table 1. Open in new tab. Open in new tab Download slide. Table 2. Table 3. Macrophage phagocytes uninfected RBCs. The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Search ADS. Plasmodium falciparum infection elicits both variant-specific and cross-reactive antibodies against variant surface antigens. The genome sequence of the human malaria parasite Plasmodium falciparum. A genetic screen for improved plasmid segregation reveals a role for Rep20 in the interaction of Plasmodium falciparum chromosomes.

Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. The chromosomal organization of the Plasmodium falciparum var gene family is conserved. Le Roch. Discovery of gene function by expression profiling of the malaria parasite life cycle. The transcriptome of the Intraerythrocytic Developmental Cycle of Plasmodium falciparum. Google Preview. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity.

A rhoptry-protein-associated mechanism of clonal phenotypic variation in rodent malaria. Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A. Erythrocyte-binding antigen mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Evidence for two-stage binding by the kDa erythrocyte binding antigen of Plasmodium falciparum. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations.

Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Developmental selection of var gene expression in Plasmodium falciparum. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.

High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Intra-cluster recombination and var transcription switches in the antigenic variation of Plasmodium falciparum. Identification of nuclear proteins that interact differentially with Plasmodium falciparum var gene promoters. Plasmodium falciparum var genes are regulated by two regions with separate promoters, on upstream of the coding region and a second within the intron. The 3D7var5. Identification of Plasmodium falciparum erythrocyte membrane protein1 PfEMP1 as the rosetting ligand of the malaria parasite P.

A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum -infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Common trafficking pathway for variant antigens destined to the surface of the Plasmodium falciparum -infected erythrocyte. Recognition of variant Rifin antigens by human antibodies induced during natural Plasmodium falciparum infections.

Stevor transcripts from Plasmodium falciparum gametocytes encode truncated polypeptides. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants.

Plasmodium falciparum -infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. The semiconserved head structure of Plasmodium falciparum erythrocyte membrane protein 1 mediates binding to multiple independent host receptors. Plasmodium falciparum -infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells. Red blood cell deformability as a predictor of anemia in severe falciparum malaria.

Maternally transmitted antibodies to pregnancy-associated variant antigens on the surface of erythrocytes infected with Plasmodium falciparum : relation to child susceptibility to malaria. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties.

Adhesion of Plasmodium falciparum -infected erythrocytes to hyaluronic acid in placental malaria. The adhesion of Plasmodium falciparum -infected erythrocytes to chondroitin sulfate A is mediated by P. Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy.

Two DBLgamma subtypes are commonly expressed by placental isolates of Plasmodium falciparum. A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern. Lekana Douki. Sequestration of Plasmodium falciparum -infected erythrocytes to chondroitin sulfate A, a receptor for maternal malaria: monoclonal antibodies against the native parasite ligand reveal pan-reactive epitopes in placental isolates. Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion. Cloning the P. CD36 peptides that block cytoadherence define the CD36 binding region for Plasmodium falciparum -infected erythrocytes.

Widespread functional specialization of Plasmodium falciparum erythrocyte membrane protein 1 family members to bind CD36 analysed across a parasite genome. An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration.

Intercellular adhesion molecule-1 and CD36 synergize to mediate adherence of Plasmodium falciparum -infected erythrocytes to cultured human microvascular endothelial cells. Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria. Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors. Short report: codon polymorphism of CD31 and susceptibility to malaria. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies.

Rosette formation in Plasmodium falciparum isolates and anti-rosette activity of sera from Gambians with cerebral or uncomplicated malaria. Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Human cerebral malaria: lack of significant association between erythrocyte rosetting and disease severity.

Cytoadherence characteristics of Plasmodium falciparum -infected erythrocytes from Malawian children with severe and uncomplicated malaria. From The Cover: A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Blood group A antigen is a co-receptor in Plasmodium falciparum rosetting. Novel fibrillar structure confers adhesive property to malaria-infected erythrocytes.

Rouleaux-forming serum proteins are involved in the rosetting of Plasmodium falciparum -infected erythrocytes. Platelet-mediated clumping of Plasmodium falciparum -infected erythrocytes is a common adhesive phenotype and is associated with severe malaria.

Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. Platelets play an important role in TNF-induced microvascular endothelial cell pathology. The role of red blood cell polymorphisms in resistance and susceptibility to malaria. Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles.

Tumor necrosis factor-a promotes sustained cyclooxygenase-2 expression: attenuation by dexamethasone and NSAIDs. Coordinate expression of inducible nitric oxide synthase and cyclooxygenase-2 genes in uterine tissues of endotoxin-treated pregnant mice. Tumor necrosis factor-a stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells.

Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Activation of a subset of human NK cells upon contact with Plasmodium falciparum -infected erythrocytes. Absence of an association between intercellular adhesion molecule-1, complement receptor-1 and interleukin-1 receptor antagonist gene polymorphisms and severe malaria in a West African population. Differential binding of clonal variants of Plasmodium falciparum to allelic forms of intracellular adhesion molecule 1 determined by flow adhesion assay.

Plasmodium falciparum malaria in sympatric ethnic groups of Burkina Faso, west Africa. Different response to plasmodium falciparum malaria in west African sympatric ethnic groups. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Human vascular endothelial cell adhesion receptors for Plasmodium falciparum -infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1.

Issue Section:. Download all figures. View Metrics. Email alerts New issue alert. In progress issue alert. Advance article alerts. Article activity alert. Receive exclusive offers and updates from Oxford Academic. But it is still not clear which receptors are involved in cerebral malaria. CD36 is the most common receptor found so far. Most laboratory strains and wild isolates can bind to this receptor. The distribution of this receptor on endothelial surfaces in the brain is marginal and its contribution to cerebral malaria is not clear. However, one recent study has suggested that platelets could function as a bridge between pRBC and endothelial receptors.

But this finding cannot explain why only a small group of parasites can cause cerebral malaria if most parasites bind to CD ICAM-1 is an endothelial receptor which has been implicated in cerebral malaria [84]. However, in vitro studies have demonstrated that the affinity of most pRBCs to ICAM-1 is weak and synergic cooperation with other receptors might be necessary for a stable adhesion [85 , 86].

One could speculate that only a limited number of parasites can bind to this receptor. Whether these parasites only contribute to cerebral malaria remains to be further studied. CD31 belongs to the immunoglobulin superfamily and is located in the junction of endothelial cells. Clinical investigation in Kenya has revealed an association between pRBC binding to this receptor and severe disease [89].

Sequence polymorphism has been observed in CD31 genes from people living in different malaria endemic areas. The significance of these polymorphisms in term of sensitivity to severe disease has not been conclusive [90 , 91]. Other parasite-derived molecules might also mediate interaction with this receptor due to the fact that trypsinization could not completely abolish the binding of FCR3S1. Autoagglutination refers to the aggregation of infected red blood cells in nonimmune serum. Both phenomena have been found associated with severe diseases. All Plasmodium species studied so far can form rosettes reviewed in [92].

But most studies have focused on P. Four independent studies in Africa have suggested that rosetting is associated with severe malaria since parasites from severe malaria patients form rosettes at a significantly higher rate than that from mild malaria patients [89 , 93—95]. These findings indicated that parasites causing severe diseases are phenotypically different from those causing mild diseases.

However, studies in Papua New Guinea and some areas in Africa failed to correlate rosetting capability and disease severity [96 , 97]. Human genetic factors might be the reason for the discrepancy between these studies [98]. Rosetting receptors are diverse. Heparan sulfate-like glycosaminoglycans, ABO blood group antigens and complement receptor 1 CR1 on human erythrocyte surface have been characterised as rosetting receptors Refs.

However, stable rosettes require participation of multiple serum components such as non-immune human immunoglobulins IgG and IgM as well as other serum proteins [ , ]. Due to human genetic diversity, the number of rosetting ligands could be more. Some P. Serum proteins and parasite-derived ligand most likely PfEMP1 are thought to mediate the binding though there is no clear clue to this phenomenon. Autoagglutinates are distinct from parasite aggregates agglutination mediated by immune sera reflecting an anti-parasite immune response.

In in vitro condition, the tendency of forming autoagglutinates is higher when the parasitemia is high though some parasites form autoagglutinates at lower parasitemia as well for review, see [92]. Another phenomenon termed clumping was reported recently by Pain et al. When platelets were added to some parasite cultures, clumps of only infected RBCs were observed. The phenomenon was obviously associated with the CD36 receptor on platelets. But the parasite ligand is not clear.

CDbinding parasites do not necessarily form clumps. It has been suggested that parasite ability to form clumps is associated with disease severity, but examination of biopsies from malaria patients has revealed that platelet accumulation in cerebral malaria is not always found together with pRBCs []. Studies on clinical isolates directly from malaria patients have found that parasites from those suffering from severe diseases were more adhesive and could bind to several human receptors [89]. Though there are relatively few studies in this perspective, multi-adhesion phenotype could be an important feature of virulent parasites.

There are several reasons that a parasite is multi-adhesive. Human genetic diversity is obviously an important factor see next section. To be able to sequester in human hosts of different genetic background, the parasites might need to have affinity to several receptors simultaneously. If the parasites could only adhere to one receptor, they may be eliminated soon due to the poor affinity to that receptor in certain distinct genetic host populations. Having a big arsenal of adhesive protein family in the genome is certainly important, but to be able to adhere simultaneously to several receptors is of revolutionary advantage to the parasites assuring their survival in the hosts.

One example is the finding that rosetting parasites are more frequently found in patients of severe malaria and most rosetting parasites are indeed multiple adhesive. One PfEMP1 domain can bind to similar receptor on different cell surface. For instance, the rosetting domain of FCR3S1. Further, domains of a PfEMP1 can bind simultaneously to different receptors. To date, multiple adhesion is not necessarily a phenotype of every parasite, but the ability to be able to bind to several human receptors certainly give the parasites a possibility to hide in the postcapillary regions where they can escape from clearance by the spleen before initiating next erythrocytic cycle.

Malaria infections have varying outcome in different individuals. While some become severely ill, others recover without any complications. Human genetic factors account partly for these variations. Several susceptibility and resistance determinants involving polymorphisms of erythrocytes, endothelial receptors or the immune system have already been defined.

In many studies red blood cell polymorphisms e. ABO blood group, sickle cell trait, G6PD deficiency, ovalocytosis have been proposed as protective factors against severe malaria for reviews, see [ , ]. However, these explanations are not established facts and the underlying mechanisms for the observed associations require further in-depth investigations. The genetic polymorphism of human immune systems is believed to be directly associated with susceptibility to malaria infections for review, see [ , ].

In a recent study, it was found that the genotype of the NK cell receptor the killer Ig-like receptor, KIR was at least one of the determinants involved in the interaction between NK cell and P. However, the study on the genetic variation of KIR receptor in malaria endemic areas requires further investigation. Discovering the immunogenetic factors associated with malaria disease is important for understanding the pathogenesis and for rational design of malaria vaccines with higher affinity to MHC molecules. The polymorphism of endothelial receptors associated with increased susceptibility to severe malaria has recently been described.

A high-frequency coding polymorphism in the N-terminal domain of ICAM-1 was found to be associated with susceptibility to cerebral malaria in Kenya but not in the Gambia [ , ]. Malaria has played a major role in selecting and maintaining protective polymorphism in endemic regions. Since cytoadhesion of pRBCs have been associated with severe disease and ICAM-1 has been implicated as one of the important receptors involved in these interactions one would assume that protective mutations in the N-terminal domain of ICAM-1, which also contains the binding site for pRBCs, could occur in malaria-endemic regions.

However this was not the case in the Kenyan study, where individuals with the mutation ICAM-1 Kilifi were more at risk for cerebral malaria. In order to understand how such polymorphism can be maintained and why it has differential effect on malaria susceptibility in different African populations Craig et al. Although simplified, one could hypothesize that this allele was originally selected for as a protective polymorphism via reduced binding of pRBCs to ICAM-1, thus reducing the risk for cerebral malaria. However, due to evolutionary process between the host and the parasite some compensatory mutations in PfEMP-1 could have been selected in parasites for high avidity ICAM-1 binding in high transmission areas, such as Kenya.

But, in low transmission areas, such as The Gambia, the allele may still be protective. However, ICAM-1 was analysed as a single receptor in those studies. The parasites might be able to bind to other receptors as well. The genetic determimants in this aspect are far from clear. Furthermore, reports on malaria susceptibility in different ethnic groups in Burkina Faso, West Africa have revealed that the Fulani population is less susceptible and more immunologically responsive to malaria than their neighbouring ethnic groups [—]. According to former reports this is not due to malaria exposure or socio-cultural circumstances [ , ].

Neither does it seem to involve other known genetic determinants. Recently, Luoni et al. To date, many genetic factors have been defined and it is likely that many more have yet to be discovered. Efforts at present are aimed at understanding the functional basis of known associations. For optimal design of any drug or vaccine, disease associated host genetic factors have to be taken into consideration.

It is thus important to further elucidate the importance of these factors in disease and health and to understand the underlying mechanisms. Disease severity in P. The severe symptoms of malaria are manifested in the erythrocytic stage of the parasite life cycle through the process of sequestration.


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Instrumental in this process is the expression of parasite-derived proteins on the pRBC surface which promote cytoadhesion and rosetting. Disruption of these adhesive events should therefore prevent the pathology of severe disease. Thus, identifying the proteins involved in these events is fruitful in the development of anti-severe malaria interventions. The most challenging obstacle is, however, the antigenic diversity of malaria antigens. As discussed earlier, all the surface exposed antigens including antigens on the free sporozoite and merozoite surface display certain degree of polymorphism.

In terms of vaccine development, sterile immunity is an unachievable goal. However, the molecule types which cause both placental and cerebral malaria are rare. Hence development of anti-severe disease interventions could be possible if there only exist a few PfEMP1 types, which are truly associated with the diseases. Currently, we have no optimal strategy to sustainably reduce or eliminate the burden of malarial disease. There is no vaccine and with a worrisome ever-increasing drug resistance our chances to win the battle against malaria are diminishing.


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  6. Nevertheless, we should be optimistic. We have now access to genome sequences, bioinformatic tools and high-throughput technologies which will ultimately provide an integrated picture of parasite biology and malaria pathogenesis and hopefully facilitate the target identification for therapeutic interventions. Analysis of the genome and the assessment of expression profiles at different stages of parasite life cycle have already amassed a great body of information.

    However, expression profiles at the mRNA level only will not provide a comprehensive picture. Immune responses recognize proteins not mRNA, and in many instances, such as alternative splice sites or post-translational modifications, mRNA transcription data are not adequate. Thus a confirmation of the gene expression profiles at the protein level is fundamental.

    Advances in proteomics together with recent developments in gene-targeting technologies will therefore be crucial for the final identification of the most promising drug targets and vaccine candidates. Ultimately it is important that these technologies are, apart from in vitro adapted cultures, also applied on field isolates in order to identify the true PfEMP1s or other proteins involved in malaria pathogenesis. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

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    Molecular aspects of malaria pathogenesis Niloofar Rasti. Oxford Academic. Google Scholar. Mats Wahlgren. Qijun Chen. Cite Citation. Permissions Icon Permissions. Abstract Plasmodium falciparum being the most lethal plasmodiae is still a major cause of the disease burden and mortality in malaria endemic areas. Malaria , Infection , Adhesion , Antigenic variation , Genome.

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    A genetic screen for improved plasmid segregation reveals a role for Rep20 in the interaction of Plasmodium falciparum chromosomes. Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. The chromosomal organization of the Plasmodium falciparum var gene family is conserved. Le Roch. Discovery of gene function by expression profiling of the malaria parasite life cycle. The transcriptome of the Intraerythrocytic Developmental Cycle of Plasmodium falciparum. Google Preview. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity.

    A rhoptry-protein-associated mechanism of clonal phenotypic variation in rodent malaria.

    Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A. Erythrocyte-binding antigen mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Evidence for two-stage binding by the kDa erythrocyte binding antigen of Plasmodium falciparum. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations.

    Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria.

    Developmental selection of var gene expression in Plasmodium falciparum. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. High diversity and rapid changeover of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Intra-cluster recombination and var transcription switches in the antigenic variation of Plasmodium falciparum.

    Identification of nuclear proteins that interact differentially with Plasmodium falciparum var gene promoters. Plasmodium falciparum var genes are regulated by two regions with separate promoters, on upstream of the coding region and a second within the intron. The 3D7var5. Identification of Plasmodium falciparum erythrocyte membrane protein1 PfEMP1 as the rosetting ligand of the malaria parasite P.

    A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum -infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Common trafficking pathway for variant antigens destined to the surface of the Plasmodium falciparum -infected erythrocyte.

    Recognition of variant Rifin antigens by human antibodies induced during natural Plasmodium falciparum infections. Stevor transcripts from Plasmodium falciparum gametocytes encode truncated polypeptides. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants.

    Plasmodium falciparum -infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. The semiconserved head structure of Plasmodium falciparum erythrocyte membrane protein 1 mediates binding to multiple independent host receptors. Plasmodium falciparum -infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells.

    Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Maternally transmitted antibodies to pregnancy-associated variant antigens on the surface of erythrocytes infected with Plasmodium falciparum : relation to child susceptibility to malaria.

    Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. Adhesion of Plasmodium falciparum -infected erythrocytes to hyaluronic acid in placental malaria.