Alfred Cortés

Publications (17)94.01 Total impact

• Article: A view on the role of epigenetics in the biology of malaria parasites.

  Alfred Cortés, Valerie M Crowley, Alejandro Vaquero, Till S Voss
  PLoS Pathogens 12/2012; 8(12):e1002943. · 9.13 Impact Factor
• Article: Transcriptional variation in the malaria parasite Plasmodium falciparum.

  Núria Rovira-Graells, Archna P Gupta, Evarist Planet, Valerie M Crowley, Sachel Mok, Lluís Ribas de Pouplana, Peter R Preiser, Zbynek Bozdech, Alfred Cortés
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  ABSTRACT: Malaria genetic variation has been extensively characterized, but the level of epigenetic plasticity remains largely unexplored. Here we provide a comprehensive characterization of transcriptional variation in the most lethal malaria parasite, Plasmodium falciparum, based on highly accurate transcriptional analysis of isogenic parasite lines grown under homogeneous conditions. This analysis revealed extensive transcriptional heterogeneity within genetically homogeneous clonal parasite populations. We show that clonally variant expression controlled at the epigenetic level is an intrinsic property of specific genes and gene families, the majority of which participate in host-parasite interactions. Intrinsic transcriptional variability is not restricted to genes involved in immune evasion, but also affects genes linked to lipid metabolism, protein folding, erythrocyte remodeling, or transcriptional regulation, among others, indicating that epigenetic variation results in both antigenic and functional variation. We observed a general association between heterochromatin marks and clonally variant expression, extending previous observations for specific genes to essentially all variantly expressed gene families. These results suggest that phenotypic variation of functionally unrelated P. falciparum gene families is mediated by a common mechanism based on reversible formation of H3K9me3-based heterochromatin. In changing environments, diversity confers fitness to a population. Our results support the idea that P. falciparum uses a bet-hedging strategy, as an alternative to directed transcriptional responses, to adapt to common fluctuations in its environment. Consistent with this idea, we found that transcriptionally different isogenic parasite lines markedly differed in their survival to heat-shock mimicking febrile episodes and adapted to periodic heat-shock with a pattern consistent with natural selection of pre-existing parasites.
  Genome Research 03/2012; 22(5):925-38. · 13.61 Impact Factor
• Article: Heterochromatin formation in bistable chromatin domains controls the epigenetic repression of clonally variant Plasmodium falciparum genes linked to erythrocyte invasion.

  Valerie M Crowley, Núria Rovira-Graells, Lluís Ribas de Pouplana, Alfred Cortés
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  ABSTRACT: Clonally variant gene expression is a common survival strategy used by many pathogens, including the malaria parasite Plasmodium falciparum. Among the genes that show variant expression in this parasite are several members of small gene families linked to erythrocyte invasion, including the clag and eba families. The active or repressed state of these genes is clonally transmitted by epigenetic mechanisms. Here we characterized the promoters of clag3.1, clag3.2 and eba-140, and compared nuclease accessibility and post-translational histone modifications between their active and repressed states. Activity of these promoters in an episomal context is similar between parasite subclones characterized by different patterns of expression of the endogenous genes. Variant expression is controlled by the euchromatic or heterochromatic state of bistable chromatin domains. Repression is mediated by H3K9me3-based heterochromatin, whereas the active state is characterized by H3K9ac. These marks are maintained throughout the asexual blood cycle to transmit the epigenetic memory. Furthermore, eba-140 is organized in two distinct chromatin domains, probably separated by a barrier insulator located within its ORF. The 5' chromatin domain controls expression of the gene, whereas the 3' domain shares the chromatin conformation with the upstream region of the neighbouring phista family gene, which also shows variant expression.
  Molecular Microbiology 02/2011; 80(2):391-406. · 5.01 Impact Factor
• Article: Analysis of Plasmodium falciparum var genes expressed in children from Papua New Guinea.

  Nicole Falk, Mirjam Kaestli, Weihong Qi, Michael Ott, Kay Baea, Alfred Cortés, Hans-Peter Beck
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  ABSTRACT: The variable antigen P. falciparum erythrocyte membrane protein-1 (PfEMP1) is a major virulence factor in malaria. A large number of var genes encode PfEMP1, and we hypothesized that a restricted PfEMP1 repertoire determines clinical disease presentation. We conducted a case-control study in Papua New Guinea and analyzed transcribed var genes in naturally infected children. var messenger RNA was isolated from 78 children with asymptomatic, mild, or severe malaria. We prepared complementary DNA from the upstream region into the DBL1alpha domain and picked, on average, 20 clones for sequencing. Twenty-five percent of centrally located var genes were shared between children, whereas only 5% of subtelomeric genes were shared, indicating lower diversity in the former group. Linkage between group B or C var upstream sequences and DBL1alpha groups was not observed, which impeded prediction by DBL1alpha analysis. A higher proportion of var group A sequences was detected in symptomatic malaria, and a subgroup of frequently encountered var genes with complex head structure seems to be associated with severe malaria. A subset of var group C genes was frequently expressed in older children with asymptomatic high levels of parasitemia. Despite this vast diversity, restricted disease-associated var genes were identified and might be used for innovative interventions based on PfEMP1.
  The Journal of Infectious Diseases 07/2009; 200(3):347-56. · 6.41 Impact Factor
• Article: Switching Plasmodium falciparum genes on and off for erythrocyte invasion.

  Alfred Cortés
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  ABSTRACT: Culture-adapted lines of the malaria parasite Plasmodium falciparum use alternative pathways for the invasion of erythrocytes. The expression of parasite ligands that are involved in the different pathways varies among parasite lines. Recently, several studies have attempted to characterize the use of different invasion pathways and the expression of specific invasion ligands in field isolates, opening the way to understand how invasion occurs in natural infections. In this review, these findings are discussed in the context of the most recent data on invasion by culture-adapted parasites to describe the current understanding of how wild parasites invade, how the variant expression of invasion ligands relates to switching between alternative invasion pathways and why so many different pathways are needed.
  Trends in Parasitology 10/2008; 24(11):517-24. · 5.14 Impact Factor
• Source

  Available from: Anthony A Holder

  Article: Epigenetic silencing of Plasmodium falciparum genes linked to erythrocyte invasion.

  Alfred Cortés, Celine Carret, Osamu Kaneko, Brian Y S Yim Lim, Alasdair Ivens, Anthony A Holder
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  ABSTRACT: The process of erythrocyte invasion by merozoites of Plasmodium falciparum involves multiple steps, including the formation of a moving junction between parasite and host cell, and it is characterised by the redundancy of many of the receptor-ligand interactions involved. Several parasite proteins that interact with erythrocyte receptors or participate in other steps of invasion are encoded by small subtelomerically located gene families of four to seven members. We report here that members of the eba, rhoph1/clag, acbp, and pfRh multigene families exist in either an active or a silenced state. In the case of two members of the rhoph1/clag family, clag3.1 and clag3.2, expression was mutually exclusive. Silencing was clonally transmitted and occurred in the absence of detectable DNA alterations, suggesting that it is epigenetic. This was demonstrated for eba-140. Our data demonstrate that variant or mutually exclusive expression and epigenetic silencing in Plasmodium are not unique to genes such as var, which encode proteins that are exported to the surface of the erythrocyte, but also occur for genes involved in host cell invasion. Clonal variant expression of invasion-related ligands increases the flexibility of the parasite to adapt to its human host.
  PLoS Pathogens 09/2007; 3(8):e107. · 9.13 Impact Factor
• Article: Placental malaria in women with South-East Asian ovalocytosis.

  Ariadna Benet, T Yee Khong, Alice Ura, Rebecca Samen, Kerry Lorry, Mata Mellombo, Livingstone Tavul, Key Baea, Stephen J Rogerson, Alfred Cortés
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  ABSTRACT: Malaria during pregnancy, which is characterized by the accumulation of infected erythrocytes in the placenta, often has severe consequences for the mother and newborn. We assessed the effect of the genetic trait South-East Asian ovalocytosis (SAO) on placental malaria in women from Papua New Guinea. In children, this trait confers protection against cerebral malaria, but not against mild malaria disease, malaria parasitemia, or severe malaria anemia. Using a case-control approach, we found that SAO women suffer from placental malaria, and SAO-infected erythrocytes can sequester in the placenta, but heavy placental infections tended to be less common in SAO than in control pregnant women. Reduced prevalence and severity of placental infection associated with SAO were observed only for primigravid women, who are the group at highest risk of suffering from severe manifestations of placental malaria. Furthermore, we found that the prevalence of the SAO trait was lower among pregnant women than among non-pregnant controls.
  The American journal of tropical medicine and hygiene 11/2006; 75(4):597-604. · 2.59 Impact Factor
• Article: Virulence of malaria is associated with differential expression of Plasmodium falciparum var gene subgroups in a case-control study.

  Mirjam Kaestli, Ian A Cockburn, Alfred Cortés, Kay Baea, J Alexandra Rowe, Hans-Peter Beck
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  ABSTRACT: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a major pathogenicity factor in falciparum malaria that mediates cytoadherence. PfEMP1 is encoded by approximately 60 var genes per haploid genome. Most var genes are grouped into 3 subgroups: A, B, and C. Evidence is emerging that the specific expression of these subgroups has clinical significance. Using field samples from children from Papua New Guinea with severe, mild, and asymptomatic malaria, we compared proportions of transcripts of var groups, as determined by quantitative polymerase chain reaction. We found a significantly higher proportion of var group B transcripts in children with clinical malaria (mild and severe), whereas a large proportion of var group C transcripts was found in asymptomatic children. These data from naturally infected children clearly show that major differences exist in var gene expression between parasites causing clinical disease and those causing asymptomatic infections. Furthermore, parasites forming rosettes showed a significant up-regulation of var group A transcripts.
  The Journal of Infectious Diseases 07/2006; 193(11):1567-74. · 6.41 Impact Factor
• Article: Adhesion of Plasmodium falciparum-infected red blood cells to CD36 under flow is enhanced by the cerebral malaria-protective trait South-East Asian ovalocytosis.

  Alfred Cortés, Mata Mellombo, Charles S Mgone, Hans-Peter Beck, John C Reeder, Brian M Cooke
  Molecular and Biochemical Parasitology 09/2005; 142(2):252-7. · 2.55 Impact Factor
• Article: A chimeric Plasmodium falciparum Pfnbp2b/Pfnbp2a gene originated during asexual growth.

  Alfred Cortés
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  ABSTRACT: The Plasmodium falciparum line 3D7-A has an unusual invasion phenotype, such that it can invade enzyme-treated and mutant red blood cells that are resistant to invasion by other parasite lines. 3D7-A has a chimeric Pfnbp2b gene that contains part of the repeat region of the paralogous gene Pfnbp2a. This chimeric gene originated by spontaneous gene conversion during normal maintenance in culture, indicating that ectopic recombination and gene conversion during asexual growth are potentially important mechanisms participating in the evolution of paralogous genes in Plasmodium. However, the presence of the chimeric Pfnbp2b gene in 3D7-A was not associated with its peculiar invasion phenotype.
  International Journal for Parasitology 03/2005; 35(2):125-30. · 3.39 Impact Factor
• Article: Allele specificity of naturally acquired antibody responses against Plasmodium falciparum apical membrane antigen 1.

  Alfred Cortés, Mata Mellombo, Rosella Masciantonio, Vince J Murphy, John C Reeder, Robin F Anders
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  ABSTRACT: Antibody responses against proteins located on the surface or in the apical organelles of merozoites are presumed to be important components of naturally acquired protective immune responses against the malaria parasite Plasmodium falciparum. However, many merozoite antigens are highly polymorphic, and antibodies induced against one particular allelic form might not be effective in controlling growth of parasites expressing alternative forms. The apical membrane antigen 1 (AMA1) is a polymorphic merozoite protein that is a target of naturally acquired invasion-inhibitory antibodies and is a leading asexual-stage vaccine candidate. We characterized the antibody responses against AMA1 in 262 individuals from Papua New Guinea exposed to malaria by using different allelic forms of the full AMA1 ectodomain and some individual subdomains. The majority of individuals had very high levels of antibodies against AMA1. The prevalence and titer of these antibodies increased with age. Although antibodies against conserved regions of the molecule were predominant in the majority of individuals, most plasma samples also contained antibodies directed against polymorphic regions of the antigen. In a few individuals, predominantly from younger age groups, the majority of antibodies against AMA1 were directed against polymorphic epitopes. The D10 allelic form of AMA1 apparently contains most if not all of the epitopes present in the other allelic forms tested, which might argue for its inclusion in future AMA1-based vaccines to be tested. Some important epitopes in AMA1 involved residues located in domain II or III but depended on more than one domain.
  Infection and Immunity 02/2005; 73(1):422-30. · 4.16 Impact Factor
• Article: Ability of Plasmodium falciparum to invade Southeast Asian ovalocytes varies between parasite lines.

  Alfred Cortés, Ariadna Benet, Brian M Cooke, John W Barnwell, John C Reeder
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  ABSTRACT: Plasmodium falciparum, the causative agent of the most lethal form of human malaria, uses multiple ligand-receptor interactions to invade host red blood cells (RBCs). We studied the invasion of P falciparum into abnormal RBCs from humans carrying the Southeast Asian ovalocytosis (SAO) trait. One particular parasite line, 3D7-A, invaded these cells efficiently, whereas all other lines studied invaded SAO RBCs to only about 20% of the extent of normal (non-SAO) cells. This result is consistent with the clinical observation that SAO individuals can experience high-density P falciparum infections and provides an explanation for previous discrepant results on invasion of SAO RBCs. Characterization of the invasion phenotype of 3D7-A revealed that efficient invasion of SAO RBCs was paralleled by relatively efficient invasion of normal RBCs treated with either neuraminidase, trypsin, or chymotrypsin and a novel capacity to invade normal RBCs treated sequentially with both neuraminidase and trypsin. Our results suggest that only parasites able to use some particular invasion pathways can invade SAO RBCs efficiently in culture. A similar situation might occur in the field.
  Blood 12/2004; 104(9):2961-6. · 9.90 Impact Factor
• Article: Diversity of Plasmodium falciparum vaccine candidate merozoite surface protein 4 (MSP4) in a natural population.

  Ariadna Benet, Livingstone Tavul, John C Reeder, Alfred Cortés
  Molecular and Biochemical Parasitology 05/2004; 134(2):275-80. · 2.55 Impact Factor
• Article: Molecular parasitology of malaria in Papua New Guinea.

  Alfred Cortés, Ingrid Felger, Hans-Peter Beck
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  ABSTRACT: Research into the molecular biology of infectious diseases is mostly associated with well-developed countries. But in the midst of tropical Papua New Guinea, highly sophisticated molecular research has being conducted over years to understand and fight malaria and other tropical diseases. Here, we review such research carried out at the Papua New Guinea Institute of Medical Research. This Institute has considerably shaped research on molecular epidemiology through its analysis of the diversity and structure of the Plasmodium falciparum population. In addition, research has been conducted on human host factors and, more recently, the molecular analysis of drug resistance and the underlying molecular mechanisms of host-parasite interactions have been investigated.
  Trends in Parasitology 07/2003; 19(6):246-9. · 5.14 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Geographical structure of diversity and differences between symptomatic and asymptomatic infections for Plasmodium falciparum vaccine candidate AMA1.

  Alfred Cortés, Mata Mellombo, Ivo Mueller, Ariadna Benet, John C Reeder, Robin F Anders
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  ABSTRACT: Plasmodium falciparum apical membrane antigen 1 (AMA1) is a prime malaria vaccine candidate. Antigenic diversity within parasite populations is one of the main factors potentially limiting the efficacy of any asexual-stage vaccine, including one based on AMA1. The DNA coding for the most variable region of this antigen, domain I, was sequenced in 168 samples from the Wosera region of Papua New Guinea, including samples from symptomatic and asymptomatic infections. Neutrality tests applied to these sequences provided strong evidence of selective pressure operating on the sequence of ama1 domain I, consistent with AMA1 being a target of protective immunity. Similarly, a peculiar pattern of geographical diversity and the particular substitutions found were suggestive of strong constraints acting on the evolution of AMA1 at the population level, probably as a result of immune pressure. In addition, a strong imbalance between symptomatic and asymptomatic infections was detected in the frequency of particular residues at certain polymorphic positions, pointing to AMA1 as being one of the determinants of the morbidity associated with a particular strain. The information yielded by this study has implications for the design and assessment of AMA1-based vaccines and provides additional data supporting the importance of AMA1 as a malaria vaccine candidate.
  Infection and Immunity 04/2003; 71(3):1416-26. · 4.16 Impact Factor
• Source

  Available from: Ivo Mueller

  Article: The population structure of Plasmodium falciparum and Plasmodium vivax during an epidemic of malaria in the Eastern Highlands of Papua New Guinea.

  Ivo Mueller, Japalis Kaiok, John C Reeder, Alfred Cortés
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  ABSTRACT: Although most of the Papua New Guinea highlands are too high for stable malaria transmission, local epidemics are a regular feature of the region. Few detailed descriptions of such epidemics are available, however. We describe the investigation of a malaria epidemic in the Obura Valley, Eastern Highlands Province, Papua New Guinea. Of the 244 samples examined by microscopy, 6.6% were positive for Plasmodium falciparum only, 9.4% were positive for Plasmodium vivax only, and 1.2% were mixed infections. MSP2 and MSP3alpha genotyping and AMA1 sequencing were used to determine the genetic variation present in a sample of P. falciparum and P. vivax infections. The P. vivax infections were found to be genetically highly diverse. In contrast, all P. falciparum samples were of a single genotype. This striking difference in genetic diversity suggests endemic, low-level local transmission for P. vivax but an outside introduction of P. falciparum as the most likely source of the epidemic.
  The American journal of tropical medicine and hygiene 12/2002; 67(5):459-64. · 2.59 Impact Factor
• Article: Plasmodium falciparum: distribution of msp2 genotypes among symptomatic and asymptomatic individuals from the Wosera region of Papua New Guinea.

  Alfred Cortés, Mata Mellombo, Ariadna Benet, Kerry Lorry, Lawrence Rare, John C Reeder
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  ABSTRACT: The merozoite surface protein 2 (MSP2) is a leading asexual-stage malaria vaccine candidate that has already proven to have an effect in phase I/IIb vaccine trials, where it was tested in combination with other antigens. Alleles of msp2 fall within two major allelic families, 3D7 and FC27. We analyzed the msp2 genotype in 306 asymptomatic and 63 symptomatic infections from the Wosera region of Papua New Guinea. The multiplicity of infection and the distribution of msp2 alleles was similar to that found in previous studies in the region, but there was no association found between FC27-type or 3D7-type forms of MSP2 and clinical malaria.
  Experimental Parasitology 106(1-2):22-9. · 2.12 Impact Factor