scholarly journals Plasmodium falciparum population genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

2020 ◽  
Author(s):  
Amy K. Bei ◽  
Daniel B. Larremore ◽  
Kazutoyo Miura ◽  
Ababacar Diouf ◽  
Nicholas K. Baro ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Development ◽  
Ex Vivo ◽  
Surface Antigens ◽  
Immune Recognition ◽  
Short Term ◽  
Polymorphic Loci ◽  
Variant Surface Antigens ◽  
Genotype Frequencies ◽  
Genetic Complexity

As transmission intensity has declined in Senegal, so has the genetic complexity of circulating Plasmodium falciparum parasites, resulting in specific genotypes emerging and persisting over years. We address whether changes in parasite genetic signatures can alter the immune repertoire to variant surface antigens, and whether such responses can influence the expansion or contraction of specific parasite genotypes in the population. We characterize parasites within genotypic clusters, defined as identical by a 24-SNP molecular barcode and a haplotype identifier for other highly polymorphic loci; we measure expression of variant surface antigens (VSA) such as PfEMP-1 by transcript expression typing and expressed var DBL1α sequencing in ex vivo and short-term adapted RNA samples; and we measure IgG responses against VSAs from short-term adapted parasites. We find that parasites within genotypic clusters are genetically identical at other highly polymorphic loci. These parasites express similar Ups var classes and largely the same dominant var DBL1α sequences ex vivo. These parasites are recognized similarly by anti-VSA antibodies after short-term adaptation to culture; however, antibody responses do not correlate with genotype frequencies over time. Both genotype-specific and multiple genotype-reactive surface IgG responses are observed in this population. Parasites with identical genomes are extremely similar in their expression and host antibody recognition of VSAs. Monitoring changes in population-level parasite genomics and transmission dynamics is critical, as fluctuations will influence the breadth of resulting host immune responses to circulating parasite genotypes. These findings suggest shared immune recognition of genetically similar parasites, which has implications for both our understanding of immunity and vaccine development strategies in malaria elimination settings.

scholarly journals In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
O. Ajibola ◽  
M. F. Diop ◽  
A. Ghansah ◽  
L. Amenga-Etego ◽  
L. Golassa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Balancing Selection ◽  
Immune Recognition ◽  
African Countries ◽  
Vaccine Candidates ◽  
D Values ◽  
Tajima’S D

AbstractGenetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

scholarly journals Immunoglobulin G Isotype Responses to Variant Surface Antigens of Plasmodium falciparum in Healthy Gabonese Adults and Children during and after Successive Malaria Attacks

2004 ◽  
Vol 72 (1) ◽  
pp. 284-294 ◽  
Author(s):  
Gerardo Cabrera ◽  
Clarisse Yone ◽  
Anne E. Tebo ◽  
Jan van Aaken ◽  
Bertrand Lell ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immunoglobulin G ◽  
Surface Antigens ◽  
Healthy Adults ◽  
Healthy Children ◽  
Variant Surface Antigens ◽  
Age Related ◽  
Adults And Children ◽  
The Individual ◽  
Malaria Episodes

ABSTRACT We assessed immunoglobulin G (IgG) isotype responses with specificity for the variant surface antigens (VSA) of heterologous Plasmodium falciparum isolates by using flow cytometry and plasma from healthy Gabonese adults and from children during and after two consecutive malaria episodes. The individual isolate-specific antibody profiles differed markedly in terms of their isotype content but were similar for healthy adults and healthy uninfected children. In healthy adults, IgG3 and IgG2 responses were the highest, while in healthy children, IgG3 and IgG4 predominated. A transiently elevated IgG1 response was observed during the second of two successive malaria episodes in children, signaling P. falciparum infection-induced cross-reactive anti-VSA responses. Our findings highlight the prominence of IgG3 in the overall profile of these responses but also indicate a marked age-related increase in the prevalence of anti-VSA antibodies of the classically noncytophilic IgG2 isotype, possibly reflecting the high frequency of the histidine-131 variant of FcγRIIA in the Gabonese population.

scholarly journals Temporal Expression and Localization Patterns of Variant Surface Antigens in Clinical Plasmodium falciparum Isolates during Erythrocyte Schizogony

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49540 ◽  
Author(s):  
Anna Bachmann ◽  
Michaela Petter ◽  
Ann-Kathrin Tilly ◽  
Laura Biller ◽  
Karin A. Uliczka ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Antigens ◽  
Temporal Expression ◽  
Variant Surface Antigens

scholarly journals Placental Malaria Induces Variant-Specific Antibodies of the Cytophilic Subtypes Immunoglobulin G1 (IgG1) and IgG3 That Correlate with Adhesion Inhibitory Activity

2005 ◽  
Vol 73 (9) ◽  
pp. 5903-5907 ◽  
Author(s):  
Salenna R. Elliott ◽  
Amy K. Brennan ◽  
James G. Beeson ◽  
Eyob Tadesse ◽  
Malcolm E. Molyneux ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Activity ◽  
Placental Malaria ◽  
Surface Antigens ◽  
Phagocytic Cells ◽  
Specific Antibodies ◽  
Variant Surface Antigens ◽  
And Control ◽  
Chondroitin Sulfate A ◽  
In Pregnancy

ABSTRACT Antibodies targeting variant antigens on the surfaces of chondroitin sulfate A (CSA)-binding malaria-infected erythrocytes have been linked to protection against the complications of malaria in pregnancy. We examined the isotype/subtype profiles of antibodies that bound to variant surface antigens expressed by CSA-adherent Plasmodium falciparum in pregnant Malawian women with and without histologically defined placental malaria. Women in their first pregnancy with placental malaria produced significantly greater amounts of immunoglobulin G1 (IgG1) and IgG3 reactive with surface antigens of malaria-infected erythrocytes than uninfected women of the same gravidity. IgG1 and IgG3 levels in infected and control women in later pregnancies were similar to those in infected women in their first pregnancy. Levels of IgG2 and IgG4 were similarly low in infected and uninfected women of all gravidities. IgM that bound to the surface of CSA-adherent P. falciparum occurred in all groups of women and malaria-naïve controls. There was a significant correlation between IgG1 and IgG3 levels, indicating that women usually produced both subtypes. Levels of IgG1 and IgG3 correlated with the ability of serum or plasma to inhibit parasite adhesion to CSA. Taken together, these data suggest that IgG1 and IgG3 dominate the IgG response to placental-type variant surface antigens. They may function by blocking parasite adhesion to placental CSA, but given their cytophilic nature, they might also opsonize malaria-infected erythrocytes for interaction with Fc receptors on phagocytic cells.

scholarly journals Effects of Pregnancy and Intensity of Plasmodium falciparum Transmission on Immunoglobulin G Subclass Responses to Variant Surface Antigens

2005 ◽  
Vol 73 (7) ◽  
pp. 4112-4118 ◽  
Author(s):  
Rosette Megnekou ◽  
Trine Staalsoe ◽  
Diane W Taylor ◽  
Rose Leke ◽  
Lars Hviid
Keyword(s):  
Plasmodium Falciparum ◽  
Gestational Age ◽  
Immunoglobulin G ◽  
Surface Antigens ◽  
Transmission Intensity ◽  
Parasite Transmission ◽  
Variant Surface Antigens ◽  
Pregnancy Status ◽  
Immunoglobulin G Subclass ◽  
Very High

ABSTRACT Placenta-sequestering Plasmodium falciparum involved in the pathogenesis of pregnancy-associated malaria (PAM) in otherwise clinically immune women expresses particular variant surface antigens (VSAPAM) on the surface of infected erythrocytes that differ from VSA found in parasitized nonpregnant individuals (non-PAM type VSA). We studied levels of immunoglobulin G (IgG) and IgG subclasses with specificity for VSAPAM and for non-PAM type VSA in pregnant and nonpregnant women from two sites with different endemicities in Cameroon. We found that VSAPAM-specific responses depended on the pregnancy status, parity, gestational age, and parasite transmission intensity, whereas only the parasite transmission intensity influenced the levels of IgG specific for non-PAM type VSA. For both types of VSA, the responses were dominated by the cytophilic subclass IgG1, followed by IgG3. In pregnant women, the levels of VSAPAM-specific antibodies either were very low or negative or were very high, whereas the levels of the antibodies specific for non-PAM type VSA were uniformly high. Interestingly, the levels of VSAPAM-specific IgG1 increased with increasing gestational age, while the levels of the corresponding IgG3 tended to decrease with increasing gestational age. The IgG subclass responses with specificity for non-PAM type VSA did not vary significantly with gestational age. Taken together, our data indicate that IgG1 and to a lesser extent IgG3 are the main subclasses involved in acquired VSAPAM-specific immunity to pregnancy-associated malaria.

scholarly journals The Association of High Prevalence of Trophozoites in Peripheral Blood with Lower Antibody Response toP. falciparumInfected Erythrocytes among Asymptomatic Children in Sudan

2016 ◽  
Vol 2016 ◽  
pp. 1-4
Author(s):  
Sara N. Mohamed ◽  
Dina A. Hassan ◽  
Abdelrahim M. El Hussein ◽  
Ihssan M. Osman ◽  
Muntasir E. Ibrahim ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Plasmodium Falciparum ◽  
Peripheral Blood ◽  
Surface Antigens ◽  
Igg Antibodies ◽  
Autologous Plasma ◽  
Variant Surface Antigens ◽  
Asymptomatic Children ◽  
Infected Rbcs ◽  
The Mean

Background. The most prominent variant surface antigens (VSAs) ofPlasmodium falciparumare the var gene-encodedPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) family, which serves as a parasite-sequestering ligand to endothelial cells. In this study we have examined the antibody reactivity of autologous plasma from symptomatic and asymptomatic malaria infected children against the infected erythrocytes’ surface antigens using flow cytometry.Methods. Ethidium-bromide-labelled erythrocytic mature forms ofP. falciparumparasites obtained from symptomatic and asymptomatic children were sequentially incubated with autologous plasma and fluorescein isothiocyanate-conjugated (FITC) antihuman IgG. Plasma antibody reactivity was detected by flow cytometry.Results. Asymptomatic children had more prevalence of trophozoites in peripheral blood (66%) compared to symptomatic children (16%),p=0.002. The mean percentage of infected RBCs reacting with autologous sera was 89.78 among symptomatic children compared to 79.62 among asymptomatic children (p=0.09). Moreover, the mean fluorescence intensity (MFI) in the asymptomatic was significantly higher compared to symptomatic children (pvalue = 0.040).Conclusion. Variant surface antigens onPlasmodium falciparuminfected RBCs from symptomatic malaria children tend to be better recognized by IgG antibodies. This may suggest a role of some IgG antibodies in severity of malaria.

scholarly journals Plasmodium falciparum schizont stage transcriptome variation among clinical isolates and laboratory-adapted clones

2018 ◽  
Author(s):  
Sarah J Tarr ◽  
Ofelia Díaz-Ingelmo ◽  
Lindsay B Stewart ◽  
Suzanne E Hocking ◽  
Lee Murray ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Development ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Differentially Expressed ◽  
Clinical Isolates ◽  
Schizont Stage ◽  
Variable Expression ◽  
The Impact

AbstractMalaria parasite genes exhibit variation in both sequence and expression level. There is much information on sequence polymorphism, but less resolution on natural variation in transcriptomes of parasites at specific developmental stages. This is largely because it is challenging to obtain highly replicated sampling of transcriptomes to overcome potentially confounding technical and biological variation. We address the issue in the major human parasite Plasmodium falciparum by obtaining RNA-seq profiles of multiple independent replicate preparations of mature schizont-stage parasites from a panel of clinical isolates recently established in culture and from long-term laboratory-adapted clones. With a goal of robustly identifying variably expressed genes, we show that increasing the numbers of biological sample replicates greatly improves the discovery rate. Generally, six independent replicates of each parasite culture is recommendable as being significantly to lower numbers, although for highly expressed genes variable expression can be detected when fewer replicates are available. A broad comparison identifies genes differing in relative expression between cultured clinical isolates and laboratory-adapted clones. Genes more highly expressed in the laboratory-adapted clones include an AP2 transcription factor gene Pf3D7_0420300 and putative methyl transferase genes. The variable expression of several known merozoite invasion ligands is confirmed, and previously uncharacterised genes are shown to be differentially expressed among clinical isolates. New RT-qPCR assays validate the variation in transcript levels of these genes, and allow quantitation of expression to be extended to a wider panel of clinical isolate samples. These variably expressed genes are new candidates for investigation as potential determinants of alternative parasite developmental pathways or targets of immunity.Author summaryUnderstanding parasite diversity and adaptation may require characterisation of gene expression variation, and is vital if chemotherapeutic or vaccine development is to consider new candidate targets, but it is technically challenging to generate precise data on clinical isolates. Here, we analyse the transcriptomes of mature Plasmodium falciparum schizonts using RNA-sequencing, using large numbers of biological replicate samples to minimise the impact of inter-replicate variation on observed patterns of differential expression. This identifies genes that are differentially expressed in long term laboratory-adapted parasites and recently cultured clinical isolates, as well as among different clinical isolates. In additional samples of schizonts grown in the first cycle ex vivo prior to any erythrocyte invasion, expression levels of a selected panel of these genes vary among isolates, but mean levels are similar to those in the continuously cultured clinical isolates, indicating that the latter are useful for experimental studies requiring biological replication.

scholarly journals Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
J. Stephan Wichers ◽  
Judith A. M. Scholz ◽  
Jan Strauss ◽  
Susanne Witt ◽  
Andrés Lill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Host Cell ◽  
Cell Invasion ◽  
Surface Antigens ◽  
Membrane Topology ◽  
Host Cell Invasion ◽  
Content Type ◽  
Variant Surface Antigens

ABSTRACT During its intraerythrocytic development, the malaria parasite Plasmodium falciparum exposes variant surface antigens (VSAs) on infected erythrocytes to establish and maintain an infection. One family of small VSAs is the polymorphic STEVOR proteins, which are marked for export to the host cell surface through their PEXEL signal peptide. Interestingly, some STEVORs have also been reported to localize to the parasite plasma membrane and apical organelles, pointing toward a putative function in host cell egress or invasion. Using deep RNA sequencing analysis, we characterized P. falciparum stevor gene expression across the intraerythrocytic development cycle, including free merozoites, in detail and used the resulting stevor expression profiles for hierarchical clustering. We found that most stevor genes show biphasic expression oscillation, with maximum expression during trophozoite stages and a second peak in late schizonts. We selected four STEVOR variants, confirmed the expected export of these proteins to the host cell membrane, and tracked them to a secondary location, either to the parasite plasma membrane or the secretory organelles of merozoites in late schizont stages. We investigated the function of a particular STEVOR that showed rhoptry localization and demonstrated its role at the parasite-host interface during host cell invasion by specific antisera and targeted gene disruption. Experimentally determined membrane topology of this STEVOR revealed a single transmembrane domain exposing the semiconserved as well as variable protein regions to the cell surface. IMPORTANCE Malaria claims about half a million lives each year. Plasmodium falciparum, the causative agent of the most severe form of the disease, uses proteins that are translocated to the surface of infected erythrocytes for immune evasion. To circumvent the detection of these gene products by the immune system, the parasite evolved a complex strategy that includes gene duplications and elaborate sequence polymorphism. STEVORs are one family of these variant surface antigens and are encoded by about 40 genes. Using deep RNA sequencing of blood-stage parasites, including free merozoites, we first established stevor expression of the cultured isolate and compared it with published transcriptomes. We reveal a biphasic expression of most stevor genes and confirm this for individual STEVORs at the protein level. The membrane topology of a rhoptry-associated variant was experimentally elucidated and linked to host cell invasion, underlining the importance of this multifunctional protein family for parasite proliferation.

scholarly journals Plasmodium falciparum Parasites Expressing Pregnancy-Specific Variant Surface Antigens Adhere Strongly to the Choriocarcinoma Cell Line BeWo

2006 ◽  
Vol 74 (5) ◽  
pp. 3035-3038 ◽  
Author(s):  
Rikke N. Haase ◽  
Rosette Megnekou ◽  
Maja Lundquist ◽  
Michael F. Ofori ◽  
Lars Hviid ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Line ◽  
Surface Antigens ◽  
Variant Surface Antigens ◽  
Choriocarcinoma Cell Line

ABSTRACT Placenta-sequestering Plasmodium falciparum parasites causing pregnancy-associated malaria express pregnancy-specific variant surface antigens (VSAPAM). We report here that VSAPAM-expressing patient isolates adhere strongly to the choriocarcinoma cell line BeWo and that the BeWo line can be used to efficiently select for VSAPAM expression in vitro.

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