Clinical malaria incidence following an outbreak in Ecuador was predominantly associated with Plasmodium falciparum with recombinant variant antigen gene repertoires

To better understand the factors underlying the continued incidence of clinical episodes of falciparum malaria in E-2020 countries targeting elimination, we have characterised Plasmodium falciparum disease transmission dynamics after a clonal outbreak on the northwest coast of Ecuador over a period of two years. We apply a novel, high-resolution genotyping method, the "varcode" based on a single PCR to fingerprint the DBLα region of the 40-60 members of the variant surface antigen-encoding var multigene family. Var genes are highly polymorphic within and between genomes, with var repertoires rapidly evolving by outcrossing during the obligatory sexual phase of P. falciparum in the mosquito. The continued incidence of clinical malaria after the outbreak in Ecuador provided a unique opportunity to use varcodes to document parasite microevolution and explore signatures of local disease transmission on the time scale of months to two years post-outbreak. We identified nine genetic varcodes circulating locally with spatiotemporal parasite genetic relatedness networks revealing that diversification of the clonal outbreak parasites by sexual recombination was associated with increased incidence of clinical episodes of malaria. Whether this was due to chance, immune selection or sexual recombination per se is discussed. Comparative analyses to other South American parasite populations where P. falciparum transmission remains endemic elucidated the possible origins of Ecuadorian varcodes. This analysis demonstrated that the majority of clinical cases were due to local transmission and not importation. Nonetheless, some of the varcodes that were unrelated to the outbreak varcode were found to be genetically related to other South American parasites. Our findings demonstrate the utility of the varcode as a high-resolution surveillance tool to spatiotemporally track disease outbreaks using variant surface antigen genes and resolve signatures of recombination in an E-2020 setting nearing elimination.

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Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure

mSphere ◽

10.1128/msphere.00097-19 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 9

Author(s):

Albert E. Zhou ◽

Andrea A. Berry ◽

Jason A. Bailey ◽

Andrew Pike ◽

Antoine Dara ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Malaria ◽

Surface Antigen ◽

Immune Evasion ◽

Clinical Malaria ◽

Malaria Episode ◽

Natural Immunity ◽

Content Type ◽

Variant Surface Antigen ◽

Malaria Exposure

ABSTRACT The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria. IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.

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Plasmodium falciparum Variant Surface Antigen Expression Patterns during Malaria

PLoS Pathogens ◽

10.1371/journal.ppat.0010026 ◽

2005 ◽

Vol 1 (3) ◽

pp. e26 ◽

Cited By ~ 116

Author(s):

Peter C Bull ◽

Matthew Berriman ◽

Sue Kyes ◽

Michael A Quail ◽

Neil Hall ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Surface Antigen ◽

Expression Patterns ◽

Antigen Expression ◽

Variant Surface Antigen ◽

Surface Antigen Expression

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Evolutionary analyses of the major variant surface antigen-encoding genes reveal population structure of Plasmodium falciparum within and between continents

PLoS Genetics ◽

10.1371/journal.pgen.1009269 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009269

Author(s):

Gerry Tonkin-Hill ◽

Shazia Ruybal-Pesántez ◽

Kathryn E. Tiedje ◽

Virginie Rougeron ◽

Michael F. Duffy ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Population Structure ◽

Surface Antigen ◽

Local Population ◽

Biological Significance ◽

Public Health Problem ◽

Major Public Health Problem ◽

Malaria Surveillance ◽

Geographic Population ◽

Variant Surface Antigen

Malaria remains a major public health problem in many countries. Unlike influenza and HIV, where diversity in immunodominant surface antigens is understood geographically to inform disease surveillance, relatively little is known about the global population structure of PfEMP1, the major variant surface antigen of the malaria parasite Plasmodium falciparum. The complexity of the var multigene family that encodes PfEMP1 and that diversifies by recombination, has so far precluded its use in malaria surveillance. Recent studies have demonstrated that cost-effective deep sequencing of the region of var genes encoding the PfEMP1 DBLα domain and subsequent classification of within host sequences at 96% identity to define unique DBLα types, can reveal structure and strain dynamics within countries. However, to date there has not been a comprehensive comparison of these DBLα types between countries. By leveraging a bioinformatic approach (jumping hidden Markov model) designed specifically for the analysis of recombination within var genes and applying it to a dataset of DBLα types from 10 countries, we are able to describe population structure of DBLα types at the global scale. The sensitivity of the approach allows for the comparison of the global dataset to ape samples of Plasmodium Laverania species. Our analyses show that the evolution of the parasite population emerging out of Africa underlies current patterns of DBLα type diversity. Most importantly, we can distinguish geographic population structure within Africa between Gabon and Ghana in West Africa and Uganda in East Africa. Our evolutionary findings have translational implications in the context of globalization. Firstly, DBLα type diversity can provide a simple diagnostic framework for geographic surveillance of the rapidly evolving transmission dynamics of P. falciparum. It can also inform efforts to understand the presence or absence of global, regional and local population immunity to major surface antigen variants. Additionally, we identify a number of highly conserved DBLα types that are present globally that may be of biological significance and warrant further characterization.

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Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

Infection and Immunity ◽

10.1128/iai.00978-12 ◽

2013 ◽

Vol 81 (4) ◽

pp. 1031-1039 ◽

Cited By ~ 8

Author(s):

Tracy Saveria ◽

Andrew V. Oleinikov ◽

Kathryn Wiliamson ◽

Richa Chaturvedi ◽

Joe Lograsso ◽

...

Keyword(s):

Escherichia Coli ◽

Plasmodium Falciparum ◽

Chondroitin Sulfate ◽

Surface Antigen ◽

Transmembrane Protein ◽

Placental Malaria ◽

Placental Tissue ◽

Content Type ◽

Variant Surface Antigen ◽

Chondroitin Sulfate A

ABSTRACTPlacental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), aPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed inEscherichia colito generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4ε, DBL5ε, DBL6ε, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4ε and to DBL5ε inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4ε and DBL5ε as vaccine candidates for pregnancy malaria and demonstrate thatE. coliis a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.

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In Vitro Variant Surface Antigen Expression in Plasmodium falciparum Parasites from a Semi-Immune Individual Is Not Correlated with Var Gene Transcription

PLoS ONE ◽

10.1371/journal.pone.0166135 ◽

2016 ◽

Vol 11 (12) ◽

pp. e0166135 ◽

Cited By ~ 5

Author(s):

Ellen Inga Bruske ◽

Sandra Dimonte ◽

Corinna Enderes ◽

Serena Tschan ◽

Matthias Flötenmeyer ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Gene Transcription ◽

Surface Antigen ◽

Antigen Expression ◽

Variant Surface Antigen ◽

Surface Antigen Expression ◽

Var Gene ◽

Immune Individual

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Plasmodium falciparum complicated malaria: Modulation and connectivity between exportome and variant surface antigen gene families

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2015.05.005 ◽

2015 ◽

Vol 201 (1) ◽

pp. 31-46 ◽

Cited By ~ 7

Author(s):

Amit Kumar Subudhi ◽

P.A. Boopathi ◽

Isha Pandey ◽

Ramandeep Kohli ◽

Rohan Karwa ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Surface Antigen ◽

Gene Families ◽

Antigen Gene ◽

Complicated Malaria ◽

Variant Surface Antigen

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Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria

The Lancet ◽

10.1016/s0140-6736(03)15386-x ◽

2004 ◽

Vol 363 (9405) ◽

pp. 283-289 ◽

Cited By ~ 173

Author(s):

Trine Staalsoe ◽

Caroline E Shulman ◽

Judith N Bulmer ◽

Ken Kawuondo ◽

Kevin Marsh ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Falciparum Malaria ◽

Surface Antigen ◽

Plasmodium Falciparum Malaria ◽

Variant Surface Antigen ◽

Clinical Consequences ◽

Specific Igg

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Determinants of Variant Surface Antigen Antibody Response in Severe Plasmodium falciparum Malaria in an Area of Low and Unstable Malaria Transmission

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.2006.01732.x ◽

2006 ◽

Vol 63 (3) ◽

pp. 232-240 ◽

Cited By ~ 2

Author(s):

T. M E. A-Elgadir ◽

T. G. Theander ◽

G. ElGhazali ◽

M. A. Nielsen ◽

I. E. A-Elbasit ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antibody Response ◽

Malaria Transmission ◽

Falciparum Malaria ◽

Surface Antigen ◽

Plasmodium Falciparum Malaria ◽

Variant Surface Antigen ◽

Antigen Antibody

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Within-household clustering of genetically related Plasmodium falciparum infections in a moderate transmission area of Uganda

10.21203/rs.3.rs-113858/v2 ◽

2021 ◽

Author(s):

Jessica Briggs ◽

Alison Kuchta ◽

Max Murphy ◽

Sofonias Tessema ◽

Emmanuel Arinaitwe ◽

...

Keyword(s):

Genetic Diversity ◽

Plasmodium Falciparum ◽

Malaria Transmission ◽

Genetic Relatedness ◽

Malaria Incidence ◽

Spatial Scales ◽

Genetic Data ◽

Fine Scale ◽

Lower Elevation ◽

Significant Difference

Abstract Background Evaluation of genetic relatedness of malaria parasites is a useful tool for understanding transmission patterns, but patterns are not easily detectable in areas with moderate to high malaria transmission. To evaluate the feasibility of detecting genetic relatedness in a moderate malaria transmission setting, relatedness of Plasmodium falciparum infections was measured in cohort participants from randomly selected households in the Kihihi sub-county of Uganda (annual entomological inoculation rate of 27 infectious bites per person). Methods All infections detected via microscopy or Plasmodium-specific loop mediated isothermal amplification from passive and active case detection during August 2011-March 2012 were genotyped at 26 microsatellite loci, providing data for 349 samples from 230 participants living in 80 households. Pairwise genetic relatedness was calculated using identity by state (IBS).Results As expected, genetic diversity was high (mean heterozygosity [He]=0.73), and the majority (76.5%) of samples were polyclonal. Despite the high genetic diversity, fine-scale population structure was detectable, with significant spatiotemporal clustering of highly related infections. Although the difference in malaria incidence between households at higher (mean 1127 metres) versus lower elevation (mean 1015 metres) was modest (1.4 malaria cases per person-year versus 1.9 per person-year, respectively), there was a significant difference in multiplicity of infection (2.2 versus 2.6, p = 0.008) and, more strikingly, a higher proportion of highly related infections within households (6.3% vs 0.9%, p = 0.0005) at higher elevation compared to lower elevation. Conclusions Genetic data from a relatively small number of diverse, multiallelic loci reflected fine scale patterns of malaria transmission. Given the increasing interest in applying genetic data to augment malaria surveillance, this study provides evidence that genetic data can be used to inform transmission patterns at local spatial scales even in moderate transmission areas.

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