Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2016

Open Access 01-12-2016 | Research

Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria

Authors: Michael F. Duffy, Rintis Noviyanti, Takafumi Tsuboi, Zhi-Ping Feng, Leily Trianty, Boni F. Sebayang, Eizo Takashima, Fransisca Sumardy, Daniel A. Lampah, Louise Turner, Thomas Lavstsen, Freya J. I. Fowkes, Peter Siba, Stephen J. Rogerson, Thor G. Theander, Jutta Marfurt, Ric N. Price, Nicholas M. Anstey, Graham V. Brown, Anthony T. Papenfuss

Published in: Malaria Journal | Issue 1/2016

Login to get access

Abstract

Background

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria. PfEMP1s can be broadly divided into three principal groups (A, B and C) and they contain conserved arrangements of functional domains called domain cassettes. Despite their tremendous diversity there is compelling evidence that a restricted subset of PfEMP1s is expressed in severe disease. In this study antibodies from patients with severe and uncomplicated malaria were compared for differences in reactivity with a range of PfEMP1s to determine whether antibodies to particular PfEMP1 domains were associated with severe or uncomplicated malaria.

Methods

Parts of expressed var genes in a severe malaria patient were identified by RNAseq and several of these partial PfEMP1 domains were expressed together with others from laboratory isolates. Antibodies from Papuan patients to these parts of multiple PfEMP1 proteins were measured.

Results

Patients with uncomplicated malaria were more likely to have antibodies that recognized PfEMP1 of Group C type and recognized a broader repertoire of group A and B PfEMP1s than patients with severe malaria.

Conclusion

These data suggest that exposure to a broad range of group A and B PfEMP1s is associated with protection from severe disease in Papua, Indonesia.
Appendix
Available only for authorised users
Literature
1.
Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell. 1995;82:77–87.CrossRefPubMed
2.
Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell. 1995;82:101–10.CrossRefPubMedPubMedCentral
3.
Su XZ, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JA, Peterson DS, et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell. 1995;82:89–100.CrossRefPubMed
4.
Rask TS, Hansen DA, Theander TG, Pedersen AG, Lavstsen T. Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes—divide and conquer. PLoS Comput Biol. 2010;6:e1000933.CrossRefPubMedPubMedCentral
5.
Marsh K, Otoo L, Hayes RJ, Carson DC, Greenwood BM. Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Trans R Soc Trop Med Hyg. 1989;83:293–303.CrossRefPubMed
6.
Newbold CI, Pinches R, Roberts DJ, Marsh K. Plasmodium falciparum: the human agglutinating antibody response to the infected red cell surface is predominantly variant specific. Exp Parasitol. 1992;75:281–92.CrossRefPubMed
7.
Chan JA, Howell KB, Reiling L, Ataide R, Mackintosh CL, Fowkes FJ, et al. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J Clin Invest. 2012;122:3227–38.CrossRefPubMedPubMedCentral
8.
Marsh K, Howard RJ. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science. 1986;231:150–3.CrossRefPubMed
9.
Gupta S, Snow RW, Donnelly C, Newbold C. Acquired immunity and postnatal clinical protection in childhood cerebral malaria. Proc Biol Sci. 1999;266:33–8.CrossRefPubMedPubMedCentral
10.
Gupta S, Snow RW. C.A. D, Marsh K, Newbold C. Immunity to non-cerebral severe malaria is acquired after one or two infections. Nature Med. 1999;5:340–3.CrossRefPubMed
11.
Bull PC, Kortok M, Kai O, Ndungu F, Ross A, Lowe BS, et al. Plasmodium falciparum-infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. J Infect Dis. 2000;182:252–9.CrossRefPubMed
12.
Nielsen MA, Staalsoe T, Kurtzhals JA, Goka BQ, Dodoo D, Alifrangis M, et al. Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity. J Immunol. 2002;168:3444–50.CrossRefPubMed
13.
Smith JD, Subramanian G, Gamain B, Baruch DI, Miller LH. Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Mol Biochem Parasitol. 2000;110:293–310.CrossRefPubMed
14.
Rowe JA, Claessens A, Corrigan RA, Arman M. Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications. Expert Rev Mol Med. 2009;11:e16.CrossRefPubMedPubMedCentral
15.
Smith JD, Rowe JA, Higgins MK, Lavstsen T. Malaria’s deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes. Cell Microbiol. 2013;15:1976–83.CrossRefPubMed
16.
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002;419:498–511.CrossRefPubMed
17.
Lavstsen T, Salanti A, Jensen AT, Arnot DE, Theander TG. Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions. Malar J. 2003;2:27.CrossRefPubMedPubMedCentral
18.
Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, et al. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol. 2003;49:179–91.CrossRefPubMed
19.
Normark J, Nilsson D, Ribacke U, Winter G, Moll K, Wheelock CE, et al. PfEMP1-DBL1alpha amino acid motifs in severe disease states of Plasmodium falciparum malaria. Proc Natl Acad. 2007;104:15835–40.CrossRef
20.
Warimwe GM, Keane TM, Fegan G, Musyoki JN, Newton CR, Pain A, et al. Plasmodium falciparum var gene expression is modified by host immunity. Proc Natl Acad Sci. 2009;106:21801–6.CrossRefPubMedPubMedCentral
21.
Kaestli M, Cockburn IA, Cortes A, Baea K, Rowe JA, Beck HP. Virulence of malaria is associated with differential expression of Plasmodium falciparum var gene subgroups in a case-control study. J Infect Dis. 2006;193:1567–74.CrossRefPubMedPubMedCentral
22.
Falk N, Kaestli M, Qi W, Ott M, Baea K, Cortes A, et al. Analysis of Plasmodium falciparum var genes expressed in children from Papua New Guinea. J Infect Dis. 2009;200:347–56.CrossRefPubMed
23.
Rottmann M, Lavstsen T, Mugasa JP, Kaestli M, Jensen AT, Muller D, et al. Differential expression of var gene groups is associated with morbidity caused by Plasmodium falciparum infection in Tanzanian children. Infect Immun. 2006;74:3904–11.CrossRefPubMedPubMedCentral
24.
Kyriacou HM, Stone GN, Challis RJ, Raza A, Lyke KE, Thera MA, et al. Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia. Mol Biochem Parasitol. 2006;150:211–8.CrossRefPubMedPubMedCentral
25.
Warimwe GM, Fegan G, Musyoki JN, Newton CR, Opiyo M, Githinji G, et al. Prognostic indicators of life-threatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med. 2012;4:129.CrossRef
26.
Kalmbach Y, Rottmann M, Kombila M, Kremsner PG, Beck HP, Kun JF. Differential var gene expression in children with malaria and antidromic effects on host gene expression. J Infect Dis. 2010;202:313–7.CrossRefPubMed
27.
Jensen AT, Magistrado P, Sharp S, Joergensen L, Lavstsen T, Chiucchiuini A, et al. Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes. J Exp Med. 2004;199:1179–90.CrossRefPubMedPubMedCentral
28.
Wang CW, Hermsen CC, Sauerwein RW, Arnot DE, Theander TG, Lavstsen T. The Plasmodium falciparum var gene transcription strategy at the onset of blood stage infection in a human volunteer. Parasitol Int. 2009;58:478–80.CrossRefPubMed
29.
Cham GK, Turner L, Lusingu J, Vestergaard L, Mmbando BP, Kurtis JD, et al. Sequential, ordered acquisition of antibodies to Plasmodium falciparum erythrocyte membrane protein 1 domains. J Immunol. 2009;183:3356–63.CrossRefPubMed
30.
Howell DP, Levin EA, Springer AL, Kraemer SM, Phippard DJ, Schief WR, et al. Mapping a common interaction site used by Plasmodium falciparum duffy binding-like domains to bind diverse host receptors. Mol Microbiol. 2008;67:78–87.CrossRefPubMed
31.
Oleinikov AV, Amos E, Frye IT, Rossnagle E, Mutabingwa TK, Fried M, et al. High throughput functional assays of the variant antigen PfEMP1 reveal a single domain in the 3D7 Plasmodium falciparum genome that binds ICAM1 with high affinity and is targeted by naturally acquired neutralizing antibodies. PLoS Pathog. 2009;5:e1000386.CrossRefPubMedPubMedCentral
32.
Turner GDH, Morrison H, Jones M, Davis TME, Looareesuwan S, Buley ID, et al. 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. Am J Pathol. 1994;145:1057–69.PubMedPubMedCentral
33.
Ochola LB, Siddondo BR, Ocholla H, Nkya S, Kimani EN, Williams TN, et al. Specific receptor usage in Plasmodium falciparum cytoadherence is associated with disease outcome. PLoS One. 2011;6:e14741.CrossRefPubMedPubMedCentral
34.
Newbold C, Warn P, Black G, Berendt A, Craig A, Snow B, et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg. 1997;57:389–98.PubMed
35.
Rogerson SJ, Tembenu R, Dobano C, Plitt S, Taylor TE, Molyneux ME. Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria. Am J Trop Med Hyg. 1999;61:467–72.PubMed
36.
Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE, Avril M, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498:502–5.CrossRefPubMedPubMedCentral
37.
Lau CK, Turner L, Jespersen JS, Lowe ED, Petersen B, Wang CW, et al. Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria. Cell Host Microbe. 2015;17:118–29.CrossRefPubMedPubMedCentral
38.
Lavstsen T, Turner L, Saguti F, Magistrado P, Rask TS, Jespersen JS, et al. Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proc Natl Acad Sci. 2012;109:E1791–800.CrossRefPubMedPubMedCentral
39.
Avril M, Tripathi AK, Brazier AJ, Andisi C, Janes JH, Soma VL, et al. A restricted subset of var genes mediates adherence of Plasmodium falciparum-infected erythrocytes to brain endothelial cells. Proc Natl Acad Sci. 2012;109:E1782–90.CrossRefPubMedPubMedCentral
40.
Claessens A, Adams Y, Ghumra A, Lindergard G, Buchan CC, Andisi C, et al. A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci. 2012;109:E1772–81.CrossRefPubMedPubMedCentral
41.
Lavstsen T, Magistrado P, Hermsen CC, Salanti A, Jensen AT, Sauerwein R, et al. Expression of Plasmodium falciparum erythrocyte membrane protein 1 in experimentally infected humans. Malar J. 2005;4:21.CrossRefPubMedPubMedCentral
42.
Magistrado PA, Lusingu J, Vestergaard LS, Lemnge M, Lavstsen T, Turner L, et al. Immunoglobulin G antibody reactivity to a group A Plasmodium falciparum erythrocyte membrane protein 1 and protection from P. falciparum malaria. Infect Immun. 2007;75:2415–20.CrossRefPubMedPubMedCentral
43.
Berger SS, Turner L, Wang CW, Petersen JE, Kraft M, Lusingu JP, et al. Plasmodium falciparum expressing domain cassette 5 type PfEMP1 (DC5-PfEMP1) bind PECAM1. PLoS One. 2013;8:e69117.CrossRefPubMedPubMedCentral
44.
Combes V, Taylor TE, Juhan-Vague I, Mege JL, Mwenechanya J, Tembo M, et al. Circulating endothelial microparticles in malawian children with severe falciparum malaria complicated with coma. JAMA. 2004;291:2542–4.PubMed
45.
Faille D, Combes V, Mitchell AJ, Fontaine A, Juhan-Vague I, Alessi MC, et al. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium. FASEB J. 2009;23:3449–58.CrossRefPubMed
46.
Heddini A, Chen Q, Obiero J, Kai O, Fernandez V, Marsh K, et al. Binding of Plasmodium falciparum-infected erythrocytes to soluble platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): frequent recognition by clinical isolates. Am J Trop Med Hyg. 2001;65:47–51.PubMed
47.
Karyana M, Burdarm L, Yeung S, Kenangalem E, Wariker N, Maristela R, et al. Malaria morbidity in Papua Indonesia, an area with multidrug resistant Plasmodium vivax and Plasmodium falciparum. Malar J. 2008;7:148.CrossRefPubMedPubMedCentral
48.
Yeo TW, Lampah DA, Kenangalem E, Tjitra E, Price RN, Anstey NM. Impaired skeletal muscle microvascular function and increased skeletal muscle oxygen consumption in severe falciparum malaria. J Infect Dis. 2013;207:528–36.CrossRefPubMedPubMedCentral
49.
Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg. 2001;65:309–17.PubMed
50.
51.
52.
Schulz MH, Zerbino DR, Vingron M, Birney E. Oases: robust de novo RNA-seq assembly across the dynamic range of expression levels. Bioinformatics. 2012;28:1086–92.CrossRefPubMedPubMedCentral
53.
54.
Cham GK, Kurtis J, Lusingu J, Theander TG, Jensen AT, Turner L. A semi-automated multiplex high-throughput assay for measuring IgG antibodies against Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) domains in small volumes of plasma. Malar J. 2008;7:108.CrossRefPubMedPubMedCentral
55.
Tsuboi T, Takeo S, Sawasaki T, Torii M, Endo Y. An efficient approach to the production of vaccines against the malaria parasite. Methods Mol Biol. 2010;607:73–83.CrossRefPubMed
56.
Tsuboi T, Takeo S, Iriko H, Jin L, Tsuchimochi M, Matsuda S, et al. Wheat germ cell-free system-based production of malaria proteins for discovery of novel vaccine candidates. Infect Immun. 2008;76:1702–8.CrossRefPubMedPubMedCentral
57.
Delucchi KL, Bostrom A. Methods for analysis of skewed data distributions in psychiatric clinical studies: working with many zero values. Am J Psychiatry. 2004;161:1159–68.CrossRefPubMed
58.
Robinson BA, Welch TL, Smith JD. Widespread functional specialization of Plasmodium falciparum erythrocyte membrane protein 1 family members to bind CD36 analysed across a parasite genome. Mol Microbiol. 2003;47:1265–78.CrossRefPubMed
59.
Duffy MF, Caragounis A, Noviyanti R, Kyriacou HM, Choong EK, Boysen K, et al. Transcribed var genes associated with placental malaria in Malawian women. Infect Immun. 2006;74:4875–83.CrossRefPubMedPubMedCentral
60.
Winter G, Chen Q, Flick K, Kremsner P, Fernandez V, Wahlgren M. The 3D7var5.2 (var COMMON) type var gene family is commonly expressed in non-placental Plasmodium falciparum malaria. Mol Biochem Parasitol. 2003;127:179–91.CrossRefPubMed
61.
Duffy MF, Brown GV, Basuki W, Krejany EO, Noviyanti R, Cowman AF, et al. Transcription of multiple var genes by individual, trophozoite-stage Plasmodium falciparum cells expressing a chondroitin sulphate A binding phenotype. Mol Microbiol. 2002;43:1285–93.CrossRefPubMed
62.
Kyes SA, Christodoulou Z, Raza A, Horrocks P, Pinches R, Rowe JA, et al. A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern. Mol Microbiol. 2003;48:1339–48.CrossRefPubMedPubMedCentral
63.
Janes JH, Wang CP, Levin-Edens E, Vigan-Womas I, Guillotte M, Melcher M, et al. Investigating the host binding signature on the Plasmodium falciparum PfEMP1 protein family. PLoS Pathog. 2011;7:e1002032.CrossRefPubMedPubMedCentral
64.
Bengtsson A, Joergensen L, Rask TS, Olsen RW, Andersen MA, Turner L, et al. A novel domain cassette identifies Plasmodium falciparum PfEMP1 proteins binding ICAM-1 and is a target of cross-reactive, adhesion-inhibitory antibodies. J Immunol. 2013;190:240–9.CrossRefPubMedPubMedCentral
65.
Montgomery J, Mphande FA, Berriman M, Pain A, Rogerson SJ, Taylor TE, et al. Differential var gene expression in the organs of patients dying of falciparum malaria. Mol Microbiol. 2007;65:959–67.CrossRefPubMedPubMedCentral
66.
Cham GK, Turner L, Kurtis JD, Mutabingwa T, Fried M, Jensen AT, et al. Hierarchical, domain type-specific acquisition of antibodies to Plasmodium falciparum erythrocyte membrane protein 1 in Tanzanian children. Infect Immun. 2010;78:4653–9.CrossRefPubMedPubMedCentral
Metadata
Title
Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria
Authors
Michael F. Duffy
Rintis Noviyanti
Takafumi Tsuboi
Zhi-Ping Feng
Leily Trianty
Boni F. Sebayang
Eizo Takashima
Fransisca Sumardy
Daniel A. Lampah
Louise Turner
Thomas Lavstsen
Freya J. I. Fowkes
Peter Siba
Stephen J. Rogerson
Thor G. Theander
Jutta Marfurt
Ric N. Price
Nicholas M. Anstey
Graham V. Brown
Anthony T. Papenfuss
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2016
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-016-1296-4

Other articles of this Issue 1/2016

Malaria Journal 1/2016 Go to the issue

Research

Monitoring iCCM referral systems: Bugoye Integrated Community Case Management Initiative (BIMI) in Uganda

Research

Global genetic diversity of the Plasmodium vivax transmission-blocking vaccine candidate Pvs48/45

Research

Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine combinations in the treatment of uncomplicated malaria in two ecological zones in Ghana

Research

Frequent blood feeding enables insecticide-treated nets to reduce transmission by mosquitoes that bite predominately outdoors

Research

Development of a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine and artemether-lumefantrine to treat Plasmodium falciparum infections in Swaziland: a pilot study

Research

Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits