Investigating the Host Binding Signature on the PfEMP1 Protein Family
The Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1) family plays a central role in antigenic variation and cytoadhesion of
P. falciparum infected erythrocytes. PfEMP1
proteins/var genes are classified into three main
subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles
in binding and disease. To investigate whether these subfamilies have diverged
in binding specificity and test if binding could be predicted by adhesion domain
classification, we generated a panel of 19 parasite lines that primarily
expressed a single dominant var transcript and assayed binding
against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC
var genes were isolated, indicating that UpsA
var gene expression is rare under in vitro
culture conditions. Consequently, three UpsA variants were obtained by rosette
purification and selection with specific monoclonal antibodies to create a more
representative panel. Binding assays showed that CD36 was the most common
adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that
CD36 and ICAM-1 binding variants were highly predicted by adhesion domain
sequence classification. Binding to other host receptors, including CSA, VCAM-1,
HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor “X”, and
Fractalkine, was rare or absent. Our findings identify a category of larger
PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They
also support that the UpsA group, in contrast to UpsB and UpsC
var genes, has diverged from binding to the major
microvasculature receptor CD36 and likely uses other mechanisms to sequester in
the microvasculature. These results demonstrate that CD36 and ICAM-1 have left
strong signatures of selection on the PfEMP1 family that can be detected by
adhesion domain sequence classification and have implications for how this
family of proteins is specializing to exploit hosts with varying levels of
anti-malaria immunity.
Vyšlo v časopise:
Investigating the Host Binding Signature on the PfEMP1 Protein Family. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002032
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002032
Souhrn
The Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1) family plays a central role in antigenic variation and cytoadhesion of
P. falciparum infected erythrocytes. PfEMP1
proteins/var genes are classified into three main
subfamilies (UpsA, UpsB, and UpsC) that are hypothesized to have different roles
in binding and disease. To investigate whether these subfamilies have diverged
in binding specificity and test if binding could be predicted by adhesion domain
classification, we generated a panel of 19 parasite lines that primarily
expressed a single dominant var transcript and assayed binding
against 12 known host receptors. By limited dilution cloning, only UpsB and UpsC
var genes were isolated, indicating that UpsA
var gene expression is rare under in vitro
culture conditions. Consequently, three UpsA variants were obtained by rosette
purification and selection with specific monoclonal antibodies to create a more
representative panel. Binding assays showed that CD36 was the most common
adhesion partner of the parasite panel, followed by ICAM-1 and TSP-1, and that
CD36 and ICAM-1 binding variants were highly predicted by adhesion domain
sequence classification. Binding to other host receptors, including CSA, VCAM-1,
HABP1, CD31/PECAM, E-selectin, Endoglin, CHO receptor “X”, and
Fractalkine, was rare or absent. Our findings identify a category of larger
PfEMP1 proteins that are under dual selection for ICAM-1 and CD36 binding. They
also support that the UpsA group, in contrast to UpsB and UpsC
var genes, has diverged from binding to the major
microvasculature receptor CD36 and likely uses other mechanisms to sequester in
the microvasculature. These results demonstrate that CD36 and ICAM-1 have left
strong signatures of selection on the PfEMP1 family that can be detected by
adhesion domain sequence classification and have implications for how this
family of proteins is specializing to exploit hosts with varying levels of
anti-malaria immunity.
Zdroje
1. KraemerSMSmithJD
2006
A family affair: var genes, PfEMP1 binding, and malaria
disease.
Curr Opin Micro
9
374
380
2. MillerLHBaruchDIMarshKDoumboOK
2002
The pathogenic basis of malaria.
Nature
415
673
679
3. FrankMDeitschK
2006
Activation, silencing and mutually exclusive expression within
the var gene family of Plasmodium falciparum.
Int J Parasitol
36
975
985
4. GardnerMJHallNFungEWhiteOBerrimanM
2002
Genome sequence of the human malaria parasite Plasmodium
falciparum.
Nature
419
498
511
5. BiggsBAAndersRFDillonHEDavernKMMartinM
1992
Adherence of infected erythrocytes to venular endothelium selects
for antigenic variants of Plasmodium falciparum.
J Immunol
149
2047
2054
6. RobertsDJCraigAGBerendtARPinchesRNashG
1992
Rapid switching to multiple antigenic and adhesive phenotypes in
malaria.
Nature
357
689
92
7. SmithJDChitnisCECraigAGRobertsDJHudson-TaylorDE
1995
Switches in expression of Plasmodium falciparum var genes
correlate with changes in antigenic and cytoadherent phenotypes of infected
erythrocytes.
Cell
82
101
110
8. Freitas-JuniorLHBottiusEPirritLADeitschKWScheidigC
2000
Frequent ectopic recombination of virulence factor genes in
telomeric chromosome clusters of P. falciparum.
Nature
407
1018
22
9. KraemerSMKyesSAAggarwalGSpringerALNelsonSO
2007
Patterns of gene recombination shape var gene repertoires in
Plasmodium falciparum: comparisons of geographically diverse
isolates.
BMC Genomics
8
45
10. RaskTSHansenDATheanderTGGormPALavstsenT
2010
Plasmodium falciparum Erythrocyte Membrane Protein 1 Diversity in
Seven Genomes - Divide and Conquer.
PLoS Comput Biol
6
e1000933
11. LavstsenTSalantiAJensenATArnotDETheanderTG
2003
Sub-grouping of Plasmodium falciparum 3D7 var genes based on
sequence analysis of coding and non-coding regions.
Malar J
2
27
12. KraemerSMSmithJD
2003
Evidence for the importance of genetic structuring to the
structural and functional specialization of the Plasmodium falciparum var
gene family.
Mol Microbiol
50
1527
38
13. RoweJAKyesSARogersonSJBabikerHARazaA
2002
Identification of a conserved Plasmodium falciparum var gene
implicated in malaria in pregnancy.
J Infect Dis
185
1207
11
14. SalantiAStaalsoeTLavstsenTJensenATSowaMP
2003
Selective upregulation of a single distinctly structured var gene
in chondroitin sulphate A-adhering Plasmodium falciparum involved in
pregnancy-associated malaria.
Mol Microbiol
49
179
91
15. TrimnellARKraemerSMMukherjeeSPhippardDJJanesJH
2006
Global genetic diversity and evolution of var genes associated
with placental and severe childhood malaria.
Mol Biochem Parasitol
148
169
180
16. HoMSinghBLooareesuwanSDavisTMBunnagD
1991
Clinical correlates of in vitro Plasmodium falciparum
cytoadherence.
Infect Immun
59
873
878
17. NewboldCWarnPBlackGBerendtACraigA
1997
Receptor-specific adhesion and clinical disease in Plasmodium
falciparum.
Am J Trop Med Hyg
57
389
98
18. OckenhouseCFHoMTandonNNVan SeventerGAShawS
1991
Molecular basis of sequestration in severe and uncomplicated
Plasmodium falciparum malaria: differential adhesion of infected
erythrocytes to CD36 and ICAM-1.
J Infect Dis
164
163
9
19. RogersonSJTembenuRDobanoCPlittSTaylorTE
1999
Cytoadherence characteristics of Plasmodium falciparum-infected
erythrocytes from Malawian children with severe and uncomplicated
malaria.
Am J Trop Med Hyg
61
467
72
20. RoweJClaessensACorriganRArmanM
2010
Adhesion of Plasmodium falciparum-infected erythrocytes to human
cells: molecular mechanisms and therapeutic implications.
Expert Rev Mol Med
11
e16
21. CookeBMBerendtARCraigAGMacGregorJNewboldCI
1994
Rolling and stationary cytoadhesion of red blood cells
parasitized by Plasmodium falciparum: separate roles for ICAM-1, CD36 and
thrombospondin.
Br J Haematol
87
162
70
22. GrayCMcCormickCTurnerGCraigA
2003
ICAM-1 can play a major role in mediating P. falciparum adhesion
to endothelium under flow.
Mol Biochem Parasitol
128
187
193
23. HoMHickeyMJMurrayAGAndoneguiGKubesP
2000
Visualization of Plasmodium falciparum-endothelium interactions
in human microvasculature: mimicry of leukocyte recruitment.
J Exp Med
192
1205
1211
24. TurnerGDMorrisonHJonesMDavisTMLooareesuwanS
1994
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
145
1057
69
25. FryAEAuburnSDiakiteMGreenARichardsonA
2008
Variation in the ICAM1 gene is not associated with severe malaria
phenotypes.
Genes Immun
9
462
469
26. CarlsonJHelmbyHHillAVBrewsterDGreenwoodBM
1990
Human cerebral malaria: association with erythrocyte rosetting
and lack of anti-rosetting antibodies.
Lancet
336
1457
60
27. RoweAObeiroJNewboldCIMarshK
1995
Plasmodium falciparum rosetting is associated with malaria
severity in Kenya.
Infect Immun
63
2323
6
28. TreutigerCJHedlundIHelmbyHCarlsonJJepsonA
1992
Rosette formation in Plasmodium falciparum isolates and
anti-rosette activity of sera from Gambians with cerebral or uncomplicated
malaria.
Am J Trop Med Hyg
46
503
510
29. FriedMDuffyPE
1996
Adherence of Plasmodium falciparum to chondroitin sulfate A in
the human placenta.
Science
272
1502
4
30. GuptaSSnowRWDonnellyCAMarshKNewboldC
1999
Immunity to non-cerebral severe malaria is acquired after one or
two infections.
Nat Med
5
340
3
31. MarshKSnowRW
1997
Host-parasite interaction and morbidity in malaria endemic
areas.
Philos Trans R Soc Lond B Biol Sci
352
1385
1394
32. BullPCLoweBSKortokMMarshK
1999
Antibody recognition of Plasmodium falciparum erythrocyte surface
antigens in Kenya: evidence for rare and prevalent variants.
Infect Immun
67
733
9
33. BullPCKortokMKaiONdunguFRossA
2000
Plasmodium falciparum-infected erythrocytes: agglutination by
diverse Kenyan plasma is associated with severe disease and young host
age.
J Infect Dis
182
252
9
34. NielsenMAStaalsoeTKurtzhalsJAGokaBQDodooD
2002
Plasmodium falciparum variant surface antigen expression varies
between isolates causing severe and nonsevere malaria and is modified by
acquired immunity.
J Immunol
168
3444
50
35. ChamGKTurnerLLusinguJVestergaardLMmbandoBP
2009
Sequential, ordered acquisition of antibodies to Plasmodium
falciparum erythrocyte membrane protein 1 domains.
J Immunol
183
3356
3363
36. ChamGKTurnerLKurtisJDMutabingwaTFriedM
2010
Hierarchical, domain type-specific acquisition of antibodies to
Plasmodium falciparum erythrocyte membrane protein 1 in Tanzanian
children.
Infect Immun
78
4653
4659
37. JensenATMagistradoPSharpSJoergensenLLavstsenT
2004
Plasmodium falciparum associated with severe childhood malaria
preferentially expresses PfEMP1 encoded by group A var
genes.
J Exp Med
199
1179
90
38. KyriacouHMStoneGNChallisRJRazaALykeKE
2006
Differential var gene transcription in Plasmodium falciparum
isolates from patients with cerebral malaria compared to
hyperparasitaemia.
Mol Biochem Parasitol
150
211
218
39. WarimweGMKeaneTMFeganGMusyokiJNNewtonCR
2009
Plasmodium falciparum var gene expression is modified by host
immunity.
Proc Natl Acad Sci U S A
106
21801
21806
40. SmithJDSubramanianGGamainBBaruchDIMillerLH
2000
Classification of adhesive domains in the Plasmodium falciparum
erythrocyte membrane protein 1 family.
Mol Biochem Parasitol
110
293
310
41. BaruchDIPasloskeBLSinghHBBiXMaXC
1995
Cloning the P. falciparum gene encoding PfEMP1, a malarial
variant antigen and adherence receptor on the surface of parasitized human
erythrocytes.
Cell
82
77
87
42. SuXZHeatwoleVMWertheimerSPGuinetFHerrfeldtJA
1995
The large diverse gene family var encodes proteins involved in
cytoadherence and antigenic variation of Plasmodium falciparum-infected
erythrocytes.
Cell
82
89
100
43. SmithJDGamainBBaruchDIKyesS
2001
Decoding the language of var genes and Plasmodium falciparum
sequestration.
Trends Parasitol
17
538
45
44. HowellDPLevinEASpringerALKraemerSMPhippardDJ
2008
Mapping a common interaction site used by Plasmodium falciparum
Duffy binding-like domains to bind diverse host receptors.
Mol Microbiol
67
78
87
45. OleinikovAVAmosEFryeITRossnagleEMutabingwaTK
2009
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
5
e1000386
46. RobinsonBAWelchTLSmithJD
2003
Widespread functional specialization of Plasmodium falciparum
erythrocyte membrane protein 1 family members to bind CD36 analysed across a
parasite genome.
Mol Microbiol
47
1265
78
47. JoergensenLBengtssonDCBengtssonARonanderEBergerSS
2010
Surface co-expression of two different PfEMP1 antigens on single
Plasmodium falciparum-infected erythrocytes facilitates binding to ICAM1 and
PECAM1.
PLoS Pathog
6
e1001083
48. GamainBGratepancheSMillerLHBaruchDI
2002
Molecular basis for the dichotomy in Plasmodium falciparum
adhesion to CD36 and chondroitin sulfate A.
Proc Natl Acad Sci U S A
99
10020
10024
49. DahlbackMNielsenMASalantiA
2010
Can any lessons be learned from the ambiguous glycan binding of
PfEMP1 domains?
Trends Parasitol
26
230
235
50. BourkePFHoltDCSutherlandCJKempDJ
1996
Disruption of a novel open reading frame of Plasmodium falciparum
chromosome 9 by subtelomeric and internal deletions can lead to loss or
maintenance of cytoadherence.
Mol Biochem Parasitol
82
25
36
51. UdeinyaIJGravesPMCarterRAikawaMMillerLH
1983
Plasmodium falciparum: effect of time in continuous culture on
binding to human endothelial cells and amelanotic melanoma
cells.
Exp Parasitol
56
207
214
52. HorrocksPPinchesRChristodoulouZKyesSANewboldCI
2004
Variable var transition rates underlie antigenic variation in
malaria.
Proc Natl Acad Sci U S A
101
11129
34
53. Vigan-WomasIGuillotteMJuilleratAVallieresCLewit-BentleyA
2011
Allelic diversity of the Plasmodium falciparum erythrocyte
membrane protein 1 entails variant-specific red cell surface
epitopes.
PLoS One
6
e16544
54. CrabbBSCookeBMReederJCWallerRFCaruanaSR
1997
Targeted gene disruption shows that knobs enable malaria-infected
red cells to cytoadhere under physiological shear stress.
Cell
89
287
296
55. RugMPrescottSWFernandezKMCookeBMCowmanAF
2006
The role of KAHRP domains in knob formation and cytoadherence of
P falciparum-infected human erythrocytes.
Blood
108
370
378
56. McCormickCJNewboldCIBerendtAR
2000
Sulfated glycoconjugates enhance CD36-dependent adhesion of
Plasmodium falciparum-infected erythrocytes to human microvascular
endothelial cells.
Blood
96
327
333
57. GardnerJPPinchesRARobertsDJNewboldCI
1996
Variant antigens and endothelial receptor adhesion in Plasmodium
falciparum.
Proc Natl Acad Sci U S A
93
3503
8
58. SmithJDCraigAGKriekNHudson-TaylorDKyesS
2000
Identification of a Plasmodium falciparum intercellular adhesion
molecule-1 binding domain: a parasite adhesion trait implicated in cerebral
malaria.
Proc Natl Acad Sci U S A
97
1766
71
59. ChattopadhyayRTanejaTChakrabartiKPillaiCRChitnisCE
2004
Molecular analysis of the cytoadherence phenotype of a Plasmodium
falciparum field isolate that binds intercellular adhesion
molecule-1.
Mol Biochem Parasitol
133
255
65
60. DuffyMFMaierAGByrneTJMartyAJElliottSR
2006
VAR2CSA is the principal ligand for chondroitin sulfate A in two
allogeneic isolates of Plasmodium falciparum.
Mol Biochem Parasitol
148
117
124
61. ViebigNKGamainBScheidigCLepolardCPrzyborskiJ
2005
A single member of the Plasmodium falciparum var multigene family
determines cytoadhesion to the placental receptor chondroitin sulphate
A.
EMBO Rep
6
775
781
62. SmithJDDeitschKW
2004
Pregnancy-associated malaria and the prospects for
syndrome-specific antimalaria vaccines.
J Exp Med
200
1093
7
63. MagistradoPSalantiATuikue NdamNGMwakalingaSBResendeM
2008
VAR2CSA expression on the surface of placenta-derived Plasmodium
falciparum-infected erythrocytes.
J Infect Dis
198
1071
1074
64. PetersJMFowlerEVKrauseDRChengQGattonML
2007
Differential Changes in Plasmodium falciparum var Transcription
during Adaptation to Culture.
The J Infect Dis
195
748
755
65. FrankMDzikowskiRAmulicBDeitschK
2007
Variable switching rates of malaria virulence genes are
associated with chromosomal position.
Mol Microbiol
64
1486
1498
66. BaruchDIMaXCSinghHBBiXPasloskeBL
1997
Identification of a region of PfEMP1 that mediates adherence of
Plasmodium falciparum infected erythrocytes to CD36: conserved function with
variant sequence.
Blood
90
3766
75
67. CrandallILandKMShermanIW
1994
Plasmodium falciparum: pfalhesin and CD36 form an
adhesin/receptor pair that is responsible for the pH-dependent portion of
cytoadherence/sequestration.
Exp Parasitol
78
203
9
68. OckenhouseCFKlotzFWTandonNNJamiesonGA
1991
Sequestrin, a CD36 recognition protein on Plasmodium falciparum
malaria- infected erythrocytes identified by anti-idiotype
antibodies.
Proc Natl Acad Sci U S A
88
3175
9
69. HandunnettiSMvan SchravendijkMRHaslerTBarnwellJWGreenwaltDEHowardRJ
1992
Involvement of CD36 on erythrocytes as a rosetting receptor for
Plasmodium falciparum-infected erythrocytes.
Blood
80
2097
104
70. MagistradoPAStaalsoeTTheanderTGHviidLJensenAT
2008
CD36 selection of 3D7 Plasmodium falciparum associated with
severe childhood malaria results in reduced VAR4 expression.
Malar J
7
204
71. HBehrCMercereau-PuijalonOMichelJ
2000
Plasmodium falciparum in the squirrel monkey (Saimiri sciureus):
infection of non-splenectomised animals as a model for exploring clinical
manifestations of malaria.
Microbes Infect
2
945
954
72. KaulDKRothEFJrNagelRLHowardRJHandunnettiSM
1991
Rosetting of Plasmodium falciparum-infected red blood cells with
uninfected red blood cells enhances microvascular obstruction under flow
conditions.
Blood
78
812
819
73. SpringerALSmithLMMackayDQNelsonSOSmithJD
2004
Functional interdependence of the DBLbeta domain and c2 region
for binding of the Plasmodium falciparum variant antigen to
ICAM-1.
Mol Biochem Parasitol
137
55
64
74. UrbanBCFergusonDJPainAWillcoxNPlebanskiM
1999
Plasmodium falciparum-infected erythrocytes modulate the
maturation of dendritic cells.
Nature
400
73
7
75. UrbanBCRobertsDJ
2002
Malaria, monocytes, macrophages and myeloid dendritic cells:
sticking of infected erythrocytes switches off host cells.
Curr Opin Immunol
14
458
465
76. MelcherMMuhleRAHenrichPPKraemerSMAvrilM
2010
Identification of a role for the PfEMP1 semi-conserved head
structure in protein trafficking to the surface of Plasmodium falciparum
infected red blood cells.
Cell Microbiol
12
1446
62
77. PatelSNLuZAyiKSerghidesLGowdaDC
2007
Disruption of CD36 impairs cytokine response to Plasmodium
falciparum glycosylphosphatidylinositol and confers susceptibility to severe
and fatal malaria in vivo.
J Immunol
178
3954
3961
78. SerghidesLSmithTGPatelSNKainKC
2003
CD36 and malaria: friends or foes?
Trends Parasitol
19
461
469
79. KalmbachYRottmannMKombilaMKremsnerPGBeckHP
2010
Differential var gene expression in children with malaria and
antidromic effects on host gene expression.
J Infect Dis
202
313
317
80. KirchgatterKPortillo HdelA
2002
Association of severe noncerebral Plasmodium falciparum malaria
in Brazil with expressed PfEMP1 DBL1 alpha sequences lacking cysteine
residues.
Mol Med
8
16
23
81. RottmannMLavstsenTMugasaJPKaestliMJensenATR
2006
Differential Expression of var Gene Groups Is Associated with
Morbidity Caused by Plasmodium falciparum Infection in Tanzanian
Children.
Infect Immun
74
3904
3911
82. Vigan-WomasIGuillotteMLeSCIgonetSPetresS
2008
An in vivo and in vitro model of Plasmodium falciparum rosetting
and autoagglutination mediated by varO, a group A var gene encoding a
frequent serotype.
Infect Immun
76
5565
5580
83. RoweJAMouldsJMNewboldCIMillerLH
1997
P. falciparum rosetting mediated by a parasite-variant
erythrocyte membrane protein and complement-receptor 1.
Nature
388
292
5
84. ReederJCCowmanAFDavernKMBeesonJGThompsonJK
1999
The adhesion of Plasmodium falciparum-infected erythrocytes to
chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane
protein 1.
Proc Natl Acad Sci U S A
96
5198
202
85. BuffetPAGamainBScheidigCBaruchDSmithJD
1999
Plasmodium falciparum domain mediating adhesion to chondroitin
sulfate A: a receptor for human placental infection.
Proc Natl Acad Sci U S A
96
12743
8
86. ViebigNKLevinEDechavanneSRogersonSJGysinJ
2007
Disruption of var2csa gene impairs placental malaria associated
adhesion phenotype.
PLoS One
2
e910
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