`h #P#` @@@ @@@@]6NlyVDr#@#p EN DB #- 5 1 i [< Q  z L r v(-6Jamieson19919'ff"33#$%&'ff(33)*+,̙-ff.33/0̙1̙2̙3̙ff4̙335̙6ff7ff8ff9ffff:ff33;ff<33=33>33?33ff@3333A33BCDEffF33GHIJKffL33MNOP̙QffR33STUVWffX33YZff[ff\ff]ffff^ff33_ff`33a33b33c33ffd3333e33fghiffj33klffmffnffoffffpff33qffrffsfftff̙uffffvff33wffxffyffzff{ffff|ff33}ff~ffffffffffffffffffffff33ffffff33ff33ff33ff33ffff3333ff33ffffffffffff33ff33333333ff333333333333̙33ff3333333333^ Jarra19992 Jensen19838 Kemp198919 Kemp19899L Khalil19988$ Klotz1991 Knowles1985N Koch19989O Kortok1998iE Kortok19999GKremsner1998J Kubes1998e Kyes19977  Lallinger1990Langreth19850g Lanzer19977b Lanzer19989. Lawler19909& Leech1982 Leech1984 Leech19843 Leech19857 Leech19906 Leech1991J Looareesuwan1998O Lowe1998.E Lowe19999 Lyon19868 Lyon19888[ Ma19959W Ma1996R Ma19971A Magowan1994 Maloy1988( Marsh1985 Marsh1986 Marsh1986  Marsh1986! Marsh1986) Marsh1986+ Marsh1987" Marsh1989, Marsh1989e Marsh1997O Marsh1998E Marsh1999] Martin19929 McBride1986Z McCulloch19952McGregor19839N McKay19980 Miller19811& Miller19828 Miller19838 Miller198381 Miller198332 Miller19833 Miller19849 Miller198483 Miller19855+ Miller19879, Miller19899. Miller19909f Miller19977OMolyneux1998.Morehead19900f Moulds1997N N'Jie1998 Nachman1989K Nash1998Neequaye19880e Newbold1997f Newbold1997O Newbold1998 Ng1989rF Nicoll19989J Niu1998Y Nowak1995 Ockenhouse1985# Ockenhouse19880$ Ockenhouse19910% Ockenhouse19910 Ofori1988N Olaleye1998 Oligino1982 Oligino1983" Otoo19899Pasloske19900\Pasloske19949[Pasloske19959WPasloske1996@RPasloske1997J Patel19985Perlmann1989e Peshu1997]Petersen19929hPeterson19955/ Philip19899< Piper1999D Piper1999aPouvelle1998bPouvelle1998a^ Preiser1999g Preuss19979* Quakyi19869h Ravetch1995V Reeder1997(C Reeder1999 Reese1985) Roberts1986+ Roberts1987, Roberts1989. Roberts1990< Roberts1999 Rock19881CRogerson1999f Rowe1997Z Rudenko1995Q Sahlen1998l Saul19888b Scherf1998(Q Schlichtherle1998c Schlichtherle19980 Schmidt1981& Schmidt1982J Schollaardt1998 Semoff19883B Sharma1991? Sharma1997% Shaw19919' Sherman1989Sherwood1984n(Sherwood19859Sherwood1986n!Sherwood19860)Sherwood19869*Sherwood19866+Sherwood19876,Sherwood19897-Sherwood19909.Sherwood19909[ Singh1995R Singh1997/ Smith1989^ Snounou1999e Snow19979/ Southwell19896 Southwell1991) Spitalnik1986* Spitalnik1986+ Spitalnik1987, Spitalnik1989. Spitalnik1990L Staalso1998 Stanley1985h Su19951Q Sundstrom1998c Sundstrom1998$ Tandon19911% Tandon19911[Taraschi19959P Targett1998 Taylor19866LTheander19988CThompson1999D Tiwari19999K Treutiger1998@ Turner19970 Udeinya1981& Udeinya19821 Udeinya19832 Udeinya19833 Udeinya19854 Udeinya19905 Udomsangpetch1989 Uni1986' Valdez19899 Van1990 Van1990% Van1991Z Van Leeuwen19955Wahlgren1989GWahlgren1998KWahlgren19988QWahlgren1998cWahlgren1998V Waller1997(% Webster1991G Weiss1998h Wellems1995h Wertheimer1995 % White1991V Wickham1997g Wiesner19977 Wilkinson19906 Wollish1991g Wunsch199777 Wycherley19906 Wycherley1991 Yamaya19899N Zhang1998LZijlstra19988LZijlstra199881998LZijlstra19988LZijlstra19988Zijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988Zijlstra19988Zijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988LZijlstra19988Zijlstra19988Zijlstra19988Zijlstra19988Zijlstra19988Zijlstra19988LZijlstra19988LZijlstra199881998LZijlstra19988LZijlstra19988LZijlstra19988 Lowe1998.E Lowe19999 Lyon19868 Lyon19888[ Ma19959W Ma1996R Ma19971A Magowan1994 Maloy1988( Marsh1985 Marsh1986 Marsh1986  Marsh1986! Marsh1986) Marsh1986+ Marsh1987" Marsh1989, Marsh1989S Marsh1997O Marsh1998E Marsh1999] Martin19929 McBride1986Z McCulloch19952McGregor19839N McKay19980 Miller19811& Miller19828 Miller19838 Miller198381 Miller198332 Miller19833 Miller19849 Miller198483 Miller19855+ Miller19879, Miller19899. Miller19909T Miller19977OMolyneux1998.Morehead19900T Moulds1997(N N'Jie1998 Nachman1989K Nash1998Neequaye19880S Newbold1997T Newbold1997O Newbold1998 Ng1989r= Nicoll1998nF Nicoll19989J Niu1998Y Nowak1995 Ockenhouse1985# Ockenhouse19880$ Ockenhouse19910% Ockenhouse19910 Ofori1988N Olaleye1998 Oligino1982 Oligino1983" Otoo19899Pasloske19900\Pasloske19949[Pasloske19959WPasloske1996@RPasloske1997J Patel19985Perlmann1989S Peshu1997]Petersen19929/ Philip19899< Piper1999D Piper1999_ Piper1999aPouvelle1998bPouvelle1998a^ Preiser1999U Preuss19979* Quakyi19869V Reeder1997(C Reeder1999 Reese1985) Roberts1986+ Roberts1987, Roberts1989. Roberts1990< Roberts1999 Rock19881CRogerson1999T Rowe1997Z Rudenko1995Q Sahlen1998l Saul19888b Scherf1998(> Schlichtherle1998H Schlichtherle1998Q Schlichtherle19980 Schmidt1981& Schmidt1982J Schollaardt1998 Semoff19883B Sharma1991? Sharma1997% Shaw19919' Sherman1989Sherwood1984n(Sherwood19859Sherwood1986n!Sherwood19860)Sherwood19869*Sherwood19866+Sherwood19876,Sherwood19897-Sherwood19909.Sherwood19909[ Singh1995R Singh1997/ Smith1989^ Snounou1999S Snow19979/ Southwell19896 Southwell1991) Spitalnik1986* Spitalnik1986+ Spitalnik1987, Spitalnik1989. Spitalnik1990L Staalso1998 Stanley1985> Sundstrom1998H Sundstrom1998Q Sundstrom1998$ Tandon19911% Tandon19911[Taraschi19959P Targett1998 Taylor19866LTheander19988CThompson1999D Tiwari19999_ Tiwari19999K Treutiger1998@ Turner19970 Udeinya1981& Udeinya19821 Udeinya19832 Udeinya19833 Udeinya19854 Udeinya19905 Udomsangpetch1989 Uni1986' Valdez19899 Van1990 Van1990% Van1991Z Van Leeuwen19955Wahlgren1989>Wahlgren1998GWahlgren1998HWahlgren1998KWahlgren19988QWahlgren1998V Waller1997(% Webster1991G Weiss1998% White1991V Wickham1997U Wiesner19977 Wilkinson19906 Wollish1991U Wunsch199777 Wycherley19906 Wycherley1991 Yamaya19899N Zhang1998LZijlstra19988N^Nu    gNZN;nNbN?. /.N\`ZHm/. mNP=@JnmFNJnf,Jn g mp(n f/- nNX@J.fBgNTNJgNZN^NuNV/ np=@ n pnd n p=@p@@p=@`.0nP0n PHnHnNPJ@fRn0.no0.S@.N^NuNV/ =n` 0.HA0.HC"Qp)@H@B@H@А2.HA2.HC"Qr2ҐPd0.HA0.HC0.HE$Rp*@H@B@H@БP Sn`0?.NT        F. S.%> Ph, J. C. Wall%R. F. Caruana, S. R. Davern, K. M. Wickham, M. E. Brown, G. V. Coppel, R. L. Cowman, A. F.h> hCowman, A. F> >hPrefe> es...0?per Boomeran`&f```N Px{;`MainAbout Now Super Boomerang...&f```N  mPOpenq ;PMHiddeno0PCancelT9M[qWhPEjecto4pPDriveT9 9TT99000126<6Cooke, B. M. Nicoll, C. L. Baruch, D. I. Coppel, R. L.zA recombinant peptide based on PfEMP-1 blocks and reverses adhesion of malaria-infected red blood cells to CD36 under flowAnimal Antigens, CD36/*metabolism Cell Adhesion Chondroitin Sulfates/metabolism Dose-Response Relationship, Drug Endothelium, Vascular/metabolism Erythrocytes/*physiology/*parasitology Hemorheology Human Peptide Fragments/metabolism Plasmodium falciparum/*physiology Protozoan Proteins/*metabolism Recombinant Proteins/metabolism Species Specificity Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.hbDuring falciparum malaria infection, severe complications ensue because parasitized red blood cells (PRBCs) adhere to endothelial cells and accumulate in the microvasculature. At the molecular level, adhesion is mediated by interaction of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) on the PRBC surface with receptors on the surface of endothelial cells, including CD36. We have shown that a recombinant 179-residue subfragment of PfEMP-1 (rC1-2[1-179]), which encompasses the CD36-binding region, inhibits and reverses adhesion of PRBCs to CD36 under physiologically relevant flow conditions. rC1-2[1-179] inhibited adhesion in a concentration-dependent manner over the range 100 pM to 2 microM, with up to 99% of adhesion blocked at the highest concentration tested. The antiadhesive activity of rC1-2[1-179] was not strain specific and almost totally ablated adhesion of four different parasite lines. Furthermore, rC1-2[1-179] showed remarkable ability to progressively reverse adhesion when flowed over adherent PRBCs for 2h. The effect of rC1-2[1-179] was, however, specific for CD36-mediated adhesion and had no effect on adhesion mediated by CSA. Interference with binding of PRBCs to the vascular endothelium using rC1-2[1-179] or smaller organic mimetics may be a useful therapeutic approach to ameliorate severe complications of falciparum malaria. Mol Microbiol 1998301 83-90lcQ f_http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.jem.org/cgi/content/full/187/1/1598080592xqChen, Q. Barragan, A. Fernandez, V. Sundstrom, A. Schlichtherle, M. Sahlen, A. Carlson, J. Datta, S. Wahlgren, M.Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparumHZTAmino Acid Sequence Animal Base Sequence Binding Sites Blood Proteins/genetics/*physiology Cloning, Molecular DNA Primers/genetics DNA, Complementary/genetics Erythrocyte Membrane/*parasitology Glycosaminoglycans/metabolism Heparitin Sulfate/metabolism Human In Vitro Ligands Malaria, Falciparum/blood/parasitology Membrane Proteins/genetics/*physiology Molecular Sequence Data Plasmodium falciparum/genetics/*physiology/*pathogenicity Polymerase Chain Reaction Protein Binding Protozoan Proteins/genetics/*physiology Recombinant Fusion Proteins/genetics Rosette Formation Support, Non-U.S. Gov'tSevere Plasmodium falciparum malaria is characterized by excessive sequestration of infected and uninfected erythrocytes in the microvasculature of the affected organ. Rosetting, the adhesion of P. falciparum-infected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting PfEMP1 contains clusters of glycosaminoglycan-binding motifs. A recombinant fusion protein (Duffy binding-like 1-glutathione S transferase; Duffy binding- like-1-GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed rosettes, block rosette reformation, and bind to a heparin-Sepharose matrix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the rosetting ligand and heparan sulfate, or a heparan sulfate-like molecule, the receptor both for PfEMP1 binding and naturally formed erythrocyte rosettes. J Exp Med 1998 187 1  15-23e98352787`YChen, Q. Fernandez, V. Sundstrom, A. Schlichtherle, M. Datta, S. Hagblom, P. Wahlgren, M.TNGDevelopmental selection of var gene expression in Plasmodium falciparummAdult Amino Acid Sequence Animal Antigenic Variation/genetics/immunology Antigens, Protozoan/genetics/immunology Cloning, Molecular Erythrocytes/parasitology *Gene Expression Regulation, Developmental *Genes, Protozoan Human Malaria/immunology/parasitology Molecular Sequence Data Plasmodium falciparum/growth & development/*genetics/immunology Protozoan Proteins/*genetics Support, Non-U.S. Gov't/The protozoan Plasmodium falciparum causes lethal malaria. Adhesion of erythrocytes infected with P. falciparum to vascular endothelium and to uninfected red blood cells (rosetting) may be involved in the pathogenesis of severe malaria. The binding is mediated by the antigenically variant erythrocyte-membrane-protein-1 (PfEMP-1), which is encoded by members of the P. falciparum var gene family. The control of expression and switching of var genes seems to lack resemblance to mechanisms operating in variant gene families of other microbial pathogens. Here we show that multiple, distinct var gene transcripts (about 24 or more) can be detected by reverse transcription and polymerase chain reaction in bulk cultures of the rosetting parasite FCR3S1.2, despite the adhesive homogeneity of the cultures. We also detected several var transcripts in single erythrocytes infected with a ring-stage parasite of FCR3S1.2, and found that different var genes are transcribed simultaneously from several chromosomes in the same cell. In contrast, we detected only one var transcript, FCR3S1.2 var-1, which encodes the rosetting PfEMP-1 protein, in individual rosette-adhesive trophozoite-infected cells, and we found only one PfEMP-1 type at the erythrocyte surface by labelling with 125iodine and immunoprecipitation. We conclude that a single P. falciparum parasite simultaneously transcribes multiple var genes but, through a developmentally regulated process, selects only one PfEMP-1 to reach the surface of the host cell. Nature 1998 394o 6691 392-50O`98160250RKBull, P. C. Lowe, B. S. Kortok, M. Molyneux, C. S. Newbold, C. I. Marsh, K.epiParasite antigens on the infected red cell surface are targets for naturally acquired immunity to malariaAge Factors Agglutination Tests Antibodies, Protozoan/blood Antibody Specificity Antigenic Variation/*immunology Antigens, Protozoan/*immunology Blood Proteins/*immunology Child Child, Preschool Cross-Sectional Studies Erythrocytes/*parasitology Human Infant Kenya/epidemiology Malaria, Falciparum/epidemiology/*immunology Odds Ratio Population Surveillance Prospective Studies Protozoan Proteins/*immunology Support, Non-U.S. Gov'tThe feasibility of a malaria vaccine is supported by the fact that children in endemic areas develop naturally acquired immunity to disease. Development of disease immunity is characterized by a decrease in the frequency and severity of disease episodes over several years despite almost continuous infection, suggesting that immunity may develop through the acquisition of a repertoire of specific, protective antibodies directed against polymorphic target antigens. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of target antigens, because these proteins are inserted into the red cell surface and are prominently exposed and because they are highly polymorphic and undergo clonal antigenic variation, a mechanism of immune evasion maintained by a large family of var genes. In a large prospective study of Kenyan children, we have used the fact that anti-PfEMP1 antibodies agglutinate infected erythrocytes in a variant-specific manner, to show that the PfEMP1 variants expressed during episodes of clinical malaria were less likely to be recognized by the corresponding child's own preexisting antibody response than by that of children of the same age from the same community. In contrast, a heterologous parasite isolate was just as likely to be recognized. The apparent selective pressure exerted by established anti-PfEMP1 antibodies on infecting parasites supports the idea that such responses provide variant-specific protection against disease.rNat Med 199843 358-60  AuthorsJournalsKeywords   5 4321 0@97187113 Turner, G.Cerebral malariaBrain/blood supply Brain Edema/etiology/pathology Cell Count Cerebral Hemorrhage/etiology/pathology Cerebral Ischemia, Transient/etiology/pathology Human Malaria, Cerebral/complications/*pathology/physiopathology Neurons/pathology Syndromeib\Malaria infection of the Central Nervous System (CNS) can cause a severe neurological syndrome termed Cerebral Malaria (CM). The central neuropathological feature of CM is the preferential sequestration of parasitised red blood cells (PRBC) in the cerebral microvasculature. The level of sequestration is related to the incidence of cerebral symptoms in severe malaria. Other neuropathological features of CM include petechial hemorrhages in the brain parenchyma, ring hemorrhages and Durck's granuloma's. Immunohisto-chemical and electron microscopy studies have shown widespread cerebral endothelial cell activation and morphological changes occur in CM, as well as focal endothelial cell damage and necrosis. The immune cell response to intravascular sequestration appears to be limited, although activation of pigment- phagocytosing monocytes is a late feature. The mechanisms by which PRBC cause coma in malaria remain unclear. In vitro parasitised erythrocytes bind to endothelial cells by specific, receptor mediated interactions with host adhesion molecules such as ICAM-1, whose expression on cerebral endothelial cells is increased during CM as part of a systemic endothelial activation. Induction of local neuro-active mediators such as nitric oxide and systemic cytokines like TNF alpha may be responsible for the rapidly reversible symptoms of the coma of CM. The recent cloning of the parasite ligand PfEMP-1, thought to mediate binding to host sequestration receptors, promises further insight into the relationship between patterns of sequestration and the incidence and pathogenesis of coma in cerebral malaria. Brain Pathol 199771 569-82F@Udeinya, I. J. Schmidt, J. A. Aikawa, M. Miller, L. H. Green, I. 1981d^Falciparum malaria-infected erythrocytes specifically bind to cultured human endothelial cellsScience 213555-557 0171 Ref11D=Udeinya, I.J. Graves, P.M. Carter, R. Aikawa, M. Miller, L.H.iPlasmodium falciparum: Effect of time in continuous culture on binding to human endothelial cells and amelanotic melanoma cellso Exp Parasitolm 198356207-214 Ref111<6Udeinya, I.J. Miller, L.H. McGregor, I.A. Jensen, J.B.zsPlasmodium falciparum strain-specific antibody blocks binding of infected erythrocytes to amelanotic melanoma cells Nature 1983 303429-431  Ref11o81Udeinya, I. J. Leech, J. Aikawa, M. Miller, L. H.aAn in vitro assay for sequestration: binding of Plasmodium falciparum-infected erythrocytes to formalin-fixed endothelial cells and amelanotic melanoma cells J ProtozoolP 198532 88-90 Ref11Udeinya, I. J.VOIn vitro and ex-vivo models of sequestration in Plasmodium falciparum infectionjAm J Trop Med Hygt 19906/Reference Number: 228; Reference Type: ArticleHBUdomsangpetch, R. Aikawa, M. Berzins, K. Wahlgren, M. Perlmann, P. 1989~wCytoadherence of knobless Plasmodium falciparum-infected erythrocytes and its inhibition by a human monoclonal antibody Nature 338$763-765 1241 Ref11 jZ]667$9R`W 96194999HABaruch, D. I. Gormely, J. A. Ma, C. Howard, R. J. Pasloske, B. L. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1hPIAnimal Antigens, CD36/metabolism Binding Sites Blood Proteins/isolation & purification/*metabolism Cell Adhesion Cell Adhesion Molecules/metabolism Erythrocyte Membrane/*metabolism Human In Vitro Intercellular Adhesion Molecule-1/metabolism Malaria, Falciparum/etiology/parasitology Membrane Glycoproteins/metabolism Membrane Proteins/isolation & purification/*metabolism Peptide Fragments/isolation & purification/metabolism Plasmodium falciparum/*metabolism/pathogenicity Protozoan Proteins/isolation & purification/*metabolism Support, Non-U.S. Gov't Support, U.S. Gov't, Non-P.H.S.tVOAdherence of mature Plasmodium falciparum parasitized erythrocytes (PRBCs) to microvascular endothelium contributes directly to acute malaria pathology. We affinity purified molecules from detergent extracts of surface-radioiodinated PRBCs using several endothelial cell receptors known to support PRBC adherence, including CD36, thrombospondin (TSP), and intercellular adhesion molecule 1 (ICAM-1). All three host receptors affinity purified P. falciparum erythrocyte membrane protein 1 (PfEMP1), a very large malarial protein expressed on the surface of adherent PRBCs. Binding of PfEMP1 to particular host cell receptors correlated with the binding phenotype of the PRBCs from which PfEMP1 was extracted. Preadsorption of PRBC extracts with anti- PfEMP1 antibodies, CD36, or TSP markedly reduced PfEMP1 binding to CD36 or TSP. Mild trypsinization of intact PRBCs of P. falciparum strains shown to express antigenically different PfEMP1 released different (125)I-labeled tryptic fragments of PfEMP1 that bound specifically to CD36 and TSP. In clone C5 and strain MC, these activities resided on different tryptic fragments, but a single tryptic fragment from clone ItG-ICAM bound to both CD36 and TSP. Hence, the CD36- and TSP-binding domains are distinct entities located on a single PfEMP1 molecule. PfEMP1, the malarial variant antigen on infected erythrocytes, is therefore a receptor for CD36, TSP, and ICAM-1. A therapeutic approach to block or reverse adherence of PRBCs to host cell receptors can now be pursued with the identification of PfEMP1 as a malarial receptor for PRBC adherence to host proteins. Proc Natl Acad Sci U S A 1996938I3497-502pihttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.bloodjournal.org/cgi/content/full/90/9/376698008145PIBaruch, D. I. Ma, X. C. Singh, H. B. Bi, X. Pasloske, B. L. Howard, R. J.Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequencehrlAmino Acid Sequence Animal *Antigens, CD36 Blood Proteins/*genetics/immunology Cell Adhesion/immunology CHO Cells Erythrocyte Membrane/immunology Erythrocytes/cytology/immunology/*parasitology Hamsters Human Malaria, Falciparum/*blood Molecular Sequence Data *Plasmodium falciparum Protozoan Proteins/*genetics/immunology Sequence Alignment Support, Non-U.S. Gov'tF@Adherence of mature parasitized erythrocytes (PE) of Plasmodium falciparum to microvascular endothelial cells contributes directly to the virulence and pathology of this human malaria. The malarial variant antigen, P falciparum erythrocyte membrane protein 1 (PfEMP1), has been implicated as the PE receptor for CD36 on endothelial cells. We identified the region of PfEMP1 that mediates adherence of PE to CD36 and showed that a recombinant protein fragment from this region blocked and reversed adherence of antigenically different parasites. Sequence variation was evident in the CD36 binding domain of different PfEMP1 genes, yet many highly conserved residues, particularly cysteine residues, are evident. This suggests a highly conserved shape that mediates adherence to CD36. Immunization with the CD36-binding domain elicited sera that are cross-reactive with the different recombinant proteins but are strain-specific for the PE surface. Novel anti- adherence therapeutics and a malaria vaccine may derived from exploitation of the structure of the CD36 binding domain of PfEMP1. Blood 19979093766-75pF?Biggs, B. A. Culvenor, J. G. Ng, J. S. Kemp, D. J. Brown, G. V.m>8Plasmodium falciparum: cytoadherence of a knobless clone Exp Parasitoln 198969 189]189-197,%Biggs, B. A. Kemp, D. J. Brown, G. V. 1989Subtelomeric chromosome deletions in field isolates of Plasmodium falciparum and their relationship to loss of cytoadherence in vitroProc Natl Acad Sci U S A86 2428-2432 0902 Ref11zsBiggs, B. A. Gooz, L. Wycherley, K. Wilkinson, D. Boyd, A. W. Forsyth, K. P. Edelman, L. Brown, G. V. Leech, J. H./leKnob-independent cytoadherence of Plasmodium falciparum to the leukocyte differentiation antigen CD36 J Exp Med 1990 1716 1883-1892^XBiggs, B. A. Gooz, L. Wycherley, K. Wollish, W. Southwell, B. Leech, J. H. Brown, G. V.2,Antigenic variation in Plasmodium falciparum 1991Proc Natl Acad Sci Usa8820 9171-917492388675b[Biggs, B. A. Anders, R. F. Dillon, H. E. Davern, K. M. Martin, M. Petersen, C. Brown, G. V.xqAdherence of infected erythrocytes to venular endothelium selects for antigenic variants of Plasmodium falciparumBBorst, P. Bitter, W. McCulloch, R. Van Leeuwen, F. Rudenko, G..(Antigenic variation in malaria [comment]Animal *Antigenic Variation Antigens, Protozoan/*genetics/immunology Blood Proteins/*genetics/immunology Erythrocytes/parasitology Genes, Protozoan Human Malaria/immunology/parasitology Membrane Proteins/genetics Plasmodium/*genetics/immunology Cell 1995821 1-4 Brown, K. N.Antigenic variation.A Non Journal Reference 19890c 59-709G" S0R. V6/Barnwell, J. W. Ockenhouse, C. F. Knowles, D.M.^ 1985Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum-infected erythrocytes to monocytes, endothelial, and C32 melanoma cells  J Immunol 135 3494-3497 0383 Ref11F@Barnwell, J. W. Asch, A. S. Nachman, R. L. Yamaya, M. Aikawa, M.A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocyteso J Clin Invest 198984 7659765-772hahttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://iai.asm.org/cgi/content/full/66/10/478398427144F?Barragan, A. Kremsner, P. G. Weiss, W. Wahlgren, M. Carlson, J.Age-related buildup of humoral immunity against epitopes for rosette formation and agglutination in African areas of malaria endemicityAdolescence *Age Factors Agglutination/*immunology *Antibody Formation Child Child, Preschool *Endemic Diseases Epitopes Erythrocytes/immunology/parasitology Gabon Human Infant Kenya Malaria, Falciparum/*epidemiology/*immunology *Rosette Formation Support, Non-U.S. Gov'taIn this report, we show an age-related buildup of agglutinating activity as well as serum activity against rosette formation in children living in areas of Kenya and Gabon where malaria is endemic. Sera from Kenyans in general exhibited a stronger and wider immune response toward the epitopes, probably reflecting a difference in transmission patterns between the two areas. Thus, our results indicate that repeated malaria attacks in areas of endemicity, and consequently exposure to different isolate-specific antigens, will elicit an antibody-mediated response eventually enabling recognition of the majority of rosetting and agglutinating antigens. The correlation between antirosetting and agglutinating capacity was poor in individual cases, indicating that the rosetting epitopes are only a minor part of the highly diverse surface-exposed antigens (mainly PfEMP1) on the surface of parasitized erythrocytes toward which antibodies may react. These data together with our previous findings that the protection against cerebral malaria correlates with presence of antirosetting antibodies shed new light on our understanding of the gradual acquisition of immunity toward severe complications of malarial infection which children reared in areas of endemicity attain.y Infect Immun 19986610 4783-7"MI`<991779224.al-Khedery, B. Barnwell, J. W. Galinski, M. R.~wAntigenic variation in malaria: a 3' genomic alteration associated with the expression of a P. knowlesi variant antigenlAmino Acid Sequence Animal Antigenic Variation/*genetics Antigens, Surface/*genetics/immunology Clone Cells Comparative Study DNA, Complementary/genetics Gene Expression Regulation *Genes, Structural, Protozoan Genes, Switch Molecular Sequence Data Multigene Family Plasmodium knowlesi/*genetics/immunology Protein Conformation Protozoan Proteins/chemistry/*genetics/immunology Recombinant Fusion Proteins/chemistry/immunology Sequence Alignment Sequence Homology, Amino Acid Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.,0*Antigenic variation of malaria parasites was discovered in P. knowlesi, using a schizont-infected cell agglutination (SICA) assay to detect variant antigens expressed at the surface of infected erythrocytes. Later studies utilizing stable clones, Pk1(A+) and its direct derivative, Pk1(B+)1+, showed that SICA[+] clones express distinct parasite-encoded antigens of approximately 200 kDa. Here we identify a P. knowlesi variant antigen gene and cDNA and demonstrate that it encodes the 205 kDa variant antigen expressed by B+ parasites. This gene belongs to a multigene family, which we term SICAvar. Its ten-exon structure with seven cysteine-rich coding modules is unique compared to P. falciparum var genes. Further, we highlight a 3' genomic alteration that we predict is related to SICAvar gene switching.Mol Cell 19993l2 131-41:4Aley, S. B. Barnwell, J. W. Daniel, W. Howard, R. J.Identification of parasite proteins in a membrane preparation enriched for the surface membrane of erythrocytes infected with Plasmodium knowlesi Mol Biochem Parasitol 19841269 69-84t0)Aley, S. B. Sherwood, J. A. Howard, R. J. 1984Knob-positive and knob-negative Plasmodium falciparum differ in expression of a strain-specific malarial antigen on the surface of infected erythrocytes J Exp Med 160L 1585-1590  0369 Ref11F@Aley, S. B. Sherwood, J. A. Marsh, K. Eidelman, O. Howard, R. J. 1986Identification of isolate-specific proteins on sorbitol-enriched Plasmodium falciparum infected erythrocytes from Gambian patients Parasitology92511-525 0488 Ref1198348522 Allred, D. R.@`YAntigenic variation in Babesia bovis: how similar is it to that in Plasmodium falciparum?@Animal Antigenic Variation Antigens, Protozoan/analysis Antigens, Surface/analysis Babesia bovis/*immunology Comparative Study Erythrocytes/parasitology Human Plasmodium falciparum/*immunology Support, U.S. Gov't, Non-P.H.S.Despite significant differences in some aspects of their life-cycles, the Apicomplexan parasites Babesia bovis and Plasmodium falciparum share many parallels. Significant among these are participation in rapid, clonal antigenic variation, and cyto-adherence and sequestration in the deep vasculature. Antigenic variation has long been thought to be primarily a mechanism of escape from antibody-mediated mechanisms of the host's immune system. In each species, the components demonstrated to participate in antigenic variation are parasite-derived proteins expressed on the infected erythrocyte's surface. Recently, the malarial component PfEMP1 has been found to be a multifunctional protein that is not only subject to antigenic variation, but also participates in cyto- adherence and rosetting (adhesion to uninfected erythrocytes). In the present review, the antigens elaborated on the surface of an erythrocyte infected with B. bovis, for immune evasion via antigenic variation, are described, and compared and contrasted with those from P. falciparum. The significance of the similarities between B. bovis and P. falciparum, and the potential for contributions to be made to our understanding of malaria through the study of babesiosis are discussed.Ann Trop Med Parasitol 1998924 461-7298206476 Aungst, M.`ZReceptor-specific adhesion and clinical disease in Plasmodium falciparum [letter; comment]Animal Antigens, CD36/*blood/metabolism Blood Proteins/metabolism Human Malaria, Cerebral/blood/*immunology Membrane Proteins/metabolism Protozoan Proteins/metabolism Reticulocytes/*immunology/metabolism Sickle Cell Trait/*blood/immunologycAm J Trop Med Hyg 1998583 2652+Barnwell, J. W. Howard, R. J. Miller, L. H. `YInfluence of the spleen on the expression of surface antigens on parasitized erythrocytesCiba Found Sympn 198394 117]117-136:3Barnwell, J.W. Howard, R.J. Coon, H.G. Miller, L.H.$ 1983Splenic requirement for antigenic variation and expression of the variant antigen on the erythrocyte membrane in cloned Plasmodium knowlesi malariaInfect Immunity40985-994 0183 Ref11B *&.b*f$97373957<6Rowe, J. A. Moulds, J. M. Newbold, C. I. Miller, L. H.tmP. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1Africa Animal Blood Proteins/genetics/*physiology Carrier Proteins Chimeric Proteins/genetics COS Cells DNA, Protozoan *Erythrocyte Aggregation Erythrocyte Membrane/parasitology Erythrocytes/pathology/*parasitology Genes, Protozoan Human In Vitro Malaria, Falciparum/blood/parasitology Molecular Sequence Data Plasmodium falciparum/genetics/*physiology Polymerase Chain Reaction Polymorphism (Genetics) Protozoan Proteins/genetics/*physiology Receptors, Cell Surface Receptors, Complement/genetics/*physiology Support, Non-U.S. Gov'to The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and form rosettes. The molecular basis of resetting is not well understood, although a group of low-molecular-mass proteins called rosettins have been described as potential parasite ligands. Infected erythrocytes also bind to endothelial cells, and this interaction is mediated by the parasite- derived variant erythrocyte membrane protein PfEMP1, which is encoded by the var gene family. Here we report that the parasite ligand for rosetting in a P. falciparum clone is PfEMP1, encoded by a specific var gene. We also report that complement-receptor 1 (CR1) on erythrocytes plays a role in the formation of rosettes and that erythrocytes with a common African CR1 polymorphism (S1(a-)) have reduced adhesion to the domain of PfEMP1 that binds normal erythrocytes. Thus we describe a new adhesive function for PfEMP1 and raise the possibility that CR1 polymorphisms in Africans that influence the interaction between erythrocytes and PfEMP1 may protect against severe malaria. Nature 1997 388 6639 292-5ujchttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.emboj.org/cgi/content/full/17/18/5418f98409545jcScherf, A. Hernandez-Rivas, R. Buffet, P. Bottius, E. Benatar, C. Pouvelle, B. Gysin, J. Lanzer, M.pAntigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum,B7Sherwood, J. A. Marsh, K. Howard, R. J. Barnwell, J. W. 1985Antibody mediated strain-specific agglutination of Plasmodium falciparum-parasitized erythrocytes visualized by ethidium bromide stainingParasite Immunol7p659-663 Ref11NGSherwood, J. A. Roberts, D. D. Spitalnik, S. L. Marsh, K. Harvey, E. B.a|uParasitized erythrocyte antigens and thrombospondin adhesion in the immunology and pathogenesis of falciparum malaria Trans Assoc Am Physicians 198699 206206-213NHSherwood, J. A. Spitalnik, S. L. Aley, S. B. Quakyi, I. A. Howard, R. J.|uPlasmodium falciparum and P. knowlesi: initial identification and characterization of malaria synthesized glycolipidse Exp ParasitolW 198662 127e127-141mhbSherwood, J. A. Roberts, D. D. Marsh, K. Harvey, E. B. Spitalnik, S. L. Miller, L.H. Howard, R.J.VPThrombospondin binding by parasitized erythrocyte isolates in falciparum malariaAm J Trop Med Hygl 198736228-233  Ref11haSherwood, J. A. Roberts, D. D. Spitalnik, S. L. Marsh, K. Harvey, E. B. Miller, L.H. Howard, R.J.i`ZStudies of the receptors on melanoma cells for Plasmodium falciparum infected erythrocytesAm J Trop Med Hyg 198940119-127G Ref11.Sherwood, J. A.Cytoadherence of malaria-infected erythrocytes. Commentary: Progress toward understanding the pathogenesis of sequestration in falciparum malaria Blood Cellst 199016 2-3 620-628981Reference Number: 764; Reference Type: Editoriali!6 N F*p4 Howard, R. J.:3Antigenic variation of bloodstage malaria parasitesz$Phil Trans Roy Soc Lond :Biol 1984 B307141-158D Ref112$Howard, R. J. Barnwell, J. W. Solubilization and immunoprecipitation of 125I-labelled antigens from Plasmodium knowlesi schizont-infected erythrocytes using non-ionic, anionic and zwitterionic detergentsf Parasitology 198488 27-36C Ref11s$Howard, R. J. Barnwell, J. W. Immunochemical analysis of surface membrane antigens on erythrocytes infected with non-cloned SICA:+: or cloned SICA:-: Plasmodium knowlesia Parasitology 198591245-261 Ref11PIHoward, R. F. Stanley, H. A. Campbell, G. H. Langreth, S. G. Reese, R. T.t|vTwo Plasmodium falciparum merozoite surface polypeptides share epitopes with a single Mr 185 000 parasite glycoproteinMol Biochem Parasitolt 198517 61-77n Ref11n82Howard, R. J. McBride, J. S. Aley, S. B. Marsh, K.Antigenic diversity and size diversity of P. falciparum antigens in isolates from Gambian patients. II. the schizont surface glycoprotein of molecular weight approximately 200 000fParasite Immunol 19868s 57-685 Ref11tHBHoward, R.J. Uni, S. Lyon, J.A. Taylor, D.W. Daniel, W. Aikawa, M.Export of Plasmodium falciparum proteins to the host erythrocyte membrane: Special problems of protein trafficking and topogenesis.a ?iNGHost-parasite cellular and molecular interactions in protozoan disease.c New York  Plenum Press 1986?i?e Ref11i Howard, R. J.<6Antigenic variation and antigenic diversity in malaria Contrib Microbiol ImmunolD 19878 176176-218nhHoward, R. J. Barnwell, J. W. Rock, E. P. Neequaye, J. Ofori, Adjei D. Maloy, W. L. Lyon, J. A. Saul, A.vpTwo approximately 300 kilodalton Plasmodium falciparum proteins at the surface membrane of infected erythrocytesMol Biochem Parasitol 198827 2-3n 207-23 Howard, R. J.Malarial proteins at the membrane of Plasmodium falciparum-infected erythrocytes and their involvement in cytoadherence to endothelial cells Prog Allergy 198841 98-147 Ref11  Howard, R.J.Plasmodium falciparum proteins at the host erythrocyte membrane: Their biological and immunological significance and novel parasite organelles which deliver them to the cell surfaceiBiol Parasitism 1988?a111-145 Ref117$Howard, R. J. Gilladoga, A. D.HAMolecular studies related to the pathogenesis of cerebral malaria Blood 1989748t2603-18Howard, R. J. Handunnetti, S. M. Hasler, T. Gilladoga, A. De, Aguiar J.C. Pasloske, B. L. Morehead, K. Albrecht, G. R. Van, Schravendijk M.R. 1990\VSurface molecules on Plasmodium falciparum-infected erythrocytes involved in adherenceAm J Trop Med HygD4324 15-29 1119 Ref11f`http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://iai.asm.org/cgi/content/full/66/4/165498187943yJakobsen, P. H. McKay, V. N'Jie, R. Olaleye, B. O. D'Alessandro, U. Zhang, G. H. Eggelte, T. A. Koch, C. Greenwood, B. M.CVODecreased antitoxic activities among children with clinical episodes of malariayPJAmino Acid Sequence Antibodies, Protozoan/blood Blood Proteins/immunology C-Reactive Protein/analysis Child, Preschool Female Haptoglobins/analysis Human Infant Limulus Test Malaria, Falciparum/*immunology Male Molecular Sequence Data Protozoan Proteins/immunology Receptors, Tumor Necrosis Factor/analysis Support, Non-U.S. Gov'tHealthy Gambian children, children with clinical Plasmodium falciparum malaria, and children with asymptomatic P. falciparum infections were studied to investigate whether antitoxic activities may contribute to protection against malarial symptoms. Markers of inflammatory reactions, soluble tumor necrosis factor receptor I, and C-reactive protein were found in high concentrations in children with symptomatic P. falciparum malaria compared with levels in children with asymptomatic P. falciparum infections or in healthy children, indicating that inflammatory reactions are induced only in children with clinical symptoms. Concentrations of soluble tumor necrosis factor receptor I and C-reactive protein were associated with levels of parasitemia. We detected antitoxic activities in sera as measured by their capacity to block toxin-induced Limulus amoebocyte lysate (LAL) activation. Symptomatic children had decreased capacity to block induction of LAL activation by P. falciparum exoantigen. The decreased blocking activity was restored in the following dry season, when the children had no clinical malaria. Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum erythrocyte membrane protein 1 and "Pfalhesin" (band #3) peptides, indicating that such IgG antibodies are stimulated by acute disease but are lost rapidly after the disease episode. Half of the children with symptomatic infections had low levels of haptoglobin, suggesting that these children had chronic P. falciparum infections which may have caused symptoms previously. Only a few of the children with asymptomatic P. falciparum infections had high parasite counts, and antitoxic immunity in the absence of antiparasite immunity appears to be rare among children in this community.m Infect Immun 1998664 1654-9:4Leech, J. H. Aley, S. B. Miller, L. H. Howard, R. J.Plasmodium falciparum malaria: cytoadherence of infected erythrocytes to endothelial cells and associated changes in the erythrocyte membraneProg Clin Biol Res 1984 15563 63-77>8Leech, J. H. Barnwell, J. W. Miller, L. H. Howard, R. J.zIdentification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes J Exp Med  1984 159h 1567-1575 Ref11CMarsh, K. Howard, R. J.hjcAntigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinantsScienceg 1986 231150-153 Ref11.'Marsh, K. Sherwood, J. A. Howard, R. J. Parasite-infected-cell-agglutination and indirect immunofluorescence assays for detection of human serum antibodies bound to antigens on Plasmodium falciparum-infected erythrocytesJ Immunol Methods 1986911J107-115n Ref11rA bE "f_http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://iai.asm.org/cgi/content/full/67/2/733f991155502,Bull, P. C. Lowe, B. S. Kortok, M. Marsh, K.}Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variantsurkAgglutination Tests Animal Antibodies, Protozoan/*immunology Antigens, Protozoan/*immunology Antigens, Surface/*immunology Blood Transfusion Child Erythrocytes/immunology Human Infant Kenya Malaria, Falciparum/blood/*immunology Plasmodium falciparum/immunology Protozoan Proteins/*immunology Reproducibility of Results Support, Non-U.S. Gov't Variation (Genetics)cLFPlasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is the name given to a family of parasite proteins that are inserted into the infected erythrocyte surface. Studies using agglutination assays have shown previously that PfEMP1 epitopes are extremely diverse. In a study in Kenya, 21 parasite isolates, including nine from children with severe malaria, were tested for agglutination by 33 pairs of plasma, 21 of which were from the corresponding children. Each plasma pair consisted of a sample taken at the time of disease (acute) and one taken 3 weeks later (convalescent). In agreement with previous studies, infection was generally followed by the induction of antibodies specific to the homologous parasite isolate. In addition however, the results show that (i) some isolates were agglutinated very frequently by heterologous plasma; (ii) unexpectedly, these frequently agglutinated isolates tended to be from individuals with severe malaria; (iii) an inverse relationship existed between the agglutination frequency of each parasite isolate in heterologous plasma and the agglutinating antibody repertoire of the homologous child at the time of disease; and (iv) A 3-month-old child apparently still carrying maternal antibodies was infected by a rarely agglutinated isolate. This child's plasma agglutinated all isolates at the time of disease, apart from the homologous isolate. These results support the idea that preexisting anti-PfEMP1 antibodies can select the variants that are expressed during a new infection and may suggest the existence of a dominant subset of PfEMP1 variants. Infect Immun 1999672 733-9n95140052>7Chaiyaroj, S. C. Coppel, R. L. Magowan, C. Brown, G. V.xqA Plasmodium falciparum isolate with a chromosome 9 deletion expresses a trypsin-resistant cytoadherence moleculeaAnimal Cell Adhesion/genetics Cell Adhesion Molecules/*genetics Cell Line *Chromosome Deletion Chromosome Mapping CHO Cells Endothelium, Vascular/parasitology Erythrocytes/parasitology Genes, Protozoan Hamsters Human Malaria/etiology Phenotype Plasmodium falciparum/*genetics/isolation & purification/pathogenicity Protozoan Proteins/genetics Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Transfection Trypsin/pharmacologySequestration of Plasmodium falciparum infected erythrocytes in the cerebral circulation is strongly implicated in the pathogenesis of cerebral malaria. From previous studies it was postulated that genes essential for cytoadherence were located on the right arm of chromosome 9 as P. falciparum isolates with a deletion in this region lost the capacity to cytoadhere in vitro and no longer expressed Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) on the surface of the infected cells. We have selected a P. falciparum isolate from Papua New Guinea for high levels of cytoadherence to human umbilical vein endothelial cells (HUVECs) and have shown that the cloned parasite has several novel properties related to cytoadherence. The cloned parasite adheres to HUVECs, does not bind to melanoma cells, and expresses a surface molecule with most of the properties of PfEMP-1, despite a deletion in the right arm of chromosome 9. Interestingly, the surface expressed PfEMP-1 in this strain is resistant to trypsin treatment and infected cells continue to cytoadhere after trypsin digestion at a concentration of 100 micrograms ml-1. The receptor on HUVECs for the cloned parasite lines is a molecule different from any previously described, as parasitized cells do not adhere to soluble intercellular adhesion molecule 1, thrombospondin, vascular cell adhesion molecule 1, E-selectin or P-selectin, nor to CD36. Our work, taken together with the results from previous studies, suggest that the ability of parasites to cytoadhere is encoded in at least two distinct genomic locations in the parasite, and the diversity of receptor-ligand interaction is greater than previously described.Mol Biochem Parasitol  1994671m 21-30<d\T%bzOckenhouse, C. F. Ho, M. Tandon, N. N. Van, Seventer Ga Shaw, S. White, N. J. Jamieson, G. A. Chulay, J. D. Webster, H. K.Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: Differential adhesion of infected erythrocytes to CD36 and ICAM-1  1991 J Infect Dis 1641163-16994256771$Pasloske, B. L. Howard, R. J.P0*Malaria, the red cell, and the endothelium@:Cell Adhesion Molecules/metabolism Endothelium, Vascular/*pathology Erythrocyte Aggregation, Intravascular/blood/pathology Erythrocytes/pathology/*parasitology Human Malaria, Falciparum/*blood/*pathology Platelet Membrane Glycoproteins/metabolism Receptors, Cytoadhesin/metabolism Receptors, Immunologic/metabolism`ZErythrocytes infected with mature stages of Plasmodium falciparum malaria adhere to vascular endothelial cells in postcapillary venules of several organs. In some patients, infected cells also form rosettes with uninfected erythrocytes. The special pathology of acute cerebral malaria appears to result from excessive adherence of infected cells in cerebral vessels coupled with occlusion of cerebral blood flow in microvessels by infected cell rosettes. Several endothelial cell proteins have been identified as potential receptors for infected erythrocyte adherence to vascular endothelium, including thrombospondin, CD36, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). The receptor on infected erythrocytes that mediates adhesion to endothelial cells has been identified as a very large malarial protein on infected cells called PfEMP1. PfEMP1 has been shown to bind to CD36 and thrombospondin in vitro. Antibody- mediated blockade or reversal of infected erythrocyte adherence to vascular endothelium is postulated not only to decrease the pathology of blood-stage malaria, but also to lead to infected cell destruction and clearance, especially in the spleen. PfEMP1 is therefore a prime candidate malarial protein for inclusion in a multicomponent asexual malaria vaccine. 1994 Annu Rev Med45 283-95 Using Smart Source Parsing|uhttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.idealibrary.com/cgi-bin/links/citation/0014-4894/91/161299144155,&Piper, K. P. Roberts, D. J. Day, K. P.xrPlasmodium falciparum: analysis of the antibody specificity to the surface of the trophozoite-infected erythrocyteAdult Agglutination Tests Animal Antibodies, Monoclonal Antibodies, Protozoan/biosynthesis/*immunology *Antibody Specificity Antigens, Protozoan/*immunology Antigens, Surface/immunology Child Comparative Study Cross-Sectional Studies Erythrocytes/immunology/*parasitology Flow Cytometry Human IgG/biosynthesis/immunology Malaria, Falciparum/immunology/parasitology Papua New Guinea Plasmodium falciparum/*immunology Support, Non-U.S. Gov'tG<6Current opinion supports the view that immunity to the surface of the trophozoite-infected erythrocyte (IE) is to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). Here we provide further evidence using the mutant cell line 1776/C10 which no longer expresses PfEMP-1 at the IE surface, due to a subtelomeric deletion in chromosome 9. We have measured antibody reactivity to this mutant in comparison to it's intact isogenic parent line 1776, which does express PfEMP-1, using the sensitive technique of flow cytometry. IgG-specific antibodies (subclass IgG1) in the plasma of hyperimmune adults, reacted to 1776 but never to the 1776/C10 mutant. Antibody subclasses were also measured in individual plasma samples to the surface of trophozoite-IE. Predominantly IgG1 antibodies were detected, with a few individual plasma having additional IgG3 antibodies. Previous studies have used the agglutination assay to measure sero-conversion to PfEMP-1. Here we show that both agglutination and flow cytometric methods are comparable, suggesting that agglutination of trophozoite-IE is mediated by IgG antibodies. Comparison of the isogenic cell lines 1776 and 1776/C10 differing in expression of PfEMP-1 provides further evidence that IgG antibodies, in particular of the cytophilic subclasses, mediate recognition of PfEMP-1. Exp Parasitol 1999912 161-9 V K.  ܂ M. Wiesner,Wunsch, S. Camargo, A. A. Lanzer, M.arum/classif ܂Lanzer, M.. p ܂in Reaction ort, Non-U.S. Gov't&Plasmodium falciparum is the major cause of malaria morbidity and mortality in the world. Biologic and antigenic diversity is a characteristic of this parasite and f`http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.cell.com/cgi/content/full/89/2/28797262069Crabb, B. S. Cooke, B. M. Reeder, J. C. Waller, R. F. Caruana, S. R. Davern, K. M. Wickham, M. E. Brown, G. V. Coppel, R. L. Cowman, A. F.zTargeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stressAnimal Antigens, CD36/metabolism Blood Platelets/metabolism Blood Proteins/analysis Cell Adhesion/*physiology Erythrocyte Membrane/chemistry/ultrastructure Erythrocytes/*cytology/*parasitology Gene Expression Molecular Sequence Data Mutagenesis Peptides/genetics/*physiology Plasmodium falciparum/*physiology Protozoan Proteins/analysis Stress, Mechanical Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. TransfectionB7Fernandez, V. Treutiger, C. J. Nash, G. B. Wahlgren, M.hpiMultiple adhesive phenotypes linked to rosetting binding of erythrocytes in Plasmodium falciparum malariaoAnimal Antigens, CD36 Antigens, Surface/biosynthesis Blood Proteins/drug effects Cell Adhesion Clone Cells Endothelium, Vascular/metabolism Erythrocytes/*parasitology Human Kenya Ligands Malaria, Falciparum/*parasitology Phenotype Plasmodium falciparum/cytology/immunology Protozoan Proteins/drug effects Receptors, Cell Surface *Rosette Formation Selection (Genetics) Support, Non-U.S. Gov't Trypsin/pharmacologyeThe cerebral form of severe malaria is associated with excessive intravascular sequestration of Plasmodium falciparum-infected erythrocytes (PRBC). Retention and accumulation of PRBC may lead to occlusion of brain microvessels and direct the triggering of acute pathologic changes. Here we report that by selection, cloning, and subcloning, we have identified rare P. falciparum parasites expressing a pan-adhesive phenotype linked to erythrocyte rosetting, a previously identified correlate of cerebral malaria. Rosetting PRBC not only bound uninfected erythrocytes but also formed autoagglutinates, adhered to endothelial cells, and bound to CD36, immunoglobulins, and the blood group A antigen. The linkage of rosetting, autoagglutination, and cytoadherence involved the coexpression on a single PRBC of ligands with multiple specificities and the binding to two or more receptors on erythrocytes and to at least two other cell adhesion molecules, including a new endothelial cell receptor for P. falciparum-infected erythrocytes. Limited proteolysis that differentially cleaved the rosetting ligand PfEMP1 from the PRBC surface abrogated all the binding phenotypes of these parasites, implicating the variant antigen PfEMP1 as a carrier of multiple ligand specificities. The results encourage the further study of pan-adhesion as a potentially important parasite phenotype in the pathogenesis of severe P. falciparum malaria. Infect Immun 1998666P2969-7597342604ZTFischer, K. Horrocks, P. Preuss, M. Wiesner, J. Wunsch, S. Camargo, A. A. Lanzer, M.rlExpression of var genes located within polymorphic subtelomeric domains of Plasmodium falciparum chromosomesAnimal Base Sequence Blood Proteins/*genetics Chromosomes/*ultrastructure Chromosomes, Yeast Artificial DNA, Protozoan/*genetics *Gene Expression Regulation *Genes, Structural, Protozoan Molecular Sequence Data Multigene Family Plasmodium falciparum/*genetics Protozoan Proteins/*genetics Recombination, Genetic Restriction Mapping Support, Non-U.S. Gov't Telomere Transcription, GeneticcPlasmodium falciparum var genes encode a diverse family of proteins, located on the surfaces of infected erythrocytes, which are implicated in the pathology of human malaria through antigenic variation and adhesion of infected erythrocytes to the microvasculature. We have constructed a complete representative telomere-to-telomere yeast artificial chromosome (YAC) contig map of the P. falciparum chromosome 8 for studies on the chromosomal organization, distribution, and expression of var genes. Three var gene loci were identified on chromosome 8, two of which map close to the telomeres at either end of the chromosome. Analysis of the previously described chromosome 2 contig map and random P. falciparum telomeric YAC clones revealed that most, if not all, 14 P. falciparum chromosomes contain var genes in a subtelomeric location. Mapping the chromosomal location of var genes expressed in a long-term culture of the P. falciparum isolate Dd2 revealed that four of the five different expressed var genes identified map within subtelomeric locations. Expression of var genes from a chromosomal domain known for frequent rearrangements has important implications for the mechanism of var gene switching and the generation of novel antigenic and adhesive phenotypes. Mol Cell Biol 19971773679-86zthttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.idealibrary.com/cgi-bin/links/citation/0882-4010/20/6396362191Fujioka, H. Aikawa, M.>7The molecular basis of pathogenesis of cerebral malarianAnimal Antigens, CD36/metabolism/physiology Blood Proteins/immunology/metabolism Cell Adhesion E-Selectin/metabolism/physiology Erythrocytes/immunology/*parasitology/ultrastructure Intercellular Adhesion Molecule-1/metabolism/physiology Malaria, Falciparum/*etiology Membrane Glycoproteins/metabolism/physiology Plasmodium falciparum/*metabolism/pathogenicity Proteins/metabolism Protozoan Proteins/immunology/metabolism Support, U.S. Gov't, Non-P.H.S. Support, U.S. Gov't, P.H.S. Vascular Cell Adhesion Molecule-1/metabolism/physiology Microb Pathog 1996202P 63-72 {Hasler, T. Handunnetti, S. M. Aguiar, J. C. Van, Schravendijk Mr Greenwood, B. M. Lallinger, G. Cegielski, P. Howard, R. J.gIn vitro rosetting, cytoadherence, and microagglutination properties of Plasmodium falciparum-infected erythrocytes from Gambian and Tanzanian patients  Bloodr 1990769  1845-1852 6/Reference Number: 856; Reference Type: Articlee ~ J4Dhahttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.pnas.org/cgi/content/full/96/8/4563L99218320F?Hayward, R. E. Tiwari, B. Piper, K. P. Baruch, D. I. Day, K. P.XQVirulence and transmission success of the malarial parasite Plasmodium falciparumfAnimal Antigens, Protozoan/genetics Cell Adhesion Erythrocyte Membrane/parasitology Genes, Structural, Protozoan Human Malaria, Falciparum/parasitology/*transmission Plasmodium falciparum/genetics/*pathogenicity Protozoan Proteins/genetics Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger/genetics Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Transcription, Genetic VirulenceVirulence of Plasmodium falciparum is associated with the expression of variant surface antigens designated PfEMP1 (P. falciparum erythrocyte membrane protein 1) that are encoded by a family of var genes. Data presented show that the transmission stages of P. falciparum also express PfEMP1 variants. Virulence in this host-parasite system can be considered a variable outcome of optimizing the production of sexual transmission stages from the population of disease-inducing asexual stages. Immunity to PfEMP1 will contribute to the regulation of this trade-off by controlling the parasite population with potential to produce mature transmission stages.pProc Natl Acad Sci U S A 1999968t 4563-8pjhttp://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://www.bloodjournal.org/cgi/content/full/91/12/480398282227LFHo, M. Schollaardt, T. Niu, X. Looareesuwan, S. Patel, K. D. Kubes, P.vpCharacterization of Plasmodium falciparum-infected erythrocyte and P- selectin interaction under flow conditionsAnimal Cell Adhesion/physiology Erythrocytes/cytology/*physiology/*parasitology Human Malaria, Falciparum/*blood P-Selectin/*physiology *Plasmodium falciparum Support, Non-U.S. Gov'tPlasmodium falciparum-infected erythrocytes (IRBC) roll on the adhesion molecule P-selectin in vitro under flow conditions that approximate the shear stress in capillary and postcapillary venules in which cytoadherence occurs in vivo. The pathological significance of this adhesive interaction is currently unknown. In this study, we further investigated the molecular interactions between IRBC and P-selectin by using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results showed that the IRBC-P- selectin interaction was Ca2+-dependent and involved the lectin domain of P-selectin and a sialic acid residue on IRBC. The sialylated P- selectin ligand was trypsin-sensitive, which suggests that it could be part of the parasite antigen PfEMP1 that interacts with CD36 and intercellular adhesion molecule-1 (ICAM-1), but different from a trypsin-resistant IRBC ligand that adheres selectively to chondroitin sulfate A. Studies on the rolling and adhesion of IRBC on activated platelets that express both CD36 and P-selectin showed that inhibition of rolling on P-selectin reduced the adhesion of some clinical parasite isolates to CD36, whereas other parasite isolates appeared to interact directly with CD36. Thus, cytoadherence under physiological flow conditions may be mediated by multiple IRBC ligands that interact with different adhesion molecules in a cooperative fashion. These findings underscore the complexity of the interactions betweeen IRBC and vascular endothelium. Bloodc 19989112 4803-9:3Hommel, M. David, P. H. Oligino, L. D. David, J. R.od]Expression of strain-specific surface antigens on Plasmodium falciparum-infected erythrocytes^Parasite Immunol 19824P409-419 Ref11*$Hommel, M. David, P.H. Oligino, L.D.JDSurface alterations of erythrocytes in Plasmodium falciparum malaria J Exp Med 1983 157n 1137-1148 Ref11 Hommel, M.PJThe role of variant antigens in acquired immunity to Plasmodium falciparumAnn Soc Belg Med Trop 19856557 57-67: Hommel, M..(Antigenic variation in malaria parasites Immunol Today6 19856| 28-33n Ref11Hommel, M. Semoff, S.mTMExpression and function of erythrocyte-associated surface antigens in malaria Biol Cell 198864183-203 Ref11 Hommel, M.4.Cytoadherence of malaria-infected erythrocytes Blood Cells  199016 2-3 605-619 6/Reference Number: 763; Reference Type: Articler$Howard, R. J. Barnwell, J. W. ZTRoles of surface antigens on malaria-infected red blood cells in evasion of immunityContemp Top Immunobiol 198412 127.127-200|z Aguiar19900 Aikawa19811& Aikawa198221 Aikawa198333 Aikawa19855 Aikawa19866 Aikawa198995 Aikawa1989cX Aikawa19966` al-Khedery1999Albrecht19900 Aley1984 Aley1984 Aley19844 Aley19868 Aley19869* Aley1986I Allred19989/ Anders19899] Anders19929 Asch19891M Aungst19989&Barnwell19829Barnwell1983nBarnwell1983nBarnwell1984Barnwell19840Barnwell19840Barnwell19840Barnwell1985nBarnwell19850(Barnwell19859Barnwell19880Barnwell19898`Barnwell19999GBarragan1998QBarragan1998[ Baruch19955W Baruch19967R Baruch1997+F Baruch19989D Baruch19999C Beeson1999b Benatar1998e Berendt19975 Berzins1989[ Bi19959R Bi19979 Biggs19899 Biggs19897 Biggs19906 Biggs1991] Biggs1992Z Bitter19956Z Borst1995b Bottius19987 Boyd1990 Brown1989  Brown1989/ Brown19899 Brown19897 Brown19906 Brown1991] Brown1992A Brown1994V Brown1997C Brown1999b Buffet1998iO Bull1998.E Bull19999g Camargo1997Campbell19850^ Capiod19999G Carlson1998Q Carlson1998" Carson198981 Carter19833V Caruana1997  Cegielski1990A Chaiyaroj1994Q Chen1998c Chen1998# Chulay19881% Chulay19919V Cooke1997F Cooke1998 Coon19838A Coppel19949V Coppel19977F Coppel19989V Cowman19977C Cowman1999V Crabb1997e Craig1997Culvenor19898N D'Alessandro1998 Daniel19848 Daniel19866Q Datta1998c Datta1998] Davern19929V Davern19977C Davern1999 David1982 David1982 David1983< Day1999D Day1999 De1990g] Dillon199297 Edelman1990N Eggelte1998Eidelman1986nLElhassan19988LElhassan19988[ Feldman1995K Fernandez1998Q Fernandez1998c Fernandez1998g Fischer1997/ Forsyth19897 Forsyth1990X Fujioka1996a Fusai1998`Galinski19999L Giha19981 Gilladoga1989 Gilladoga19907 Gooz19906 Gooz1991W Gormely19961 Graves198330 Green1981& Green1982" Greenwood1989  Greenwood1990N Greenwood1998h Guinet19951a Gysin1998b Gysin1998c Hagblom1998  Handunnetti1990 Handunnetti1990) Harvey19869+ Harvey19877, Harvey19899  Hasler19908 Hasler1990& Hay1982" Hayes1989D Hayward1999hHeatwole1995bHernandez-Rivas1998h Herrfeldt1995% Ho1991uJ Ho1998  Hommel19829  Hommel19832  Hommel19853 Hommel19853 Hommel19883 Hommel19903gHorrocks1997 Howard19838 Howard19838 Howard19848 Howard19848 Howard19843 Howard19848 Howard19848 Howard19849 Howard19848 Howard19858 Howard19858( Howard19858 Howard19868 Howard19868 Howard19866 Howard19868! Howard19868* Howard19869 Howard19876+ Howard19879 Howard19886 Howard19888 Howard19888 Howard19898, Howard19899 Howard19909 Howard19909. Howard19909\ Howard19949[ Howard19959W Howard19966R Howard19979LJakobsen19988NJakobsen19988$Jamieson19919%Jamieson19919Jamieson19919Jamieson19919%Jamieson19919Jamieson19919Jamieson19919Jamieson19919%Jamieson19919%Jamieson19919%Jamieson19919%Jamieson19919%Jamieson19919%Jamieson19919Jamieson19919%Jamieson19919Jamieson19919%Jamieson19919Jamieson19919%Jamieson19919%Jamieson19919Jamieson19919results in sterile immunity to Plasmodium yoelii, with no parasites detected in blood. Although such immunity depends upon high titer Abs at challenge, high doses of immune sera transferred into naive mice reduce parasitemia (and protect from death) but do not result in a similar degree of protection (with most mice experiencing high peak parasitemias); this finding suggests that ongoing parasite- specific immune responses postchallenge are essential. We analyzed this postchallenge response by transferring Abs into manipulated but malaria- naive mice and observed that Abs cannot protect SCID, nude, CD4+ T cell- depleted, or B cell knockout mice, with all mice dying. Thus, in addition to the Abs that develop following MSP119 vaccination, a continuing active immune response postchallenge is required for protection. MSP119-specific Abs can adoptively transfer protection to strains of mice that are not protected following vaccination with MSP119, suggesting that the Ags targeted by the immune response postchallenge include Ags apart from MSP119. These data have important implications for the development of a human malaria vaccine. J Immunolo 1999 162127309-14>7Hogh, B. Marbiah, N. T. Burghaus, P. A. Andersen, P. K.Relationship between maternally derived anti-Plasmodium falciparum antibodies and risk of infection and disease in infants living in an area of Liberia, west Africa, in which malaria is highly endemic 1995Infection & Immunity6310 4034-8 Oct"Holder, A. A. Freeman, R. R.VPImmunization against blood-stage rodent malaria using purified parasite antigens 1981 Nature 2949 361361-364 "Holder, A. A. Freeman, R. R.|Biosynthesis and processing of a Plasmodium falciparum schizont antigen recognized by immune serum and a monoclonal antibody 1982 J Exp Med 156 1528 1528-15382+Holder, A. A. Freeman, R. R. Newbold, C. I.Serological cross-reaction between high molecular weight proteins synthesized in blood schizonts of Plasmodium yoelii, Plasmodium chabaudi and Plasmodium falciparum 1983Mol Biochem Parasitol9 191191-196"Holder, A. A. Freeman, R. R.@:Protective antigens of rodent and human bloodstage malaria 1984$Philos Trans R Soc Lond :Biole"Holder, A. A. Freeman, R. R.The three major antigens on the surface of Plasmodium falciparum merozoites are derived from a single high molecular weight precursor 1984 J Exp Med 160 624$624-629˹Z0aF$R˹D<B@ALtr "Holder, A. A. Freeman, R. R.ZSCharacterization of a high molecular weight protective antigen of Plasmodium yoeliie 1984 Parasitology88 211211-219tPJHolder, A. A. Lockyer, M. J. Odink, K. G. Sandhu, J. S. Riveros, Moreno V.pjPrimary structure of the precursor to the three major surface antigens of Plasmodium falciparum merozoites 1985 Nature 317t 270e270-273 JDHolder, A. A. Sandhu, J. S. Hillman, Y. Davey, L. S. Nicholls, S. C.b\Processing of the precursor to the major merozoite surface antigens of Plasmodium falciparum 1987 Parasitology94 199199-208P3Holder, A. A Hillman, Y Nicholls, S. $#Ye v" D>Marsh, K. Otoo, L. Hayes, R. J. Carson, D. C. Greenwood, B. M.Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection Trans Roy Soc Trop Med Hyg 1989833293-303  Ref11 97471051ZSNewbold, C. I. Craig, A. G. Kyes, S. Berendt, A. R. Snow, R. W. Peshu, N. Marsh, K.R,%PfEMP1, polymorphism and pathogenesiss~Animal Blood Proteins/immunology/*metabolism Cell Adhesion Cell Adhesion Molecules/metabolism Endothelium, Vascular Erythrocyte Membrane/metabolism Human Malaria, Falciparum/etiology Membrane Proteins/immunology/*metabolism Plasmodium falciparum/metabolism/*pathogenicity Polymorphism (Genetics) Protozoan Proteins/immunology/*metabolism Receptors, Cell Surface/metabolism VirulenceThe virulence of Plasmodium falciparum relative to the other species of malarial parasite which infect humans is thought to be due to this parasite's ability to adhere to endothelial cells lining small blood vessels and, in some cases, to its ability to form rosettes with uninfected erythrocytes. The latter phenotype has been found more frequently in cases of severe disease. The former property means that only the younger, asexual, intra-erythrocytic forms circulate whereas the more mature developmental stages are sequestered in the vasculature of a variety of organs. When large numbers of parasites accumulate in a vulnerable target organ such as the brain, the the life-threatening condition of cerebral malaria may result. While the factors that control whether or not cerebral malaria develops are not clearly defined, one crucial determinant my be the endothelial receptors utilised by the infecting isolate. Many such receptors have been identified, including CD36, thrombospondin, ICAM-1, VCAM, E-selectin and chondroitin-4-sulphate. The results of laboratory, field, post- mortem and direct receptor-binding studies indicate that, of the receptors currently identified, ICAM-1 binding is more likely to be associated with the development of cerebral malaria. The molecule expressed on the surface of the infected erythrocyte which mediates adherence to endothelium belongs to a large family of clonally variable antigens encoded by the var genes. The evidence for this conclusion and progress in defining the regions of var-gene products responsible to receptor-specific binding are discussed. Finally, the organization of the var genes within and between parasites is discussed in relation to the evolution of the var-gene family and its functions of antigenic variation and endothelial adhesion.Ann Trop Med Parasitol 1997915 551-795365775 Nowak, R.r81Malaria. How the parasite disguises itself [news]rkAnimal Antigenic Variation/*genetics Antigens, Protozoan/genetics/immunology Blood Proteins/*genetics/immunology/physiology Erythrocyte Membrane *Genes, Protozoan Human Malaria, Falciparum/immunology/parasitology Membrane Proteins/*genetics/immunology *Multigene Family Plasmodium falciparum/*genetics/immunology Protozoan Proteins/*genetics/immunology/physiologycScience 1995 269i 5225 755P&Ockenhouse, C. F. Chulay, J. D.CPlasmodium falciparum sequestration: OKM5 antigen (CD36) mediates cytoadherence of parasitized erythrocytes to a myelomonocytic cell linen J Infect Dis 1988 157a 584n584-588rB