Host erythrocyte receptors for rosetting
McQuaid F, Rowe JA. Rosetting revisited: a critical look at the evidence for host erythrocyte receptors in Plasmodium falciparum rosetting. Parasitology. 2019  28:1-43. PMID:31455446
NAME Characteristics STUDIES* COMMENTS
ABO BLOOD GROUP ANTIGENS Differ based on terminal sugar:              A= N-acetyl-D-galactosamine,               B= D-galactose, Larger rosettes in parasites cultured in A, B, AB compared to O (Carlson & Wahlgren, 1992 PMID: 1402677; Udomsangpetch et al., 1993  PMID: 8447516; Barragan et al., 2000b PMID: 10768996) Blood group A antigen is the most well-validated host rosetting receptor.
O is predominant blood group in sub-Saharan Africa Rosettes from group O patients are more easily disrupted by immune sera and  removal of A/B antigen decreases rosette size (Barragan et al., 2000b PMID: 10768996) Both PfEMP1 (Vigan-Womas et al., 2012  PMID: 22807674) and RIFINs (Goel et al., 2015 PMID: 25751816) may interact with A antigen
Blood group O protects against severe malaria (Rowe et al., 2007 PMID: 17959777; Fry et al., 2008 PMID: 18003641 ; Tekeste & Petros, 2010 PMID: 20939876; Rout et al., 2012 PMID: 22818742; Malaria Genomic Epidemiology Network, 2014; Ndila et al., 2018 PMID: 30033078 ; Degarege et al., 2019 PMID: 30029997) Parasites from group O patients have lower rosetting compared to parasites from non-O patients (Rowe et al., 1995 PMID: 7768616; Rowe et al., 2007 PMID: 1795977; Rout et al., 2012 PMID: 22818742) Challenging to manipulate therapeutically
Blood group antigen binding site mapped to NTS-DBLa domain of PfEMP1-VarO (Vigan-Womas et al., 2012 PMID: 22807674)
COMPLEMENT RECEPTOR 1 (CR1) Membrane glycoprotein responsible for regulating the complement system (Thielen et al., 2018 PMID: 29397262) Rosetting reduced in CR1 deficient erythrocytes (Rowe et al., 1997 PMID: 9230440) Further work needed to assess the relative importance of CR1 in rosetting isolates and potential as a therapeutic target
Polymorphisms affect CR1 copy number, molecular weight and sequence (Schmidt et al., 2015 PMID: 25816986) Soluble CR1 and CR1 antibodies disrupt rosettes in some parasite isolates (Rowe et al., 1997 PMID: 9230440; Rowe et al., 2000 PMID: 11086071; Vigan-Womas et al., 2012  PMID: 22807674) Soluble recombinant CR1 has been considered for therapeutic use in humans e.g. cardiac and renal disease (Li et al., 2006 PMID: 17081086 ; Reddy et al., 2017 PMID: 27977428)
RBC CR1 deficiency protects in medium-high (Cockburn et al., 2004 PMID: 14694201; Sinha et al., 2009 PMID: 19480840; Rout et al., 2011 PMID: 22818742; Panda et al., 2012 PMID: 23152904 ) but not low malaria transmission areas (Nagayasu et al., 2001 PMID: 11425154; Teeranaipong et al., 2008 PMID: 18954261 ). Essential region mapped to C3b binding site on CR1 (Rowe et al., 2000 PMID: 11086071 )
CR1 Knops blood group polymorphisms associated with severe malaria (Opi et al., 2018 PMID: 29690995)
HEPARAN SULFATE (HS)** Glycosaminoglycan Heparin partially disrupts rosettes in some isolates (Udomsangpetch et al., 1989 PMID: 2654325; Carlson et al., 1992 PMID: 1599054; Rogerson et al., 1994 PMID: 7521140; Rowe et al., 1994 PMID: 8001661; Barragan et al., 1999 PMID: 9990341) Limited evidence that HS is present on mature RBCs (Vogt et al., 2004 PMID: 15209561)
Heparin is a highly sulfated form of HS that is only found in mast cells Heparinase treatment reported to reduce rosetting in two culture-adapted parasite lines (Barragan et al., 1999 PMID: 9990341) Further work needed to determine whether HS is present on normal erythrocytes and acts as a rosetting receptor
HS is a receptor for P. falciparum sporozoite invasion of hepatocytes (ב Heparin binds to rosetting iRBCs (Barragan et al., 2000a; Heddini et al., 2001) and to rosette-mediating PfEMP1 (Barragan et al., 2000a PMID: 10828049; Vogt et al., 2003 PMID: 1243368; Juillerat et al., 2010 PMID: 20045435 ; Juillerat et al., 2011 PMID: 21402930; Adams et al., 2014 PMID: 24343658 ) Therapeutic potential due to PfEMP1 binding and rosette disruption. Clinical trials of low anticoagulant heparin ongoing (Leitgeb et al., 2017 PMID: 29244851)
HS is a receptor for infected erythrocyte cytoadherence to endothelial cells (Vogt et al., 2003 PMID: 1243368; Adams et al., 2014 PMID: 24343658 ) Soluble CS did not disrupt rosettes (Rogerson et al., 1994 PMID: 752114; Rowe et al., 1994 PMID: 8001661)
CHONDROITIN SULFATE (CS) Glycosaminoglycan Chondroitinase treatment reduced rosetting in one parasite line only (Barragan et al., 1999 PMID: 9990341)  No evidence that CS is present on mature RBC
Receptor for infected erythrocyte placental sequestration in pregnancy malaria  (Fried & Duffy, 1996 PMID: 8633247) Minimal evidence for a role in rosetting
CD36 Widely distributed membrane protein and scavenger receptor (Silverstein & Febbraio, 2009 PMID: 19471024) Antibodies disrupt rosettes in single culture-adapted line only (Handunnetti et al., 1992) Minimal evidence for a widespread role in rosetting
Deficiency is common in Africa but not associated with severe malaria (Fry et al., 2009 PMID: 19403559) PfEMP1 variants that mediate rosetting are group A types that do not bind CD36 (Robinson et al., 2003 PMID: 12603733)
GLYCOPHORIN C (GYPC) Red cell membrane protein responsible for Gerbich blood group (Jaskiewicz et al., 2018 PMID: 29540278) Reduced rosetting with GYPC antibodies and GYPC knockdown RBCs (Niang et al., 2014 PMID: 25011110) (single culture-adapted parasite line tested) Further work needed to assess the relative importance of GYPC in P. falciparum rosetting isolates and potential as a therapeutic target
Receptor for merozoite invasion of erythrocytes (Maier et al., 2003 PMID: 1646190) Gerbich negative erythrocytes formed rosettes normally with five P. falciparum lines (Rowe et al., 1997 PMID: 9230440).
“Gerbich negative” blood group common in Melanesians (Patel et al., 2001 PMID: 11719395), but no evidence yet for association with protection against severe malaria. Possible role in P. vivax rosetting (Lee et al., 2014 PMID: 24652986)
GLYCOPHORIN A (GYPA) Sialoglycoprotein which, along with Glycophorin B, constitutes the MNS blood group GYPA deficient erythrocytes showed reduced rosetting with RIFIN transfected parasites  (Goel et al., 2015 PMID: 25751816) Further work needed to assess the relative importance of GYPA in P. falciparum rosetting isolates and potential as a therapeutic target
Receptor for merozoite invasion of erythrocytes (Sim et al., 1994 PMID: 8009226) GYPA antibodies had no inhibitory effect on rosetting (Lee et al., 2014 PMID: 24652986) (Niang et al., 2014 PMID: 25011110)
GYPA polymorphisms are associated with protection against severe malaria (Band et al., 2015 PMID: 2641675; Leffler et al., 2017). GYPA null erythrocytes formed rosettes with five culture-adapted P. falciparum lines (Rowe et al., 1997 PMID: 9230440 )
UNKNOWN RECEPTOR/S Possibly carbohydrate or protease-resistant protein Protease and heparinase treated erythrocytes capable of forming rosettes (Udomsangpetch et al., 1989 PMID: 2654325; Rowe et al., 1994 PMID: 8001661) Further work needed to identify novel rosetting receptors
*Note: Parasite strains used are not consistent between studies with a wide range of culture-adapted and clinical isolates in use. Results are therefore not necessarily generalizable from single studies.
**Note:  Many studies included here use heparin instead of/in addition to heparan sulfate
Adams et al., 2014 PMID: 24343658
Band et al., 2015 PMID: 2641675 
Barragan et al., 1999 PMID: 9990341
Barragan et al., 2000a PMID: 10828049
Barragan et al., 2000b PMID: 10768996
Carlson & Wahlgren, 1992 PMID: 1402677
Carlson et al., 1992 PMID: 1599054 
Cockburn et al., 2004 PMID: 14694201
Degarege et al., 2019 PMID: 30029997
Fried & Duffy, 1996 PMID: 8633247
Fry et al., 2008 PMID: 18003641
Fry et al., 2009 PMID: 19403559
Goel et al., 2015 PMID: 25751816
Handunnetti et al., 1992 PMID: 1382720
Heddini et al., 2001 PMID: 11500463
Jaskiewicz et al., 2018 PMID: 29540278
Juillerat et al., 2010 PMID: 20045435
Juillerat et al., 2011 PMID: 21402930
Lee et al., 2014 PMID: 24652986
Leffler et al., 2017 PMID: 28522690
Leitgeb et al., 2017 PMID: 29244851)
Li et al., 2006 PMID: 17081086
Ndila et al., 2018 PMID: 30033078
Niang et al., 2014 PMID: 25011110
Niang et al., 2014 PMID: 25011110
Opi et al., 2018 PMID: 29690995
Panda et al., 2012 PMID: 23152904
Patel et al., 2001 PMID: 11719395
Reddy et al., 2017 PMID: 27977428
Robinson et al., 2003 PMID: 12603733
Rogerson et al., 1994 PMID: 752114 
Rout et al., 2011 PMID: 22818742
Rowe et al., 1994 PMID: 8001661
Rowe et al., 1995 PMID: 7768616
Rowe et al., 1997 PMID: 9230440
Rowe et al., 2000 PMID: 11086071
Rowe et al., 2007 PMID: 17959777
Schmidt et al., 2015 PMID: 25816986
Silverstein & Febbraio, 2009 PMID: 19471024
Sim et al., 1994 PMID: 8009226
Sinha et al., 2009 PMID: 19480840
Tekeste & Petros 2010 PMID: 20939876
Thielen et al., 2018 PMID: 29397262
Udomsangpetch et al., 1989 PMID: 2654325
Udomsangpetch et al., 1993  PMID: 8447516
Vigan-Womas et al., 2012  PMID: 22807674
Vogt et al., 2003 PMID: 1243368 
Vogt et al., 2004 PMID: 15209561
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