| 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 | ||