Table 1.

Summary of host erythrocyte receptors for Plasmodium falciparum rosetting

Name	Characteristics	Studiesa	Comments
ABO blood group antigens	Differ based on terminal sugar: A = N-acetyl-D-galactosamine, B = D-galactose, O (H-antigen) = L-Fucose O is a predominant blood group in sub-Saharan Africa Blood group O protects against severe malaria (Rowe et al., 2007; Fry et al., 2008; Tekeste and Petros, 2010; Rout et al., 2012; Malaria Genomic Epidemiology Network, 2014; Ndila et al., 2018; Degarege et al., 2019)	Larger rosettes in parasites cultured in A, B, AB compared to O (Carlson and Wahlgren, 1992; Udomsangpetch et al., 1993; Barragan et al., 2000b) Parasites from group O patients have lower mean rosette frequencies than those from non-O patients (Rowe et al., 1995; Rowe et al., 2007; Rout et al., 2012) 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) Blood group antigen binding site mapped to NTS-DBLα the domain of PfEMP1-VarO (Vigan-Womas et al., 2012)	Blood group A antigen is the most well-validated host rosetting receptor Both PfEMP1 (Vigan-Womas et al., 2012) and RIFINs (Goel et al., 2015) may interact with A antigen Challenging to manipulate therapeutically
Complement receptor 1 (CR1)	Membrane glycoprotein responsible for regulating the complement system (Thielen et al., 2018) Polymorphisms affect CR1 copy number, molecular weight and sequence (Schmidt et al., 2015) RBC CR1 deficiency protects in medium-high (Cockburn et al., 2004; Sinha et al., 2009; Rout et al., 2011; Panda et al., 2012) but not low malaria transmission areas (Nagayasu et al., 2001; Teeranaipong et al., 2008). CR1 Knops blood group polymorphisms associated with severe malaria (Opi et al., 2018)	Rosetting reduced in CR1 deficient erythrocytes (Rowe et al., 1997) Soluble CR1 and CR1 antibodies disrupt rosettes in some parasite isolates (Rowe et al., 1997; Rowe et al., 2000; Vigan-Womas et al., 2012) Essential region mapped to the C3b binding site on CR1 (Rowe et al., 2000)	Further work needed to assess the relative importance of CR1 in rosetting isolates and potential as a therapeutic target Soluble recombinant CR1 has been considered for therapeutic use in humans, e.g. cardiac and renal disease (Li et al., 2006; Reddy et al., 2017)
Heparan sulphate (HS)b	Glycosaminoglycan Heparin is a highly sulfated form of HS that is only found in mast cells HS is a receptor for P. falciparum sporozoite invasion of hepatocytes (Frevert et al., 1993) HS is a receptor for infected erythrocyte cytoadherence to endothelial cells (Vogt et al., 2003; Adams et al., 2014)	Heparin partially disrupts rosettes in some isolates (Udomsangpetch et al., 1989; Carlson et al., 1992; Rogerson et al., 1994; Rowe et al., 1994; Barragan et al., 1999) Heparinase treatment reported to reduce rosetting in two culture-adapted parasite lines (Barragan et al., 1999) Heparin binds to rosetting IE (Barragan et al., 2000a; Heddini et al., 2001) and to rosette-mediating PfEMP1 (Barragan et al., 2000a; Vogt et al., 2003; Juillerat et al., 2010; Juillerat et al., 2011; Adams et al., 2014)	Limited evidence that HS is present on mature RBCs (Vogt et al., 2004) Further work needed to determine whether HS is present on normal erythrocytes and acts as a rosetting receptor Therapeutic potential due to PfEMP1 binding and rosette disruption. Clinical trials of low anticoagulant heparin ongoing (Leitgeb et al., 2017)
Chondroitin sulphate (CS)	Glycosaminoglycan Receptor for infected erythrocyte placental sequestration in pregnancy malaria (Fried and Duffy, 1996)	Soluble CS did not disrupt rosettes (Rogerson et al., 1994; Rowe et al., 1994) Chondroitinase treatment reduced rosetting in one parasite line only (Barragan et al., 1999)	No evidence that CS is present on mature RBC Minimal evidence for a role in rosetting
CD36	Widely distributed membrane protein and scavenger receptor (Silverstein and Febbraio, 2009) Deficiency is common in Africa but not associated with severe malaria (Fry et al., 2009)	Antibodies disrupt rosettes in single culture-adapted line only (Handunnetti et al., 1992) PfEMP1 variants that mediate rosetting are group A types that do not bind CD36 (Robinson et al., 2003)	Minimal evidence for a widespread role in rosetting
Glycophorin C (GYPC)	Red cell membrane protein responsible for Gerbich blood group (Jaskiewicz et al., 2018) Receptor for merozoite invasion of erythrocytes (Maier et al., 2003) ‘Gerbich-negative’ blood group common in Melanesians (Patel et al., 2001), but no evidence yet for association with protection against severe malaria	Reduced rosetting with GYPC antibodies and GYPC knockdown RBCs (Niang et al., 2014) (single culture-adapted parasite line tested) Gerbich-negative erythrocytes formed rosettes normally with five P. falciparum lines (Rowe et al., 1997) Possible role in P. vivax rosetting (Lee et al., 2014)	Further work needed to assess the relative importance of GYPC in P. falciparum rosetting isolates and potential as a therapeutic target
Glycophorin A (GYPA)	Sialoglycoprotein which, along with glycophorin B, constitutes the MNS blood group Receptor for merozoite invasion of erythrocytes (Sim et al., 1994) GYPA polymorphisms are associated with protection against severe malaria (Band et al., 2015; Leffler et al., 2017).	GYPA-deficient erythrocytes showed reduced rosetting with RIFIN transfected parasites (Goel et al., 2015) GYPA antibodies had no inhibitory effect on rosetting (Lee et al., 2014) (Niang et al., 2014) GYPA null erythrocytes formed rosettes with five culture-adapted P. falciparum lines (Rowe et al., 1997)	Further work needed to assess the relative importance of GYPA in P. falciparum rosetting isolates and potential as a therapeutic target
Unknown receptor/s	Possibly carbohydrate or protease-resistant protein	Protease and heparinase treated erythrocytes capable of forming rosettes (Udomsangpetch et al., 1989; Rowe et al., 1994)	Further work needed to identify novel rosetting receptors

^aParasite 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.

^bMany studies included here use heparin instead of/in addition to heparan sulphate.