Lack of Evidence from Studies of Soluble Protein Fragments that Knops Blood Group Polymorphisms in Complement Receptor-Type 1 Are Driven by Malaria

Abstract

Complement receptor-type 1 (CR1, CD35) is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K D = 0.8–1.1 µM) and C4b (K D = 5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

“…CR1 interacts with two P. falciparum proteins, the malarial adhesin PfEMP1 (14) and the PfRh4 invasion ligand (15), but the binding sites have been located to the C3b and C4b binding sites of CR1, respectively (20,21). Consistent with these locations, Tetteh-Quarcoo et al (56) observed no difference between the Knops blood group variants McC a/b and Sl1/2 in the ability of the CR1 fragment CCP15-25 to interact with PfRh4 or to disrupt PfEMP1-dependent P. falciparum rosetting (56). It should be mentioned that the same study assigned the C1q binding site to a CR1 region encompassing CCPs 15-25, with a suggested major contribution of CCPs 15-17, using recombinant CR1 fragments produced in yeasts and treated with endoglycosidase H (56).…”

Association of Complement Receptor Type-1 (CD35) Gene Polymorphism with P. falciparum Malarial infection in Vindhyan region of Madhya Pradesh, India

“…Our study is also showing high expression of CR1 on RBCs facilitate binding of plasmodium and increased level of TNF-α Cytokine in blood. TNF-α is anti-inflammatory cytokine and act as a marker to malarial infection [24]. TNF-α level in Healthy and case population reveal strong association (P<0.0001***) that is similar to P.B.…”

More than just immune evasion: Hijacking complement by Plasmodium falciparum

“…The two copies of Site 2 (i.e. CCPs 8-10 and 15-17) bind C3b and C4b efficiently (Tetteh-Quarcoo et al, 2012) and act as cofactors for Factor I cleavage of C3b and C4b (Ross et al, 1982). In the full length ectodomain (which corresponds to soluble CR1 (sCR1)) these sites cooperate to bind the principle ligands C3b and C4b thus leading to higher affinities than observed for each single site (TettehQuarcoo et al, 2012;Tham et al, 2011).…”

“…Laboratory experiments with the E1590/G1601 phenotype showed reduction of rosette formation (Rowe et al, 1997). More recently the underlying Knops antigens were examined for their ability to influence CR1 functional activities, but no difference was found (Tetteh-Quarcoo et al, 2012). In addition, the Knops antigen variants did not exhibit any inhibition of either parasites invasion or rosette formation (Tetteh-Quarcoo et al, 2012).…”

“…More recently the underlying Knops antigens were examined for their ability to influence CR1 functional activities, but no difference was found (Tetteh-Quarcoo et al, 2012). In addition, the Knops antigen variants did not exhibit any inhibition of either parasites invasion or rosette formation (Tetteh-Quarcoo et al, 2012). It has also been investigated whether the Sl2/McC b alleles associate with reduced susceptibility to severe malaria, but several studies failed to produce concordant results (Gandhi et al, 2009;Jallow et al, 2009;Thathy et al, 2005;Zimmerman et al, 2003).…”