A human complement receptor 1 polymorphism that reduces<i>Plasmodium falciparum</i>rosetting confers protection against severe malaria

Cockburn, Ian A.; Mackinnon, Margaret J.; O’Donnell, A.; Allen, Stephen; Moulds, Joann M.; Baisor, Moses; Bockarie, Moses J.; Reeder, John C.; Rowe, J. Alexandra

doi:10.1073/pnas.0305306101

Cited by 218 publications

(208 citation statements)

References 49 publications

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“…Thus, receptor polymorphisms and host immune responses against individual ligands might lead to inhibition of particular invasion pathways. The population of Madang, PNG, has the lowest CR1 levels reported to date (28). Our results indicate that the PfRh4-CR1 invasion pathway was less effective in the presence of low-CR1 erythrocytes, most likely due to limited receptor availability.…”

Section: Discussionmentioning

confidence: 45%

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

Tham

Wilson

Lopaticki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

195

205

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Plasmodium falciparum is responsible for the most severe form of malaria disease in humans, causing more than 1 million deaths each year. As an obligate intracellular parasite, P. falciparum's ability to invade erythrocytes is essential for its survival within the human host. P. falciparum invades erythrocytes using multiple host receptor-parasite ligand interactions known as invasion pathways. Here we show that CR1 is the host erythrocyte receptor for PfRh4, a major P. falciparum ligand essential for sialic acid-independent invasion. PfRh4 and CR1 interact directly, with a K d of 2.9 μM. PfRh4 binding is strongly correlated with the CR1 level on the erythrocyte surface. Parasite invasion via sialic acid-independent pathways is reduced in low-CR1 erythrocytes due to limited availability of this receptor on the surface. Furthermore, soluble CR1 can competitively block binding of PfRh4 to the erythrocyte surface and specifically inhibit sialic acid-independent parasite invasion. These results demonstrate that CR1 is an erythrocyte receptor used by the parasite ligand PfRh4 for P. falciparum invasion.malaria | red blood cell | merozoite | reticulocyte-binding-like homologue

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Section: Discussionmentioning

confidence: 45%

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

Tham

Wilson

Lopaticki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

195

205

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“…The extra affinity provided by the hydrophobic component of the binding site enables M proteins to compete for binding with glycosaminoglycans and with the convertase even when the latter is in excess following amplification. Because M proteins exploit some positively charged residues that are important for both glycosaminoglycan binding and complement regulation, it is less likely that C4BP variants with low affinity for M proteins will provide an advantage to the host, as proposed for CR1 and resistance to Plasmodium falciparum-induced rosetting in malaria-exposed populations (46). The conformational change that accompanies binding was unexpected, given that the free form of the protein has a preexisting defined orientation.…”

Section: Discussionmentioning

confidence: 99%

Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor

Jenkins

Mark

Ball

et al. 2006

Journal of Biological Chemistry

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Human C4b-binding protein (C4BP) protects host tissue, and those pathogens able to hijack this plasma glycoprotein, from complement-mediated destruction. We now show that the first two complement control protein (CCP) modules of the C4BP ␣-chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein. Structure determination by NMR reveals two tightly coupled CCP modules in an elongated arrangement within this region of C4BP. Chemical shift perturbation studies demonstrate that the N-terminal, hypervariable region of M4 binds to a site including strand 1 of CCP module 2. This interaction is accompanied by an intermodular reorientation within C4BP. We thus provide a detailed picture of an interaction whereby a pathogen evades complement.Bacteria that enter human blood or tissues will be opsonized by complement and destroyed by phagocytes unless they have a means of overcoming attack by the complement system. An extensively studied example of such a virulence mechanism is the ability of many Streptococcus pyogenes M proteins to bind the key human complement regulator C4b-binding protein (C4BP), 2 an interaction that endows the bacteria with resistance to phagocytosis (1). C4BP is a polymeric, soluble, glycoprotein (ϳ200 mg/liter in plasma) (2). The M proteins, classical bacterial virulence factors first recognized over 75 years ago (3), are fibrillar surface structures exhibiting antigenic variation within a 50 -100-amino acid residue hypervariable N terminus (4, 5). Expression of M protein is important for the ability of S. pyogenes to cause the diseases associated with this pathogen: acute pharyngitis and impetigo (6). Many other pathogens share the ability to sequester C4BP (7-12). Thus escape from complement attack by hijacking of C4BP is emerging as a widespread contributor to immune evasion strategies and is a therapeutic target.The complement system, a vital molecular component of innate immunity, consists of plasma and cell-surface proteins that conspire to rid the body of infectious particles (13,14). Because complement is potentially harmful to host tissue it is tightly regulated. Like other members of the regulators of complement activation (RCA) protein family, the plasma protein C4BP acts upon the bimolecular C3 convertases that are the main drivers of the complement cascade. The C3 convertases cleave and thereby activate the third component of complement, C3, leading to deposition of C3b on the surface of an unprotected particle such as an invading microorganism. This process, known as opsonization, marks the particle as a target for phagocytosis. C3b also nucleates assembly of further convertase complexes and progression of the cascade toward formation of the membrane attack complex. C4BP regulates the C3 convertase of the classical pathway, a complex of C4b and C2a, by acting as a cofactor for the proteolysis of C4b (15, 16) and accelerating the decay of C4b⅐C2a complexes deposited on host cells (17...

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“…For example, in Europeans, the rs11118133 T allele also correlates with decreased rosetting of malaria with erythrocytes, 17,18 a property that may offer protection against cerebral malaria, and in Papua New Guinea this polymorphism correlates with decreased disease severity. 21,23 Importantly, the rs2274567 G allele that is within the dominant Sardinian haplotype has been found at much higher frequency in malaria endemic than in non-endemic regions of India. 20 Recently, Tham et al 14 have provided strong evidence that CR1 is the host erythrocyte receptor for the reticulocyte-binding-like homolog protein PfRh4, a major P. falciparum ligand that is essential for sialic-acidindependent invasion.…”

Section: Introductionmentioning

confidence: 99%

Evidence for malaria selection of a CR1 haplotype in Sardinia

et al. 2011

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Complement receptor 1 (CR1) levels have been associated with malarial susceptibility and/or severity of the disease in different population groups, and CR1 is a receptor for Plasmodium falciparum. In this study, multiple CR1 single-nucleotide polymorphisms (SNPs) showed strong evidence of population differentiation between Sardinian and other European ethnic groups. Cross population algorithms comparing haplotype structure and differences in haplotype and allele frequency distribution provided additional support for natural selection of CR1 in Sardinia. The predominant Sardinian CR1 haplotype included SNPs that are associated with decreased CR1 levels in Europeans and other population groups. Previous studies have shown that the SNPs within the dominant Sardinian haplotype have a significantly higher frequency in a malaria endemic compared with non-endemic regions in India. Together with the historical evidence of the prevalence of malaria in Sardinia, these data support the role of malaria leading to positive selection of this CR1 haplotype in Sardinia.

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A human complement receptor 1 polymorphism that reducesPlasmodium falciparumrosetting confers protection against severe malaria

Cited by 218 publications

References 49 publications

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor

Evidence for malaria selection of a CR1 haplotype in Sardinia

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