Article

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

The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(40):17327-32. DOI: 10.1073/pnas.1008151107
Source: PubMed

ABSTRACT

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.

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    • "To test the CR1 phenotype of the PNH erythrocytes 200 μl of whole blood from the PNH patient or a healthy control were used to extract DNA using the QIAamp DNA Blood Mini Kit (Qiagen). Samples were genotyped for the SNP (A/G) in the CR1 gene at nucleotide 3650 in exon 22, which was analysed by restriction enzyme digest by RsaI, as described in (Tham et al., 2010; Xiang et al., 1999). In brief, a 682 base pair spanning sequence within exon 22 was amplified via PCR using the cloned Pfu ® DNA Polymerase (Agilent Technologies) according to the suppliers protocol and the forward primer 5'-ttcacattggatagccagagc-3' and the reverse primer 5'-ccagaggttaatctccctgga-3'. "
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    ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients. Novel C3-opsonin targeted complement inhibitors act earlier in the cascade, at the level of activated C3 and are engineered from parts of the natural complement regulator Factor H (FH) or complement receptor 2 (CR2). This inhibitor class comprises three variants of “miniFH” and the clinically developed “FH-CR2” fusion-protein (TT30). We show that the approach of FH-CR2 to target C3-opsonins was more efficient in preventing complement activation induced by foreign surfaces, whereas the miniFH variants were substantially more active in controlling complement on PNH erythrocytes. Subtle differences were noted in the ability of each version of miniFH to protect human PNH cells. Importantly, miniFH and FH-CR2 interfered only minimally with complement-mediated serum killing of bacteria when compared to untargeted inhibition of all complement pathways by eculizumab. Thus, the molecular design of each C3-opsonin targeted complement inhibitor determines its potency in respect to the nature of the activator/surface providing potential functionality in PNH.
    No preview · Article · Jan 2016 · Immunobiology
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    • "Interestingly, RBC invasion involves the human complement receptor CR-1, which is recognized by the reticulocyte-binding-like protein Rh4 located on the apical pole of the MZ (Spadafora et al., 2010; Tham et al., 2010). Approximately 1000 CR-1 receptors cover the RBC surface, recognize C3b-opsonized immune complexes and transport these to the liver-resident Kupffer cells for phagocytosis (Taylor et al., 1997; van Lookeren Campagne et al., 2007). "
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    ABSTRACT: The acquisition of regulatory proteins is a means of blood-borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL-1 and CFHR-1 to their surface, and FH-binding is trypsin-resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH-mediated protection via anti-FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Cellular Microbiology
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    • "During invasion, merozoite adhesins localize to the apical tip of the merozoite and interact with specific host receptors to initiate parasite entry [29]. A number of studies show that P. falciparum uses a key functional site in C receptor type-1 (CR1) for invasion of human Es [30], [31], [32]. CR1 is also the receptor for C3b, and as shown in Figure 3, the clustering of C3b deposition bears the hallmark of CR1 clustered distribution on the E [33]. "
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    ABSTRACT: Background Complement (C) is a crucial part of the innate immune system and becomes over activated during malaria, resulting in depletion of C components, especially those for lectin pathway (LP), thereby compromising the host's innate defense. In this study, involvement of P. falciparum antigens in C activation was investigated. Methods A highly synchronous culture of the Dd2 clone of P. falciparum was established in a serum free medium. Supernatants harvested from rings, trophozoites and schizonts at various parasite densities were tested for ability to activate C by quantifying amount of C3b deposited on erythrocytes (E). Uninfected sham culture was used as control. Remnants of each C pathway were determined using Wieslab complement System Screenkit (Euro-diagnostica, Sweden). To identify MBL binding antigens of LP, culture supernatants were added to MBL sepharose columns and trapped antigens eluted with increasing concentrations of EDTA (10 mM, 50 mM and 100 mM) and then desalted before being tested for ability to activate C. The EDTA eluate with highest activity was run on a polyacrylamide gel and silver stained proteins analyzed by mass spectroscopy. Results Antigens released by P. falciparum growing in culture activated C leading to C3b deposition on E. Maximal activation at 7% parasitemia was associated with schizont stage (36.7%) compared to 22% for rings, 21% for trophozoites and 3% for sham culture. All the three pathways of C were activated, with highest activation being for the alternative pathway (only 6% of C activation potential remained), 65% for classiical and 43% for the LP. Seven MBL binding merozoite proteins were identified by mass spectrometry in the 50 mM EDTA eluate. Conclusions MBL binding merozoite adhesins with ability to activate C pathway were identified. The survival advantage for such pronounced C activation is unclear, but opsonisation could facilitate recognition and invasion of E.
    Full-text · Article · Aug 2014 · PLoS ONE
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