Role of nonimmune IgG bound to PfEMP1 in placental malaria.

Infections with Plasmodium falciparum during pregnancy lead to the accumulation of parasitized red blood cells (infected erythrocytes, IEs) in the placenta. IEs of P. falciparum isolates that infect the human placenta were found to bind immunoglobulin G (IgG). A strain of P. falciparum cloned for IgG binding adhered massively to placental syncytiotrophoblasts in a pattern similar to that of natural infections. Adherence was inhibited by IgG-binding proteins, but not by glycosaminoglycans or enzymatic digestion of chondroitin sulfate A or hyaluronic acid. Normal, nonimmune IgG that is bound to a duffy binding-like domain beta of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) might at the IE surface act as a bridge to neonatal Fc receptors of the placenta.

Rouleaux-forming serum proteins are involved in the rosetting of Plasmodium falciparum-infected erythrocytes.

Excessive sequestration of Plasmodium falciparum-infected (pRBC) and uninfected erythrocytes (RBC) in the microvasculature, cytoadherence, and rosetting, have been suggested to be correlated with the development of cerebral malaria. P. falciparum erythrocyte membrane protein-1 (PfEMP1) is the parasite-derived adhesin which mediates rosetting. Herein we show that serum proteins are crucial for the rosette formation of four strains of parasites (FCR3S1, TM284, TM180, and R29), whereas the rosettes of a fifth strain (DD2) are serum independent. Some parasites, e.g., FCR3S1, can be depleted of all rosettes by washes in heparin and Na citrate and none of the rosettes remain when the parasite is grown in foetal calf serum or ALBUMAX. Rosettes of other parasites are less sensitive; e.g., 20% of TM180 and R29 and 70% of TM284 rosettes still prevail after cultivation. A serum fraction generated by ion-exchange chromatography and poly-ethylene-glycol precipitation restored 50% of FCR3S1 and approx 40 to 100% of TM180 rosettes. In FCR3S1, antibodies to fibrinogen reverted the effect of the serum fraction and stained fibrinogen bound to the pRBC surface in transmission electron microscopy. Normal, nonimmune IgM and/or IgG was also found attached to the pRBC of the four serum-dependent strains as seen by surface immunofluorescens. Our results suggest that serum proteins, known to participate in rouleaux formation of normal erythrocytes, produce stable rosettes in conjunction with the recently identified parasite-derived rosetting ligand PfEMP1.

The time course of cytoadhesion, immunoglobulin binding, rosette formation, and serum-induced agglutination of Plasmodium falciparum-infected erythrocytes.

We describe morphologic characteristics of acridine orange-stained Plasmodium falciparum-infected erythrocytes and the sequential expression of several adhesion phenomena. In particular, we have studied when the adhesive and antigenic modifications appear on the infected erythrocyte surface that mediate binding to C32 melanoma cells (cytoadherence) or to erythrocytes (rosette formation) during a complete 48-hr life cycle of the parasite. The C32 melanoma cell binding started at about 12 hr and was seen during the whole life cycle with a peak around 28 hr (650 infected erythrocytes/100 C32 melanoma cells). Rosettes started to appear and immunoglobulin was found bound to the parasitized red blood cell (PRBC) somewhat later (16-20 hr). These adhesive events culminated at the mid-trophozoite/schizont stage (24-36 hr) with rosette formation and an immunoglobulin binding rate of about 50%, which decreased to about half of the peak values at the end of the life cycle. Serum-induced agglutination of the infected erythrocytes was also most extensive at 24-36 hr, but agglutination was seen with all late stage parasites, i.e., both trophozoites and schizonts at 24-48 hr of age. Taken together, adhesion to C32 melanoma cells starts prior to that of rosette formation, immunoglobulin binding, or serum-induced agglutination.

Extensive immunoglobulin binding of Plasmodium falciparum-infected erythrocytes in a group of children with moderate anemia.

Immunoglobulins (Ig) from healthy, nonimmune individuals bind to the surfaces of Plasmodium falciparum-infected erythrocytes (RBC). In order to investigate the presence of this parasite phenotype in wild isolates and its potential association with malarial anemia, we conducted a study of 207 anemic or nonanemic children with malaria in Gabon. Surface Ig binding to infected RBC was detected for 83% of the isolates. No difference in Ig binding between the groups was observed, but all isolates which exhibited extensive Ig binding were found in a group of moderately anemic children.

Novel fibrillar structure confers adhesive property to malaria-infected erythrocytes.

Infections with the malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected by mature forms of the parasite. Sequestration seems critical for the survival of the parasite, but may lead to excessive binding in the microvasculature and death of the human host. We report here that a novel electrondense fibrillar structure, containing immunoglobulins M or M and G, is found at the surface of infected erythrocytes that adhere to host cells. In cases of cerebral malaria, fibrillar strands are also seen in the microvasculature at autopsy. Our findings may explain the adhesive mechanism by which malaria-infected erythrocytes cause the vascular obstruction seen in complicated malaria infections.

Rosetting.

Why do some individuals get severe falciparum malaria while others don't? Rosetting (the binding of uninfected erythrocytes to Plasmodium falciparum-infected erythrocytes), together with endothelial cytoadherence, has been shown to play a crucial role in the obstruction of the microvosculoture in P. falciparum malaria. Here, Mats Wahlgren, Victor Fernandez, Carin Scholonder and Johan Carlson review the literature surrounding rosetting.

Anti-idiotypic antibodies against Puumala virus glycoprotein-specific monoclonal antibodies inhibit virus infection in cell cultures.

Rabbit anti-idiotypic antibodies (anti-ids) were generated against three bank vole and one human monoclonal antibody (MAb) specific for the two envelope glycoproteins of Puumala virus (G1 and G2). The anti-ids were purified by sequential immunoaffinity chromatography. Each anti-id inhibited the antigen binding of its respective MAb in a competitive ELISA. This inhibition, and the absence of cross-reactivity among the anti-ids for heterologous MAbs, showed that they all were specific for unique determinants on the antigen binding site of the homologous MAb. The anti-ids reacted with non-infected Vero E6 cells when examined by immunofluorescence and ELISA, indicating the presence of antibodies that mimic epitopes on the virus. Preincubation of Vero E6 cells with two of the anti-ids produced against neutralizing MAbs inhibited Puumala virus infection, suggesting that these two anti-ids blocked a cellular component involved in virus infection.