The destruction of erythrocytes and defects in erythropoiesis are among the most frequently observed causes of morbidity in severe Plasmodium falciparum malaria. The molecular mechanisms involved remain unclear, despite extensive investigation. We show here, for the first time, that tagging with the parasite rhoptry protein ring surface protein 2 (RSP2) is not restricted to the surfaces of normal erythrocytes, as previously reported, but that it extends to erythroid precursor cells in the bone marrow of anemic malaria patients. Monoclonal mouse antibodies and human sera from patients with severe anemia, reacting with RSP2-tagged erythrocytes, induced cell destruction by phagocytosis and complement activation in vitro. Our observations reveal a new parasite mechanism implicated in the destruction of normal erythrocytes and probably dyserythropoiesis in malaria patients. These data suggest that the tagging of host cells with RSP2 may trigger anemia in falciparum malaria. IntroductionAnemia is undoubtedly the most common complication of Plasmodium falciparum infection 1,2 and is particularly severe in children and pregnant women living in endemic areas. Anemia is caused partly by the loss of red blood cells, both infected erythrocytes (IEs) and uninfected erythrocytes (UEs), which are destroyed by hemolysis or phagocytosis. 3 Rigidification of the membranes of IEs and UEs during infection may be an important factor in the destruction of these cells during passage through the spleen. 4,5 There seem to be many causes of anemia, and the underlying mechanisms remain elusive.Our recent studies on ring surface protein 2 (RSP2) suggest that this rhoptry molecule occasionally binds to the surface of UEs. 6 RSP2 has been identified as the highly conserved Rap2 gene found in all P falciparum isolates examined to date 7 (Sterkers Y., L. C., da Rocha M., Scheidig C., Lepolard C., Cowman A., G. J., and Scherf A., manuscript in preparation). Experimental evidence indicates that merozoites transfer RSP2 to the surfaces of erythrocytes, probably during aborted invasions, 6 suggesting a possible link to anemia in malaria patients.In this work, we used anti-RSP2 monoclonal antibodies and sera from P falciparum-infected anemia patients to investigate the role of RSP2 in the destruction of red blood cells. By modeling in vitro and ex vivo observations, we show that anti-RSP2 antibodies specifically react with cells of the erythroid lineage tagged with RSP2. We present experimental evidence that the antibody response against RSP2 can induce phagocytosis and complement binding to RSP2-tagged erythrocytes, leading to the destruction of otherwise normal erythrocytes. Finally, we show that merozoites can also label leukemic erythroblasts in vitro and erythroid precursors in the bone marrow of malaria patients with RSP2, possibly leading to erythropoietic dysfunction. Thus, we describe here a novel molecular mechanism of host-parasite interaction that may have severe consequences in malaria patients. Materials and methods Parasites and ce...

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). P. falciparum isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSAbinding, placental P. falciparum isolates

Chronic Q fever, which principally manifests as endocarditis, is characterized by Coxiella burnetii persistence and an impaired cell-mediated immune response. The long-term persistence of pathogens has been associated with the expansion of regulatory T cells (Tregs), the CD4(+) T-cell subset that is characterized by the expression of CD25 and Foxp3. We investigated the presence of Tregs in patients with acute Q fever (n = 17), known to exhibit an efficient immune response, patients with Q fever endocarditis (n = 54) and controls (n = 27) by flow cytometry. The proportion of CD3(+) , CD4(+) and CD8(+) T cells was similar in controls and patients with Q fever. The percentage of CD4(+) T cells that expressed CD25 was similar in controls and patients with Q fever. The population of CD4(+) T cells that expressed both CD25 and Foxp3 was significantly (P < 0.001) increased in patients with Q fever endocarditis compared with controls. Our data suggest that the expansion of Tregs may be critical for the chronic evolution of Q fever.