Steve M. Taylor; Carla Cerami; Rick M. Fairhurst

“ It is during this time that parasites sequentially invade and egress from their host RBCs and cause the signs and symptoms of malaria. While developing within the RBC, the parasite traffics proteins to the RBC surface that mediate binding to extracellular host receptors and enable the parasite to sequester in the placenta, brain, and virtually every other organ. The attenuation of malaria by repeated, sub-lethal P. falciparum infections suggests a significant role for adaptive immunity, but the targets of this attenuating immune response remain largely obscure. ”

“ These genetic traits—including hemoglobin S (HbS) , hemoglobin C (HbC) , and α-thalassemia—are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait) . Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. ”

“ In combining mouse models of human cerebral malaria and of human sickle-cell trait, Ferreira et al. [82] demonstrated that mice carrying RBCs with human HbS were protected from cerebral malaria. Furthermore, they provided evidence that this protection is associated with chronically elevated production of HO-1 and with reduced production of inflammatory cerebral chemokines during infection. However, the interpretation that HO-1 activity may mediate HbS-associated protection from malaria in mice is complicated by elegant recent work on severe malaria in humans [83] . ”

“ As noted above, field evidence indicates that hemoglobinopathies do not impair parasite infection but instead attenuate malaria; this pattern suggests that protection from malaria syndromes is not mediated against the pre-erythrocytic stages of the P. falciparum life-cycle, and that hemoglobinopathies may influence the transition from parasite infection to disease. ”

“ Two major pathogenic phenotypes of iRBCs have been described: those that mediate binding of iRBCs to endothelial receptors (“cytoadherence”) [37] and those that mediate binding of iRBCs to uninfected RBCs (“rosetting”) [38] , [39] . Both adherence phenotypes are conferred by the expression of P. falciparum erythrocyte membrane protein 1 (PfEMP1) [40] – [41] , a family of highly variant proteins that are concentrated in protuberant structures called “knobs” on the iRBC surface. Different PfEMP1 variants mediate the binding of iRBCs to microvascular endothelial cells (via CD36, ICAM-1, etc.) ”

“ It remains to be fully investigated whether they enhance IgG recognition of specific variants of PfEMP1 or other surface antigens that are known to play a role in malaria immunity.
Antibody-mediated phagocytosis of iRBCs is believed to be an important effector mechanism in protection from malaria. Investigations with normal RBCs have demonstrated that monocytes preferentially phagocytose iRBCs compared to uninfected RBCs, and that this preference is potentiated by the binding of IgG to iRBCs [101] . ”

“ Remarkably, these simple polymorphisms confer dramatic levels of protection from a complex disease: for HbAS, the substitution of glycine with valine at amino acid position 6 in only one of two β-globin chains reduces a child's risk of severe falciparum malaria by about 90% [7] .
Table 1 "The major hemoglobinopathies: epidemiology, molecular pathology, and clinical phenotype. (10.1371/journal.ppat.1003327.t001) "The human genome normally contains four copies of α-globin genes (in paired copies on chromosome 16: genotype αα/αα) and two copies of β-globin genes (on chromosome 11) . ”

“ In falciparum malaria, these innate immune responses are potently initiated through the activation of TLRs on leukocytes by both PfGPI [69] and hemozoin (the product of heme polymerization) [70] , [71] , as well as by microvascular inflammation caused by PfEMP1-mediated binding of iRBCs to endothelium (see above) [72] . In murine models, the outcome of malaria is sensitive to experimental manipulation of multiple host innate response molecules, such as tumor necrosis factor (TNF) , interferon-γ [73] , and erythropoietin [74] , suggesting their role in mediating differential infection outcome. ”

“ The innate host defense response encompasses myriad stereotypical pathways that are activated by microorganisms and orchestrated to mitigate insults while minimizing collateral toxicity (reviewed in [61] ) . ”

“ For HbS-containing RBCs specifically, several reports have implicated enhanced sickling of iRBCs as a mechanism of malaria protection. Luzzatto et al. [33] and Roth et al. [34] separately reported increased sickling of HbAS iRBCs at low oxygen tension compared to HbAA iRBCs. Similarly, Friedman [27] described comparable parasite growth rates in HbAA, HbAS, and HbSS RBCs at high oxygen tension (18%) , but sickling and destruction of parasites in HbAS and HbSS RBCs at lower oxygen tensions (1%–5%) that more closely mimic the micro-aerophilic environment of post-capillary venules in vivo. ”

“ Cross-sectional studies of children with hemoglobinopathies in Nigeria [94] , the Gambia [95] , Cameroon [96] , Gabon [97] , [98] , and Burkina Faso [99] have yielded inconsistent results, with some demonstrating higher seroreactivity to specific or variant surface P. falciparum antigens of heterologous parasites in HbAS children, and others reporting no differences. These findings were explored by measuring seroreactivity to a panel of 491 P. falciparum proteins in Malian children before and after a well-defined malaria transmission season [100] ”

“ Nwachuku-Jarrett, ES & Reddy, S, “Increased sickling of parasitised erythrocytes as mechanism of resistance against malaria in the sickle-cell trait”, Lancet 1: 319–321, [ [pmid:4189578 LuzzattoLNwachuku-JarrettESReddyS] ] ↑ Roth, EF; Friedman, M; Ueda, Y; Tellez, I & Trager, W, “Sickling rates of human AS red cells infected in vitro with Plasmodium falciparum malaria”, Science 202: 650–652, [ [pmid:360396 RothEFJrFriedmanMUedaYTellezITragerWet al] ] ↑ Chen, SY ”

“ Howard, RJ & Pasloske, BL, “Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1”, Proc Natl Acad Sci U S A 93: 3497–3502, [ [pmid:8622965 BaruchDIGormelyJAMaCHowardRJPasloskeBL] ] ↑ Carlson, J; Helmby, H; Hill, AV; Brewster, D & Greenwood, BM, “Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies”, Lancet 336: 1457–1460, [ [pmid:1979090 CarlsonJHelmbyHHillAVBrewsterDGreenwoodBMet al] ] ↑ Kaul, DK; Roth, EF ”

“ Guinet, F & Herrfeldt, JA, “The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes”, Cell 82: 89–100, [ [pmid:7606788 SuXZHeatwoleVMWertheimerSPGuinetFHerrfeldtJAet al] ] ↑ Baruch, DI; Pasloske, BL; Singh, HB; Bi, X & Ma, XC, “Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes”, Cell 82: 77–87, [ [pmid:7541722 BaruchDIPasloskeBLSinghHBBiXMaXCet al] ] ↑ Raventos-Suarez, C ”

“ Latz, E & Monks, BG, “Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9”, Proc Natl Acad Sci U S A 104: 1919–1924, [ [pmid:17261807 ParrochePLauwFNGoutagnyNLatzEMonksBGet al] ] ↑ Jaramillo, M; Plante, I; Ouellet, N; Vandal, K & Tessier, PA, “Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection”, J Immunol 172: 3101–3110, [ [pmid:14978116 JaramilloMPlanteIOuelletNVandalKTessierPAet al] ] ↑ Tripathi, AK ”

“ Telen, MJ & Chi, JT, “The genomic analysis of erythrocyte microRNA expression in sickle cell diseases”, PLoS One 3: e2360, [ [pmid:18523662 ChenSYWangYTelenMJChiJTdoi:10.1371/journal.pone.0002360] ] ↑ Sangokoya, C; Telen, MJ & Chi, JT, “microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease”, Blood 116: 4338–4348, [ [pmid:20709907 SangokoyaCTelenMJChiJT] ] ↑ Baruch, DI ”