Bound IEs were then fixed with 2% glutaraldehyde in PBS for 2?h at RT

Bound IEs were then fixed with 2% glutaraldehyde in PBS for 2?h at RT. tools to identify conserved epitopes shared between different variants and to characterize the interactions between VAR2CSA and CSA. Malaria remains one of the most prevalent infectious diseases in the world, affecting 207 million people per year and causing an estimated 627,000 subsequent deaths, mostly among children below five years of age and pregnant women1. Among the 5 plasmodia species generally infecting Humans, is usually responsible of the most severe malaria cases and deaths. The pathogenicity of has been linked to the ability of infected erythrocytes (IEs) to adhere to the host endothelium or to the syncytio-trophoblastic layer of the placenta2. By mediating cytoadhesion of IEs to host receptors, has developed an immune evasion strategy that prevents the transit of IEs through the spleen’s reddish pulp and their subsequent retention and clearance by the reddish pulp macrophages3,4. IEs cytoadhesion is usually mediated by users of the erythrocyte membrane protein 1 (PfEMP1), a parasite protein expressed at the surface of IEs and encoded by the highly diverse gene family5,6,7. In malaria endemic areas, individuals progressively acquire protective clinical immunity during child years and adults are generally guarded against the severe clinical outcomes of the disease8. However, first-time pregnant women become once again susceptible to malaria. Pregnancy associated malaria (PAM) is usually linked to the massive accumulation of IEs and monocytes in the placental intervillous spaces9, leading to maternal anemia and hypertension as well as stillbirth, preterm delivery, intra-uterine growth retardation and low birth-weight10,11. Overall, PAM considerably increases the morbidity and mortality of both mother and child. Indeed, reports indicate that as many as Vildagliptin 363,000 neonates and at Vildagliptin least 10,000 maternal deaths may be attributable to PAM every 12 months11. IEs isolated from placentas of women suffering from PAM (IEs-PAM) present a unique adhesive phenotype contrasting with IEs isolated from other tissues. Indeed IEs-PAM bind to the sulfated glycosaminoglycan chondroitin-4-sulfate (CSA) and not to endothelial receptors such as CD36 and ICAM-112,13. Low-sulfated chondroitin sulfate-proteoglycans (CSPGs) have been detected in the placental intervillous space by the end of the third month of gestation14, thus offering a potential anchor point for the IEs-PAM. However, a recent study provides evidences that women in the first trimester of pregnancy could already be infected with parasites expressing VAR2CSA, suggesting that this placental tropism of is already established during the first 12 weeks of pregnancy15. Following successive pregnancies, women become resistant to PAM as they develop antibodies able to recognize IEs-PAM from different part of the world and block their binding to placental CSA16. This would suggest that the CSA-ligand expressed by placental parasites possess conserved antigenic determinants. The identification of such epitopes would therefore be a crucial advance for the design of an effective vaccine against PAM. The PfEMP1 variant VAR2CSA has been identified as the parasite ligand to placental CSA17,18,19,20. VAR2CSA is usually a high molecular weight protein, with a 300?kDa extracellular region organized in 6 Duffy-binding like (DBL) domains and a distinctive cysteine-rich interdomain region (CIDRPAM)21. Although VAR2CSA stands today as the main candidate for any PAM-vaccine, the substantial antigenic polymorphism and the lack of comprehensive structural information regarding the CSA-binding site of the protein limit our understanding of placental sequestration mechanisms and represent therefore significant challenges for any vaccine and therapeutic development against PAM. Recent studies have Rabbit Polyclonal to ARX shown that the presence of a single CSA-binding site is usually formed by a higher-order domain name organization including multiple domains22,23. The N-terminal region of VAR2CSA plays a major role in CSA adhesion and antibodies targeting that region are able to prevent the adhesion of IEs-PAM to CSA24,25,26,27,28. The identification of conformational regions, conserved between the Vildagliptin different polymorphic forms of VAR2CSA as well as the characterization of crucial epitopes connected to the high-affinity CSA-binding site would open new avenues in Vildagliptin the rational design of a vaccine against PAM. Camelidae have a unique immune system able to produce functional immunoglobulins G devoid of light chains called.