All PfEMP1s are transmembrane protein with ATS segments are cytoplasmic, and the remainder of the polypeptide portions are extracellular. as therapeutics for PAM. malaria and parasite sequestration Blood stage contamination by the family of protozoan parasites causes malaria, a devastating disease in many Adapalene countries of the world. Although several species of the parasite infect humans, severe clinical conditions, including cerebral and other organ-related fatal complications, are mainly associated with contamination [1,2]. This is due to the unique ability of to sequester in the microvascular endothelia of various organs through the adherence of infected red blood cells (IRBCs) to the endothelial surface molecules Adapalene such as CD36 (cluster of differentiation 36) and intracellular adhesion molecule 1 [2C4]. The adherence and accumulation of IRBCs lead to the recruitment of immune cells, causing severe inflammation, endothelial damage, and vital organ dysfunction and failure [2C4]. In malaria-endemic areas, through multiple infections, children acquire protective immunity that includes the development of inhibitory antibodies against IRBC adhesion [5,6]. Thus, regardless of gender, adults are generally resistant to malaria. Blocking of IRBC adherence by adhesion-specific antibodies enables the host to efficiently control contamination by the clearance of IRBCs through the spleen, thereby avoiding organ-related pathogenesis [3,4]. However, in the case of women, this situation changes when they become pregnant, especially during the first pregnancy [7,8]. In pregnant women, seizes the availability of a new organ, the placenta, as a new opportunity for its survival by overcoming the preexisting protective immunity [7,8]. The placenta contains chondroitin sulfate proteoglycan (CSPG) receptors bearing chondroitin 4-sulfate (C4S) chains to which IRBCs can bind [9]. However, C4S are Adapalene either not available or scarcely present around the endothelial surface [10]. Hence C4S-adherent IRBCs do not sequester in organs other than the placenta. Since, as in the case of men, women prior to their first pregnancy were not exposed to C4S-adherent parasites, they lack C4S-IRBC adhesion inhibitory antibodies [10C12]. Multiplication of the C4S-selected parasites and accumulation of IRBCs prospects to the infiltration of mononuclear cells, causing inflammation and impairment of placental function. Eventually these processes result in pregnancy associated malaria (PAM), which is usually characterized by stillbirth, spontaneous abortion, premature delivery, low birth weight babies, and severe anemia and mortality in the mother [10C15]. During the first and second pregnancies, women acquire anti-adhesive antibodies Rabbit Polyclonal to CDK5 against C4S-adherent parasites [10C12,16C18]. Sera from multigravid pregnant women in different malaria endemic regions of the world have been shown to inhibit the binding of various placental IRBC isolates to C4S [11,16C19]. In addition, multigravid women maintain immunological memory to the anti-adhesion antibody responses [17]. This universal nature of the anti-adhesion antibodies indicates the involvement of conserved structural elements in the IRBC-C4S interactions. Further, notably, the presence of IRBC-C4S adhesion inhibitory antibodies has been shown to be associated with the reduced risk of PAM [12,18,19]. Thus, there is a considerable desire for understanding the molecular and structural interactions involved in IRBC adherence to placental CSPG from the point of view of developing a vaccine and/or small molecule inhibitor-based therapeutics for PAM. What parasite protein mediates IRBC sequestration in the placenta? A family of 200 to 400 kDa antigenically variant proteins called erythrocyte membrane protein 1 (PfEMP1) expressed around the IRBC surface is thought to mediate IRBC adherence to numerous host receptors (Box 1) [2C4,20,21]. PfEMP1s are encoded by a repertoire of ~60 (variant) genes, a group of polymorphic genes present in the genome. The expression of genes is usually tightly regulated [3]. In a clonal parasite populace, only one PfEMP1 variant is usually expressed, enabling IRBCs to bind to a specific host receptor [22]. In response, the host produces specific anti-adhesive antibodies, thereby blocking IRBC sequestration and allowing for parasite clearance by the spleen. However, as the parasite clonal populace expands, it switches at a rate of 0.03 to 2% to different adherent phenotypes by expressing other PfEMP1s [23]. Since the host lacks inhibitory antibodies against these newly expressed PfEMP1s, Adapalene parasite phenotypes having different adhesive receptor specificity get selected and multiply. Development of antibodies against these adhesive phenotypes eventually results in broad protective immunity thereby preventing the IRBC sequestration and development of Adapalene organ related severe pathologies. Box 1. Structural features of PfEMP1s Each PfEMP1 consists of a large extracellular polypeptide and a highly conserved acidic intracellular segment (ATS) that are joined by a short transmembrane segment (TMS) [2C4,21; Physique I]. The extracellular polypeptide portion consists of multiple Duffy binding-like (DBL) adhesive domains.