This study also found thrombin could detach IT4var19 IEs already adherent to human lung microvascular endothelial cells

This study also found thrombin could detach IT4var19 IEs already adherent to human lung microvascular endothelial cells. and endothelial protein C receptor (EPCR). Bioinformatic analyses of PfEMP1 protein sequences from 15 genomes found the C1s motif was present in most PfEMP1 variants. Prediction of C1s cleavage and loss of binding to endothelial receptors was further corroborated by screening of several different parasite lines. These observations suggest that the parasites have managed susceptibility for cleavage by the serine protease, C1s, and provides evidence for any complex relationship between the complement system and the cytoadhesion virulence determinant. is the most virulent spp., causing the most deaths from malaria parasites (1). This virulence is largely due to the parasites ability to invade all ages of erythrocytes and its binding to the endothelium. In their late stages, infected erythrocytes (IEs) attach to endothelial cells to escape blood circulation and the killing mechanisms in the spleen (2). The sequestration of IEs in host organs reduces blood flow and promotes coagulopathy, inflammation, and vascular leakage (3, 4). In severe infections, sequestration of parasites in the brain may cause breakdown of the bloodCbrain barrier and AB-MECA cerebral edema leading to death or neurologic sequelae to those who survive (2, 5C7). IE sequestration is usually mediated by users of the erythrocyte membrane protein 1 (PfEMP1) family (8C10), which are exported to the IE surface where they bind specific AB-MECA endothelial receptors. PfEMP1 are single-pass membrane proteins, with the intracellular acidic terminal segment (ATS) anchored in the erythrocyte membrane by intracellular parasite and host cytoskeleton proteins. The PfEMP1 extracellular region can vary in size from 200 to 500 kDa by the number and type of different receptor-binding Duffy binding-like (DBL) and cysteine-rich interdomain region (CIDR) domains (11). Despite varying in sequence, all PfEMP1 contain an N-terminal DBLCCIDR domain name complex, termed the head structure, which segregates the protein family into a few mutually unique binding phenotypes (as examined in ref. 12). Thus, most PfEMP1 bind either endothelial protein C receptor (EPCR) via their CIDR1 domain name or CD36 via their CIDR2C6 domain name, and a minority of PfEMP1 head structures have CIDR, , or domain name types with unknown binding specificity (12). The head structure can be followed by two to seven additional domains. The function of the PfEMP1s C-terminal domains is not fully resolved; however, some bind leukocyte adhesion receptor intercellular adhesion molecule 1 (ICAM-1; via the DBL domain name) (13), platelet endothelial cell adhesion molecule (PECAM1) (14), integrin V3 (15), or hyaluronan\binding protein 1 (HABP1) (16). Other domains have been found to bind serum proteins, nonimmune IgG (17) and IgM (18) and 2-macroglobulin (19), facilitating cytoadherence to uninfected erythrocytes (rosetting) and escape from antibody or match acknowledgement (20). The exception to these rules is the VAR2CSA PfEMP1 variant, which is usually defined by six tightly connected and unique DBL domains, which form a single multidomain complex to bind placental chondroitin sulfate A (CSA) (21). Whereas multiple adhesion properties have been mapped to PfEMP1 adhesion domains, less attention has been placed on the interdomain regions, which are characterized by aspartic acid and glutamic acid-rich regions and proline residues, but some also contain conserved motifs (11). The interdomain regions have been thought to function as spacers between the adhesion domains, and a AB-MECA function has not been ascribed to the conserved motifs. Each parasite genome encodes 60 PfEMP1 variants, but only one PfEMP1 will be expressed by each individual parasite. PfEMP1 are key targets of acquired immunity to malaria. Expression of one of many variants among parasites released from your liver (22), and the ability to switch PfEMP1 expression at each blood stage cycle, provides the parasite optimal chances of survival regardless of the immune status of the host (8). The PfEMP1 binding phenotypes are linked to clinical end result of contamination. VAR2CSA-mediated sequestration in the placenta is the cause of severe malaria in pregnancy (23, 24), whereas parasites expressing EPCR-binding PfEMP1 is usually associated with severe malaria pathogenesis in nonimmune individuals, and parasites expressing CD36-binding PfEMP1 appear to be linked to uncomplicated infections in semi-immune AB-MECA individuals (25C33). Pathogens that live in human serum have frequently developed mechanisms to evade complement-mediated lysis, and there are now several examples of how blood stage malaria parasites interact with the complement system [examined by Kennedy et al. (34)]. For instance, there is evidence that merozoites acquire C1 esterase inhibitor during reddish blood cell invasion to control match activation (35). The present study was initiated to explain the loss of IE binding to EPCR after exposure to human sera or human plasma from malaria-naive people, but not to bovine sera (30). Previous work suggested the inhibitory serum component was neither albumin nor IgM, and the inhibitory activity AB-MECA persisted SBMA after IgG depletion from serum.