Toxoplasma gondii CDPK1 (TgCDPK1) was found to be the target of the toxoplasmocidal compound 1NM-PP1. When TgCDPK1 was mutated at position 128 from glycine to methionine, resistance was gained. Inhibition of gliding motility without inhibition of micronemal secretion by 1NM-PP1 suggests a function for TgCDPK1 in gliding motility.
Erythrocyte invasion is critical to the pathogenesis and survival of the malarial parasite, Plasmodium falciparum. This process is partly mediated by proteins that belong to the Duffy binding-like family, which are expressed on the merozoite surface. One of these proteins, BAEBL (also known as EBA-140), is thought to bind to glycophorin C in a sialic acid-dependent manner. In this report, by the binding assay between recombinant BAEBL protein and enzyme-treated erythrocytes, we show that the binding of BAEBL to erythrocytes is mediated primarily by sialic acid and partially through heparan sulfate (HS). Because BAEBL binds to several kinds of HS proteoglycans or purified HS, the BAEBL-HS binding was found to be independent of the HS proteoglycan peptide backbone and the presence of sialic acid moieties. Furthermore, both the sialic acid-and HS-dependent binding were disrupted by the addition of soluble heparin. This inhibition may be the result of binding between BAEBL and heparin. Invasion assays demonstrated that HS-dependent binding was related to the efficiency of merozoite invasion. These results suggest that HS functions as a factor that promotes the binding of BAEBL and merozoite invasion. Moreover, these findings may explain the invasion inhibition mechanisms observed following the addition of heparin and other sulfated glycoconjugates.Malaria caused by Plasmodium falciparum kills approximately 1 million people per year. After entering the human bloodstream, the parasite propagates asexually via repeated cycles of erythrocyte invasion, cell division, and cell rupture. The process by which the parasitic merozoites invade erythrocytes involves the following steps: attachment, apical reorientation, junction formation, and the formation of a protective parasitophorous vacuole (1).The Duffy binding-like (DBL) 2 family is composed of adhesion molecules that are critical for junction formation between the apical end of the merozoite and the erythrocyte surface.Proteins in this family, such as EBA-175 (erythrocyte-binding antigen-175), are homologous to Plasmodium vivax Duffybinding protein. These proteins contain one or more DBL domains, which are composed of conserved cysteine residues and are associated with erythrocyte binding (2). EBA-175 is bound to glycophorin A on the erythrocyte surface in a sialic acid-dependent manner (3). However, erythrocytes that are treated with neuraminidase remain susceptible to the merozoites of some clones (4), indicating the existence of sialic acidindependent invasion pathways. These alternative pathways are thought to be mediated, at least in part, by other members of the DBL family (5).Parasite growth is inhibited by the addition of heparin, some sulfated saccharide anions, and sulfated chemical compounds (6 -11). Although the inhibition mechanisms remain unclear, these reports suggest the possibility that sulfated moieties play a role in merozoite invasion. In addition to invasion, heparan sulfate (HS) is believed to function as a receptor for PfEMP1 (P. falciparum erythr...
BackgroundcAMP-dependent protein kinase (PKA) has been implicated in the asexual stage of the Toxoplasma gondii life cycle through assaying the effect of a PKA-specific inhibitor on its growth rate. Since inhibition of the host cell PKA cannot be ruled out, a more precise evaluation of the role of PKA, as well as characterization of the kinase itself, is necessary.Methodology/Principal FindingThe inhibitory effects of two PKA inhibitors, H89, an ATP-competitive chemical inhibitor, and PKI, a substrate-competitive mammalian natural peptide inhibitor, were estimated. In the in vitro kinase assay, the inhibitory effect of PKI on a recombinant T. gondii PKA catalytic subunit (TgPKA-C) was weaker compared to that on mammalian PKA-C. In a tachyzoite growth assay, PKI had little effect on the growth of tachyzoites, whereas H89 strongly inhibited it. Moreover, T. gondii PKA regulatory subunit (TgPKA-R)-overexpressing tachyzoites showed a significant growth defect.Conclusions/SignificanceOur data suggest that PKA plays an important role in the growth of tachyzoites, and the inhibitory effect of substrate-competitive inhibitor PKI on T. gondii PKA was low compared to that of the ATP competitive inhibitor H89.
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