The glycobiology of Plasmodium, Toxoplasma, and Eimeria
Bushkin, Gary Guy
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Members of the phylum Apicomplexa, which include many important, diverse parasites with global distribution, can be divided to two groups: those that spread by arthropod bites such as Plasmodium, the cause of malaria, and those that spread by ingestion of walled forms, such as Toxoplasma and Eimeria, cause of disseminated infections in humans and bloody diarrhea in chickens, respectively. While there is positive selection for sites of asparagine-linked glycosylation (N-glycans) in most eukaryotes that use N-glycans for quality control of glycoprotein folding , we show here that there is negative selection against N-glycans in apicomplexans that have a chloroplast-derived organelle called the apicoplast. Plasmodium has deletions of enzymes that synthesize N-glycans and therefore makes N-glycans with fewer sugar residues than other eukaryotes. In contrast, Toxoplasma has relatively long N-glycans but there is a sharply reduced density of N-glycan sites in the apicoplast-targeted proteins. Toxoplasma is spread by oocysts, which are walled parasites shed by cats, or by tissue cysts, which are walled parasites present in undercooked meat. We show here that oocyst walls of Toxoplasma and Eimeria have an inner layer in which fibrils of β-1,3-linked glucan, a major component of fungal walls, form a trabecular scaffold. Echinocandins, which are anti-fungal drugs that target glucan synthase, inhibit oocyst production by chickens infected with Eimeria, showing that the parasite glucan synthase is druggable and that β-glucan is essential for oocyst wall formation. The glucan hydrolase of Toxoplasma has a novel β-glucan-binding domain and is present in the inner layer of the oocyst wall. The oocyst walls of Toxoplasma and Eimeria, as well as the tissue cyst wall of Toxoplasma, are acid-fast like the mycobacteria wall. Toxoplasma and Eimeria have enzymes like those of mycobacteria that synthesize acid-fast lipids, which are present in organic extracts of the oocyst walls. These results suggest a new model of the oocyst wall, in which the outer layer is like that of mycobacteria, while the inner layer is like that of fungi.
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