Malaria sporozoites and circumsporozoite proteins bind specifically to sulfated glycoconjugates

Abstract

Abstract. Circumsporozoite (CS) proteins, which densely coat malaria (Plasmodia) sporozoites, contain an amino acid sequence that is homologous to segments in other proteins which bind specifically to sulfated glycoconjugates. The presence of this homology suggests that sporozoites and CS proteins may also bind sulfated glycoconjugates. To test this hypothesis, recombinant P. yoelii CS protein was examined for binding to sulfated glycoconjugate-Sepharoses. CS protein bound avidly to heparin-, fucoidan-, and dextran sulfate-Sepharose, but bound comparatively poorly to chondroitin sulfate A-or C-Sepharose. CS protein also bound with significantly lower affinity to a heparan sulfate biosynthesis-deficient mutant cell line compared with the wild-type line, consistent with the possibility that the protein also binds to sulfated glycoconjugates on the surfaces of cells. This possibility is consistent with the observation that CS protein binding to hepatocytes, cells invaded by sporozoites during the primary stage of malaria infection, was inhibited by fucoidan, pentosan polysulfate, and heparin.The effects of sulfated glycoconjugates on sporozoite infectivity were also determined. P. berghei sporozoites bound specifically to sulfatide (galactosyl[3-sulfate]/~l-lceramide), but not to comparable levels of cholesterol-3-sulfate, or several examples of neutral glycosphingolipids, gangliosides, or phospholipids. Sporozoite invasion into hepatocytes was inhibited by fucoidan, heparin, and dextran sulfate, paralleling the observed binding of CS protein to the corresponding Sepharose derivatives. These sulfated glycoconjugates blocked invasion by inhibiting an event occurring within 3 h of combining sporozoites and hepatocytes. Sporozoite infectivity in mice was significantly inhibited by dextran sulfate 500,000 and fucoidan. Taken together, these data indicate that CS proteins bind selectively to certain sulfated glycoconjugates, that sporozoite infectivity can be inhibited by such compounds, and that invasion of host hepatocytes by sporozoites may involve interactions with these types of compounds.

Entry of Listeria monocytogenes in Mammalian Epithelial Cells: An Updated View

“…Heterologous expression of ActA in the nonpathogenic species L. innocua allows bacterial internalization in epithelial polarized and nonpolarized cells (Caco-2, MCDK, HeLa, and Vero) but not in COS-1 fibroblasts, suggesting that ActA is sufficient to directly activate an invasion pathway specific for epithelial cells (Suárez et al 2001). The amino-terminal region of ActA is similar to the domain of the Plasmodium falciparum circumsporozoite protein involved in heparate sulfate recognition and hepatocyte binding (Pancake et al 1992;Coppi et al 2007) and it has been shown that the presence of heparan sulfate at the surface of CHO cells is required for the entry of L. monocytogenes in an ActA-dependent manner (Alvarez- Dominguez et al 1997). The in vivo conditions in which the ActA invasion-associated function would be critical for virulence remain to be characterized.…”

Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

“…Lactoferrin (aa [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] CAVS QPETKCFQRNMRKI/R yoelii CS, apoE, and lactoferrin. Boldface italics indicate amino acid residues of CS protein required for binding to HSPGs (22).…”

“…Within minutes after intravenous injection into mice, CS accumulates in the space of Disse on the plasma membrane of hepatocyte microvilli (18). Heparinase treatment of liver sections that have been incubated with CS, and other in vitro experiments using hepatocytes and HepG2 cells as targets, demonstrate that CS binds to HSPGs (19,20). The proteoglycan-binding portion of CS (19,21) is region II-plus (22), a stretch of amino acids highly conserved in all species of malaria parasites (23).…”

Untitled

“…TRAP and CSP are also contributing to the gliding motility of sporozoites [30][31][32][33]. CSP is also able to bind with other sulfates like heparin or dextrose sulfate and these may inhibit sporozoite infectivity, motility and block an invasion of the hepatocytes.…”