REMNANT LIPOPROTEINS INHIBIT MALARIA SPOROZOITE INVASION OF HEPATOCYTES

Remnants of lipoproteins, intestinal chylomicrons, and very low densit y lipoproteins (VLDL), are rapidly cleared from plasma and enter hepat ocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs ), and that their subsequent internalization into hepatocytes is media ted by members of the LDL-receptor gene family. Similarly to lipoprote in remnants, malaria sporozoites are removed from the blood circulatio n by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein ( CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin , a protein with antibacterial properties found in breast milk and neu trophil granules, is also rapidly cleared from the circulation by hepa tocytes, and can inhibit the hepatic uptake of lipoprotein remnants. H ere we provide evidence that sporozoites, lactoferrin, and renmant lip oproteins are cleared from the blood by similar mechanisms. CS, lactof errin, and renmant lipoproteins compete in vitro and in vivo for bindi ng sites on liver cells. The relevance of this binding event for sporo zoite infectivity is highlighted by our demonstration that apoliprotei n E-enriched beta-VLDL and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LD L-receptor knockout (LDLR-/-) mice maintained on a high fat diet, as c ompared with littermates maintained on a normal diet. We conclude that the clearance of lipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.