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Malaria-infected mosquitoes inoculate Plasmodium sporozoites into the subcutaneous connective tissue of the mammalian host. Within minutes after entering a capillary at the bite site, thesporozoites travel to the liver where they invade their initial target cells, the hepatocytes.  Sporozoite arrest in the liver sinusoid is thought to be mediated by the specific binding of the two major Plasmodium sporozoite surface proteins, the circumsporozoite protein (CSP) and the thrombospondin-related adhesive protein (TRAP), to the unique heparan sulfate proteoglycans (HSPGs) of the liver [1]. Earlier work had shown that the interaction occurs between highly sulfated heparin-like oligosaccharides in heparan sulfate and two domains in CSP, a thrombospondin-like cell-adhesive region II-plus at the C-terminus and a positively charged motif upstream from the conserved region I. Similarly, the ectodomain of TRAP contains two adhesive motifs, an integrin-like A domain and a thrombospondin-like adhesive domain, that interact with host cell proteoglycans [2]. Heparan sulfate from the liver exhibits an unusually high degree of sulfation compared to heparan sulfate species from all other tissues [3]. This unique composition is most likely the reason for the remarkably selective targeting of recombinant CS protein to the liver, which occurs despite the presence of HSPGs on most other cell types. The vascular endothelium, in particular, expresses a heparan sulfate species which is clearly undersulfated.  Once arrested in the liver sinusoid, Plasmodium sporozoites have to cross the sinusoidal cell layer to invade hepatocytes. It was proposed that sporozoites infect hepatocytes directly by squeezing through the endothelial fenestration [4], although they exceed the maximum pore size of the sieve plates by an order of magnitude [5]. This event, however, has never been observed, nor have sporozoites been found passing through the cytoplasm of endothelial cells. Others suggested that Kupffer cells use their scavenger function to remove sporozoites from the bloodstream by phagocytosis, and that a small percentage of the parasites traverses the Kupffer cells fast enough to escape respiratory burst and lysosomal digestion and to invade hepatocytes [6].  We analyzed the proteoglycans involved in sporozoite targeting to the liver and the route of the parasites take into the liver parenchyma.

Kupffer and stellate cell proteoglycans mediate malaria sporozoite targeting to the liver.