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

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 heparinlike oligosaccharides in heparan sulfate and two domains in CSP, a thrombospondin-like cell-adhesive region IIplus 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.