Proteoglycans mediate malaria sporozoite targeting to the liver

Abstract

Summary Malaria sporozoites are rapidly targeted to the liver where they pass through Kupffer cells and infect hepatocytes, their initial site of replication in the mammalian host. We show that sporozoites, as well as their major surface proteins, the CS protein and TRAP, recognize distinct cell type‐specific surface proteoglycans from primary Kupffer cells, hepatocytes and stellate cells, but not from sinusoidal endothelia. Recombinant Plasmodium falciparum CS protein and TRAP bind to heparan sulphate on hepatocytes and both heparan and chondroitin sulphate proteoglycans on stellate cells. On Kupffer cells, CS protein predominantly recognizes chondroitin sulphate, whereas TRAP binding is glycosaminoglycan independent. Plasmodium berghei sporozoites attach to heparan sulphate on hepatocytes and stellate cells, whereas Kupffer cell recognition involves both chondroitin sulphate and heparan sulphate proteoglycans. CS protein also interacts with secreted proteoglycans from stellate cells, the major producers of extracellular matrix in the liver. In situ binding studies using frozen liver sections indicate that the majority of the CS protein binding sites are associated with these matrix proteoglycans. Our data sug‐gest that sporozoites are first arrested in the sinusoid by binding to extracellular matrix proteoglycans and then recognize proteoglycans on the surface of Kupffer cells, which they use to traverse the sinusoidal cell barrier.

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

“…Spz may have interacted directly or indirectly with KC. According to the shift in MHC class I expression, spz affected the majority of Mac3 + KC, suggesting a rather extensive modulation, typically achievable by a soluble factor or possibly by CS protein, which binds to proteoglycans on the KC [28] and also inhibits protein synthesis [10]. Moreover, down-regulation of class I by spz in vitro appears to involve KC independent of other liver cells.…”

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

“…Several lines of evidence suggest that this arrest is mediated by the interaction between the major surface protein of sporozoites, the circumsporozoite protein (CSP) and the highly sulfated HSPGs of hepatocytes [35][36][37][38][39]. Recombinant CSP binds specifically to hepatic HSPGs and in vivo, the physiologic ligands for hepatic HSPGs, namely lactoferrin and lipoprotein remnants, delay CSP clearance from the circulation and inhibit sporozoite infection of hepatocytes [40].…”

“…The addition of sulfate moieties to HSPG GAGs is one of these modifications and as stated above, liver HSPGs are more highly sulfated compared to HSPGs from other organs [43], suggesting that the degree of GAG chain sulfation could account for the selective targeting of sporozoites to the liver. Indeed it has been found that CSP binds preferentially to cells expressing HSPGs with highly sulfated GAGs [38,39] and that sporozoite attachment to cells decreases as the degree of GAG chain sulfation decreases [38]. One confounding issue is that these highly sulfated HSPGs are found behind the endothelial cell barrier.…”

“…The endothelial cells of the liver sinusoids, however, have open fenestrations that allow for direct contact between the blood circulation and the underlying loose basement membrane known as the space of Disse. Recently it has been suggested that the majority of the highly sulfated HSPGs that "capture" sporozoites are located in the space of Disse and not on the hepatocyte surface which is some distance behind the endothelial cell barrier [39]. These HSPGs are primarily produced by stellate cells [44], a unique dendritic-shaped cell found in this location [45] and like the HSPGs of hepatocytes, they are highly sulfated and bind to recombinant CSP and sporozoites [39], lending support to the idea that it is HSPGs in the space of Disse that arrest circulating sporozoites.…”

CD81 : une tétraspanine impliquée dans l’infection parPlasmodium

“…Chez l'hôte vertébré, le cycle de Plasmodium passe par deux stades invasifs successifs, les stades sporozoïte et mérozoïte, qui infectent respectivement les hépatocytes et les érythrocytes ( Figure 1). Les sporozoïtes, transmis à l'hôte lors d'une piqûre par un moustique femelle du genre Anopheles, passent dans la circulation sanguine puis sont rapidement séquestrés au niveau du foie (en quelques minutes) via l'interaction de la circumsporozoite protein (CSP), protéine majeure de la surface des sporozoïtes, et de la thrombospondin-related anonymous protein (TRAP), avec les glycosaminoglycanes (GAG) proéminents dans les sinusoïdes hépatiques [1]. Les sporozoïtes traversent ensuite l'espace de Disse et pénètrent activement dans les hépatocytes, par invagination de la membrane plasmique aboutissant à la formation d'une vacuole parasitophore (Figure 2).…”