Cell-Passage Activity Is Required for the Malarial Parasite to Cross the Liver Sinusoidal Cell Layer

Abstract

Liver infection is an obligatory step in malarial transmission, but it remains unclear how the sporozoites gain access to the hepatocytes, which are separated from the circulatory system by the liver sinusoidal cell layer. We found that a novel microneme protein, named sporozoite microneme protein essential for cell traversal (SPECT), is produced by the liver-infective sporozoite of the rodent malaria parasite, Plasmodium berghei. Targeted disruption of the spect gene greatly reduced sporozoite infectivity to the liver. In vitro cell invasion assays revealed that these disruptants can infect hepatocytes normally but completely lack their cell passage ability. Their apparent liver infectivity was, however, restored by depletion of Kupffer cells, hepatic macrophages included in the sinusoidal cell layer. These results show that malarial sporozoites access hepatocytes through the liver sinusoidal cell layer by cell traversal motility mediated by SPECT and strongly suggest that Kupffer cells are main routes for this passage. Our findings may open the way for novel malaria transmission-blocking strategies that target molecules involved in sporozoite migration to the hepatocyte.

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…A peptide must be appropriately adjusted in the binding groove of antigen-presenting cell MHC class II molecules, consisting of two membrane-anchored chains [R and ], to become immunogenic, thereby allowing residues interacting with amino acids from the P 1 , P 4 , P 6 , and P 9 pockets of these molecules 46 to fit appropriately into such pockets 47 [ Figures 3A,B] and thereby leading to H-bond formation between the backbone atoms of the peptide and class II amino acid residues. 46-49 These 11 H-bonds stabilize peptide binding to this molecule, and if the other residues (-P 2 , -P 1 , P 2 , P 3 , P 5 , P 7 , P 8 , and P 10 ) are appropriately orientated in the opposite direction to the class II molecule groove, then these residues interact with the different variable regions of the TCR chains (R and ) called CDR 1 , CDR 2 , and CDR 3 to form the correct MHC II-peptide-TCR complex, thereby inducing appropriate immune system activation [47][48][49] and antibody production.…”

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

“…Although we are still far from a molecular understanding of this process, four proteins involved in cell traversal recently have been identified. Three of these, SPECT 1 (sporozoite microneme protein essential for cell traversal) and SPECT 2 (also called perforin-like protein 1; PLP1) and CelTOS (cell traversal protein for ookinetes and sporozoites) were identified using EST databases [25][26][27][28] while the fourth, a phospholipase (PL) was found using an RNA subtraction screen that identified genes up-regulated in salivary gland sporozoites [29,30]. Expression of SPECT 1, SPECT 2 and PL are specific to salivary gland sporozoites whereas CelTOS is expressed by both ookinetes and salivary gland sporozoites.…”

Molecular and functional aspects of parasite invasion

“…The recent discovery of a sporozoite microneme protein essential for cell traversal (SPECT) sheds new light on migration into the liver. Interestingly, this novel protein helps sporozoites gain access to hepatocytes by crossing the liver sinusoidal cell at the level of the Kupffer cells [21].…”