ABSTRACT
The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite's hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wild-type parasites. This study identifies a host-parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies.
Subject(s)
Liver/parasitology , Malaria/parasitology , Membrane Proteins/metabolism , Plasmodium berghei/physiology , Protozoan Proteins/metabolism , beta 2-Glycoprotein I/metabolism , Animals , Animals, Genetically Modified , Binding Sites , Down-Regulation , Genes, Protozoan , HEK293 Cells , Hepatocytes/parasitology , Humans , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Plasmodium berghei/genetics , Plasmodium berghei/growth & development , Protein Binding , RNA Interference , RNA, Small Interfering/genetics , Sequence Deletion , Sporozoites/physiology , Vacuoles/parasitology , beta 2-Glycoprotein I/antagonists & inhibitors , beta 2-Glycoprotein I/geneticsABSTRACT
We performed a bioinformatical analysis of protein export elements (PEXEL) in the putative proteome of the malaria parasite Plasmodium falciparum. A protein family-specific conservation of physicochemical residue profiles was found for PEXEL-flanking sequence regions. We demonstrate that the family members can be clustered based on the flanking regions only and display characteristic hydrophobicity patterns. This raises the possibility that the flanking regions may contain additional information for a family-specific role of PEXEL. We further show that signal peptide cleavage results in a positional alignment of PEXEL from both proteins with, and without, a signal peptide.
