title: Manipulation of the Host Cell Membrane duringPlasmodiumLiver Stage Egress.
abstract: A crucial step in the life cycle ofPlasmodiumparasites is the transition from the liver stage to the blood stage. Hepatocyte-derived merozoites reach the blood vessels of the liver inside host cell-derived vesicles called merosomes. The molecular basis of merosome formation is only partially understood. Here we show thatPlasmodium bergheiliver stage merozoites, upon rupture of the parasitophorous vacuole membrane, destabilize the host cell membrane (HCM) and induce separation of the host cell actin cytoskeleton from the HCM. At the same time, the phospholipid and protein composition of the HCM appears to be substantially altered. This includes the loss of a phosphatidylinositol 4,5-bisphosphate (PIP2) reporter and the PIP2-dependent actin-plasma membrane linker ezrin from the HCM. Furthermore, transmembrane domain-containing proteins and palmitoylated and myristoylated proteins, as well as glycosylphosphatidylinositol-anchored proteins, lose their HCM localization. Collectively, these findings provide an explanation of HCM destabilization duringPlasmodiumliver stage egress and thereby contribute to our understanding of the molecular mechanisms that lead to merosome formation.IMPORTANCEEgress from host cells is an essential process for intracellular pathogens, allowing successful infection of other cells and thereby spreading the infection. Here we describe the molecular details of a novel egress strategy ofPlasmodiumparasites infecting hepatocytes. We show that toward the end of the liver stage, parasites induce a breakdown of the host cell actin cytoskeleton, leading to destabilization of the host cell plasma membrane. This, in turn, results in the formation of membrane vesicles (merosomes), in which parasites can safely migrate from liver tissue to the bloodstream to infect red blood cells and start the pathogenic phase of malaria.
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland burda@bnitm.de.
authors.forename: Paul-Christian
authors.initials: PC
authors.lastname: Burda
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Caldelari
authors.affiliation: Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Volker T
authors.initials: VT
authors.lastname: Heussler
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000469:parasitology*; D008565:Membrane Proteins / Q000032:analysis*; D008807:Mice, Inbred BALB C; D010743:Phospholipids / Q000032:analysis*; D010962:Plasmodium berghei / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D010743:Phospholipids