Rapid Membrane Disruption by a Perforin-Like Protein Facilitates Parasite Exit from Host Cells

• DOI: 10.1126/science.1165740
• Publication Date: 2008-12-19T02:39:43Z
• Authors: Björn F. C. Kafsack; Janethe D. O. Pena; Isabelle Coppens; Sandeep Ravindran; John C. Boothroyd; Vern B. Carruthers
• Keywords: Models, Molecular; 0303 health sciences; Cell Membrane Permeability; Ionophores; Perforin; Protein Conformation; Cell Membrane; Molecular Sequence Data; Protozoan Proteins; Intracellular Membranes; Permeability; Protein Structure, Secondary; Host-Parasite Interactions; Protein Structure, Tertiary; 03 medical and health sciences; Vacuoles; Animals; Humans; Amino Acid Sequence; Toxoplasma; Calcimycin; Cells, Cultured

Perforin-like proteins are expressed by many bacterial and protozoan pathogens, yet little is known about their function or mode of action. Here, we describe Toxoplasma perforin-like protein 1 (TgPLP1), a secreted perforin-like protein of the intracellular protozoan pathogen Toxoplasma gondii that displays structural features necessary for pore formation. After intracellular growth, TgPLP1-deficient parasites failed to exit normally, resulting in entrapment within host cells. We show that this defect is due to an inability to rapidly permeabilize the parasitophorous vacuole membrane and host plasma membrane during exit. TgPLP1 ablation had little effect on growth in culture but resulted in a reduction greater than five orders of magnitude of acute virulence in mice. Perforin-like proteins from other intracellular pathogens may play a similar role in microbial egress and virulence.