title: Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Björn F C
authors.initials: BF
authors.lastname: Kafsack
authors.forename: Janethe D O
authors.initials: JD
authors.lastname: Pena
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.forename: Sandeep
authors.initials: S
authors.lastname: Ravindran
authors.forename: John C
authors.initials: JC
authors.lastname: Boothroyd
authors.forename: Vern B
authors.initials: VB
authors.lastname: Carruthers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D006790:Host-Parasite Interactions; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054353:Perforin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D014617:Vacuoles / Q000378:metabolism* / Q000469:parasitology*
chemical_list: D007476:Ionophores; D015800:Protozoan Proteins; C534951:perforin-like protein 1, Toxoplasma gondii; D054353:Perforin; D000001:Calcimycin