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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.

SUBMITTER: Kafsack BF

PROVIDER: S-EPMC2662845 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells.

Kafsack Björn F C BF Pena Janethe D O JD Coppens Isabelle I Ravindran Sandeep S Boothroyd John C JC Carruthers Vern B VB

Science (New York, N.Y.) 20081218 5913

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 d ...[more]

PMID: 19095897

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Project description:UnlabelledChlamydia trachomatis is an obligate intracellular bacterium that is a globally important human pathogen. The chlamydial plasmid is an attenuating virulence factor, but the molecular basis for attenuation is not understood. Chlamydiae replicate within a membrane-bound vacuole termed an inclusion, where they undergo a biphasic developmental growth cycle and differentiate from noninfectious into infectious organisms. Late in the developmental cycle, the fragile chlamydia-laden inclusion retains its integrity by surrounding itself with scaffolds of host cytoskeletal proteins. The ability of chlamydiae to developmentally free themselves from this cytoskeleton network is a fundamental virulence trait of the pathogen. Here, we show that plasmidless chlamydiae are incapable of disrupting their cytoskeletal entrapment and remain intracellular as stable mature inclusions that support high numbers of infectious organisms. By using deletion mutants of the eight plasmid-carried genes (?pgp1 to ?pgp8), we show that Pgp4, a transcriptional regulator of multiple chromosomal genes, is required for exit. Exit of chlamydiae is dependent on protein synthesis and is inhibited by the compound C1, an inhibitor of the type III secretion system (T3S). Exit of plasmid-free and ?pgp4 organisms, which failed to lyse infected cells, was rescued by latrunculin B, an inhibitor of actin polymerization. Our findings describe a genetic mechanism of chlamydial exit from host cells that is dependent on an unknown pgp4-regulated chromosomal T3S effector gene.ImportanceChlamydia's obligate intracellular life style requires both entry into and exit from host cells. Virulence factors that function in exiting are unknown. The chlamydial inclusion is stabilized late in the infection cycle by F-actin. A prerequisite of chlamydial exit is its ability to disassemble actin from the inclusion. We show that chlamydial plasmid-free organisms, and also a plasmid gene protein 4 (pgp4) null mutant, do not disassociate actin from the inclusion and fail to exit cells. We further provide evidence that Pgp4-regulated exit is dependent on the chlamydial type III secretion system. This study is the first to define a genetic mechanism that functions in chlamydial lytic exit from host cells. The findings also have practical implications for understanding why plasmid-free chlamydiae are highly attenuated and have the ability to elicit robust protective immune responses.

Project description:BackgroundHost-parasite protein interactions (HPPI) are those interactions occurring between a parasite and its host. Host-parasite protein interaction enhances the understanding of how parasite can infect its host. The interaction plays an important role in initiating infections, although it is not all host-parasite interactions that result in infection. Identifying the protein-protein interactions (PPIs) that allow a parasite to infect its host has a lot do in discovering possible drug targets. Such PPIs, when altered, would prevent the host from being infected by the parasite and in some cases, result in the parasite inability to complete specific stages of its life cycle and invariably lead to the death of such parasite. It therefore becomes important to understand the workings of host-parasite interactions which are the major causes of most infectious diseases.ObjectiveMany studies have been conducted in literature to predict HPPI, mostly using computational methods with few experimental methods. Computational method has proved to be faster and more efficient in manipulating and analyzing real life data. This study looks at various computational methods used in literature for host-parasite/inter-species protein-protein interaction predictions with the hope of getting a better insight into computational methods used and identify whether machine learning approaches have been extensively used for the same purpose.MethodsThe various methods involved in host-parasite protein interactions were reviewed with their individual strengths. Tabulations of studies that carried out host-parasite/inter-species protein interaction predictions were performed, analyzing their predictive methods, filters used, potential protein-protein interactions discovered in those studies and various validation measurements used as the case may be. The commonly used measurement indexes for such studies were highlighted displaying the various formulas. Finally, future prospects of studies specific to human-plasmodium falciparum PPI predictions were proposed.ResultWe discovered that quite a few studies reviewed implemented machine learning approach for HPPI predictions when compared with methods such as sequence homology search and protein structure and domain-motif. The key challenge well noted in HPPI predictions is getting relevant information.ConclusionThis review presents useful knowledge and future directions on the subject matter.

Dataset Information

Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells.

Publications

Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells.

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