Dataset Information

Host Cell Vimentin Restrains Toxoplasma gondii Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with TgROP18.

ABSTRACT: The obligate intracellular parasite, Toxoplasma gondii, manipulates the cytoskeleton of its host cells to facilitate infection. A significant rearrangement of host cell vimentin around Toxoplasma parasitophorous vacuoles is observed during the course of infection. ROP18 (TgROP18) is a serine-threonine kinase secreted by T. gondii rhoptry and a major virulence factor; however, the mechanisms by which this kinase modulates host factors remain poorly understood. Different and dynamic patterns of vimentin solubility, phosphorylation, and expression levels were observed in host cells infected with T. gondii strain RH and RH ?rop18 strains, suggesting that TgROP18 contributes to the regulation of these dynamic patterns. Additionally, host cell vimentin was demonstrated to interact with and be phosphorylated by TgROP18. A significant increase in T. gondii infection rate was observed in vimentin knockout human brain microvessel endothelial cells (HBMEC), while vimentin knockout or knock down in host cells had no impact on parasite proliferation and egress. These results indicate that host cell vimentin can inhibit T. gondii invasion. Interestingly, western blotting of different mouse tissues indicated that the lowest vimentin expression level was present in the brain, which may explain the mechanism underlying the nervous system tropism of T. gondii, and the phenomenon of huge cyst burdens developing in the mouse brain during chronic infection.

SUBMITTER: He C

PROVIDER: S-EPMC5666328 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Host Cell Vimentin Restrains Toxoplasma gondii Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with TgROP18.

He Cheng C Kong Ling L Zhou Lijuan L Xia Jing J Wei Haixia H Liu Min M Peng Hongjuan H

International journal of biological sciences 20170905 9

The obligate intracellular parasite, Toxoplasma gondii, manipulates the cytoskeleton of its host cells to facilitate infection. A significant rearrangement of host cell vimentin around Toxoplasma parasitophorous vacuoles is observed during the course of infection. ROP18 (TgROP18) is a serine-threonine kinase secreted by T. gondii rhoptry and a major virulence factor; however, the mechanisms by which this kinase modulates host factors remain poorly understood. Differen ...[more]

PMID: 29104504

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Project description:BackgroundRhoptry protein 18 (ROP18) is a key virulence factor of Toxoplasma gondii. The host's immune responses mediated by immune-related GTPases (IRGs) could be blocked by ROP18's kinase activity. ROP18 also interacts with various substrates, such as activating transcription factor 6 beta (ATF6β) and affects multiple physiological functions within host cells, thereby inducing intense virulence. In this study, competitive inhibitors targeted to ROP18 were subjected to virtual screening based on the principle of structure-based drug design (SBDD).MethodsThe preparation of the ROP18 structure was conducted using the "Structure Prepare" function of Molecular Operating Environment (MOE) software. The ATP-binding pocket was selected as the starting point for virtual screening. Construction of the pharmacophore model used Extended Hückel Theory (EHT) half-quantitative measurement and construction, as well as the characteristics of Type I kinase inhibitors. The pharmacophore model of ROP18 was imported into the Specs database for small molecule similarity screening using EHT pharmacophore measurement. Hit compounds were selected using the functions of London dG and generalized-born volume integral/weighted surface area (GBVI/WSA) scoring. The top 100 hits were analyzed by molecular docking and structure activity relationships (SAR) analysis.ResultsThe final pharmacophore comprised three typical characteristics: three hydrogen bond acceptors/donors, two ring aromatic features occupying the hydrophobic core, and one cation group feature targeted to the terminus of ATP. A total of 1314 hit compounds analogous to ROP18 pharmacophore were passed through the Specs. After two rounds of docking, 25 out of 100 hits were identified as belonging to two main scaffold types: phthalimide ring structure, thiazole ring and styrene structure. Additionally, the screen also identified 13 inhibitors with distinct scaffold types. The docking models and SAR analysis demonstrated that these hits could engage in multiple hydrogen bonds, salt bridges halogen bonds, and hydrophobic interactions with ROP18, and para-position halo substituents on the benzene ring may enhance their affinity scoring.ConclusionsA pharmacophore against the ROP18 ATP-binding pocket was successfully constructed, and 25 representative inhibitors from 15 scaffold clusters were screened using the Specs database. Our results provide useful scaffold types for the chemical inhibition of ROP18 or alternative conformations to develop new anti-toxoplasmosis drug leads.

Dataset Information

Host Cell Vimentin Restrains Toxoplasma gondii Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with TgROP18.

Publications

Host Cell Vimentin Restrains <i>Toxoplasma gondii</i> Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with <i>Tg</i>ROP18.

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