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Molecular Dynamics Simulations Reveal Novel Interacting Regions of Human Prion Protein to Brucella abortus Hsp60 Protein.

ABSTRACT: The distinctive morphology characteristics of microfold cells (M cells) allow the vaccine antigen not only to interact with immune cells directly, but also to effectively stimulate mucosal immune responses via receptors on its apical surface. Human prion protein, a transmembrane receptor for Brucella abortus Hsp60, is highly expressed on the M cell surface. Nonetheless, this protein tends to express in inclusion body in prokaryotic hosts. In this study, the shorter interacting regions of human prion protein were identified via computational methods such as docking and molecular dynamics simulations to minimize its aggregation tendency. The computational calculations revealed three novel human prion protein-interacting regions, namely PrP125, PrP174, and PrP180. In accordance with in silico prediction, the biologically synthesized peptides fusing with GST tag demonstrated their specific binding to Hsp60 protein via pull-down assay. Hence, this finding laid the groundwork for M-cell targeting candidate validation through these newly identified interacting regions.

SUBMITTER: Le-Dao HA

PROVIDER: S-EPMC9838441 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Molecular Dynamics Simulations Reveal Novel Interacting Regions of Human Prion Protein to Brucella abortus Hsp60 Protein.

Le-Dao Hoang-Anh HA Dinh Thuan-Thien TT Tran Thuoc Linh TL Lee Vannajan Sanghiran VS Tran-Van Hieu H

Molecular biotechnology 20230112 4

The distinctive morphology characteristics of microfold cells (M cells) allow the vaccine antigen not only to interact with immune cells directly, but also to effectively stimulate mucosal immune responses via receptors on its apical surface. Human prion protein, a transmembrane receptor for Brucella abortus Hsp60, is highly expressed on the M cell surface. Nonetheless, this protein tends to express in inclusion body in prokaryotic hosts. In this study, the shorter interacting regions of human p ...[more]

PMID: 36633832

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Project description:BackgroundHuman brucellosis caused by the facultative intracellular pathogen Brucella spp. is an endemic bacterial zoonosis manifesting as acute or chronic infections with high morbidity. Treatment typically involves a combination therapy of two antibiotics for several weeks to months, but despite this harsh treatment relapses occur at a rate of 5-15%. Although poor compliance and reinfection may account for a fraction of the observed relapse cases, it is apparent that the properties of the infectious agent itself may play a decisive role in this phenomenon.Methodology/principal findingsWe used B. abortus carrying a dual reporter in a macrophage infection model to gain a better understanding of the efficacy of recommended therapies in cellulo. For this we used automated fluorescent microscopy as a prime read-out and developed specific CellProfiler pipelines to score infected macrophages at the population and the single cell level. Combining microscopy of constitutive and induced reporters with classical CFU determination, we quantified the protective nature of the Brucella intracellular lifestyle to various antibiotics and the ability of B. abortus to persist in cellulo despite harsh antibiotic treatments.Conclusion/significanceWe demonstrate that treatment of infected macrophages with antibiotics at recommended concentrations fails to fully prevent growth and persistence of B. abortus in cellulo, which may be explained by a protective nature of the intracellular niche(s). Moreover, we show the presence of bona fide intracellular persisters upon antibiotic treatment, which are metabolically active and retain the full infectious potential, therefore constituting a plausible reservoir for reinfection and relapse. In conclusion, our results highlight the need to extend the spectrum of models to test new antimicrobial therapies for brucellosis to better reflect the in vivo infection environment, and to develop therapeutic approaches targeting the persister subpopulation.

Dataset Information

Molecular Dynamics Simulations Reveal Novel Interacting Regions of Human Prion Protein to Brucella abortus Hsp60 Protein.

Publications

Molecular Dynamics Simulations Reveal Novel Interacting Regions of Human Prion Protein to Brucella abortus Hsp60 Protein.

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