Dataset Information

Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells.

ABSTRACT: bacterial amyloidosis, prion-like, RepA-WH1, intercellular transmission,proteotoxic cross-aggregation

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Vivian de los Rios

LAB HEAD: Rafael Giraldo

PROVIDER: PXD018245 | Pride | 2020-05-26

REPOSITORIES: Pride

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Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells.

Revilla-García Aida A Fernández Cristina C Moreno-Del Álamo María M de Los Ríos Vivian V Vorberg Ina M IM Giraldo Rafael R

mBio 20200414 2

RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent of mitochondrial impairment in human cells affected by neurodegeneration. To fulfill all the criteria to qualify as a prion-like ...[more]

PMID: 32291306

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Project description:Hearing loss is most commonly caused by the destruction of mechanosensory hair cells in the ear. This condition is usually permanent: Despite the presence of putative hair-cell progenitors in the cochlea, hair cells are not naturally replenished in adult mammals. Unlike those of the mammalian ear, the progenitor cells of nonmammalian vertebrates can regenerate hair cells through- out life. The basis of this difference remains largely unexplored but may lie in molecular dissimilarities that affect how progenitors respond to hair-cell death. We analyzed gene expression in hair-cell progenitors of the lateral-line system. We developed a transgenic line of zebrafish called alpl:mCherry that expresses a red fluorescent protein in the presumptive hair-cell progenitors known as mantle cells. Fluorescence-activated cell sorting from the skins of transgenic larvae, followed by microarray-based expression analysis, revealed a constellation of transcripts that are specifically enriched in these cells versus hair cells and non-fluorescent skin cells. Gene expression analysis after hair-cell ablation uncovered a cohort of genes that are differentially regulated early in regeneration, suggesting possible roles in the response of progen- itors to hair-cell death. These results provide a resource for studying hair-cell regeneration and the biology of sensory progenitor cells. Two sets of analyses were performed. The first compared baseline expression levels in four sorted cell types from two different transgenic lines of zebrafish, alpl:mCherry;pou4f3:GFP and alpl:mCherry:ET20. alpl:mCherry;pou4f3:GFP larvae express GFP in hair cells and mCherry in mantle cells. alpl:mCherry:ET20 larvae express GFP in most mantle cells and mChery in all mantle cells. The four cell types compared were GFP+ hair cells, mCherry+ mantle cells, mCherry+/GFP+ mantle cells from alpl:mCherry:ET20 larvae, and non-fluorescent (NF) cells. Two hair-cell, five mCherry+ mantle cell, four mCherry+/GFP+ mantle cell, and six NF cell samples were analyzed. This excludes a few samples that were discardced based on failure to cluster by principal component analysis. A second analysis, separately imported, compared gene expression in mCherry+ mantle cells and NF cells at four time points following chemical ablation of hair cells with copper sulfate. These were one, three, five, and eleven hours after treatment (hpCu). Untreated samples served as controls. For mCherry+ cells, five untreated and four each of 1 hpCu, 3 hpCu, 5 hpCu and 11 hpCu were analyzed. For NF cells, six untreated, seven 1 hpCu, and four each of 3 hpCu, 5 hpCu and 11 hpCu samples were analyzed. Untreated mCherry+ and NF cells were shared between both analyses.

Project description:Human regulatory T cells (TR) cells have potential for the treatment of immune mediated diseases, such as graft versus host disease, but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human TR cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimulation with a superagonistic anti-CD28 antibody (clone 9D4) and IL-2 partially reversed the proliferative defect, and this correlated with reversal of the defective calcium mobilization in these cells. Dendritic cells were effective at promoting TR cell proliferation, and under these conditions the proliferative capacity of TR cells was comparable to conventional CD4 lymphocytes. Blocking TGF-beta activity abrogated IL-10 expression from these cells, while addition of TGF-beta resulted in IL-10 production. These data demonstrate the ability of dendritic cells to provide proper costimulation to overcome the anergic phenotype of TR cells. In addition, these data demonstrate for the first time that TGF-beta is critical to enable TR cells to express IL-10. In order to confirm that our isolation strategy resulted in cells with characteristics of TR cells, we performed gene expression profiling of highly purified TR cells from two different individuals, which were compared to the gene expression profile of naÃ¯ve CD4+CD45RA+ cells. We first performed hierarchical clustering of the gene expression profiles of unactivated naÃ¯ve and TR cells from the two individuals. We show that the gene expression patterns of TR cells were highly similar between the two samples (correlation coefficient of 0.82), as were the gene expression profiles of naÃ¯ve CD4 cells between the two samples (correlation coefficient of 0.91). After averaging the gene expression signal from these two individuals, we compared the gene expression profile of unactivated TR cells with naÃ¯ve CD4 cells and show that TR cells over-express a variety of genes known to be associated with a TR phenotype (e.g. CTLA-4, IKZF2, IL-2RA). In addition, we also detected very high levels of expression of genes not typically associated with a TR phenotype, with the highest level of expression of IL-1 receptors in resting TR cells (Figure 2). These data confirm that the sorting strategy was effective at isolating T cells expressing a TR phenotype.

			Action	DRS
	A31VControl.msf	Msf
	A31VControl.mzML	Mzml
	A31VControl.raw	Raw
	A31VControl_Hsapiens.msf	Msf
	A31VGFP.msf	Msf

Dataset Information

Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells.

Dataset's files

Publications

Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells.

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