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Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation

Numerous bacterial pathogens manipulate host cell processes to promote infection and ultimately cause disease through the action of proteins that they directly inject into host cells. Identification of the targets and molecular mechanisms of action used by these bacterial effector proteins is critic...

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Autores principales: Kramer, Roger W, Slagowski, Naomi L, Eze, Ngozi A, Giddings, Kara S, Morrison, Monica F, Siggers, Keri A, Starnbach, Michael N, Lesser, Cammie F
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797620/
https://www.ncbi.nlm.nih.gov/pubmed/17305427
http://dx.doi.org/10.1371/journal.ppat.0030021
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author Kramer, Roger W
Slagowski, Naomi L
Eze, Ngozi A
Giddings, Kara S
Morrison, Monica F
Siggers, Keri A
Starnbach, Michael N
Lesser, Cammie F
author_facet Kramer, Roger W
Slagowski, Naomi L
Eze, Ngozi A
Giddings, Kara S
Morrison, Monica F
Siggers, Keri A
Starnbach, Michael N
Lesser, Cammie F
author_sort Kramer, Roger W
collection PubMed
description Numerous bacterial pathogens manipulate host cell processes to promote infection and ultimately cause disease through the action of proteins that they directly inject into host cells. Identification of the targets and molecular mechanisms of action used by these bacterial effector proteins is critical to understanding pathogenesis. We have developed a systems biological approach using the yeast Saccharomyces cerevisiae that can expedite the identification of cellular processes targeted by bacterial effector proteins. We systematically screened the viable yeast haploid deletion strain collection for mutants hypersensitive to expression of the Shigella type III effector OspF. Statistical data mining of the results identified several cellular processes, including cell wall biogenesis, which when impaired by a deletion caused yeast to be hypersensitive to OspF expression. Microarray experiments revealed that OspF expression resulted in reversed regulation of genes regulated by the yeast cell wall integrity pathway. The yeast cell wall integrity pathway is a highly conserved mitogen-activated protein kinase (MAPK) signaling pathway, normally activated in response to cell wall perturbations. Together these results led us to hypothesize and subsequently demonstrate that OspF inhibited both yeast and mammalian MAPK signaling cascades. Furthermore, inhibition of MAPK signaling by OspF is associated with attenuation of the host innate immune response to Shigella infection in a mouse model. These studies demonstrate how yeast systems biology can facilitate functional characterization of pathogenic bacterial effector proteins.
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spelling pubmed-17976202007-02-16 Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation Kramer, Roger W Slagowski, Naomi L Eze, Ngozi A Giddings, Kara S Morrison, Monica F Siggers, Keri A Starnbach, Michael N Lesser, Cammie F PLoS Pathog Research Article Numerous bacterial pathogens manipulate host cell processes to promote infection and ultimately cause disease through the action of proteins that they directly inject into host cells. Identification of the targets and molecular mechanisms of action used by these bacterial effector proteins is critical to understanding pathogenesis. We have developed a systems biological approach using the yeast Saccharomyces cerevisiae that can expedite the identification of cellular processes targeted by bacterial effector proteins. We systematically screened the viable yeast haploid deletion strain collection for mutants hypersensitive to expression of the Shigella type III effector OspF. Statistical data mining of the results identified several cellular processes, including cell wall biogenesis, which when impaired by a deletion caused yeast to be hypersensitive to OspF expression. Microarray experiments revealed that OspF expression resulted in reversed regulation of genes regulated by the yeast cell wall integrity pathway. The yeast cell wall integrity pathway is a highly conserved mitogen-activated protein kinase (MAPK) signaling pathway, normally activated in response to cell wall perturbations. Together these results led us to hypothesize and subsequently demonstrate that OspF inhibited both yeast and mammalian MAPK signaling cascades. Furthermore, inhibition of MAPK signaling by OspF is associated with attenuation of the host innate immune response to Shigella infection in a mouse model. These studies demonstrate how yeast systems biology can facilitate functional characterization of pathogenic bacterial effector proteins. Public Library of Science 2007-02 2007-02-16 /pmc/articles/PMC1797620/ /pubmed/17305427 http://dx.doi.org/10.1371/journal.ppat.0030021 Text en © 2007 Kramer et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kramer, Roger W
Slagowski, Naomi L
Eze, Ngozi A
Giddings, Kara S
Morrison, Monica F
Siggers, Keri A
Starnbach, Michael N
Lesser, Cammie F
Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title_full Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title_fullStr Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title_full_unstemmed Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title_short Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation
title_sort yeast functional genomic screens lead to identification of a role for a bacterial effector in innate immunity regulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797620/
https://www.ncbi.nlm.nih.gov/pubmed/17305427
http://dx.doi.org/10.1371/journal.ppat.0030021
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