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Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection.

Yoshikawa T, Hill TE, Yoshikawa N, Popov VL, Galindo CL, Garner HR, Peters CJ, Tseng CT - PLoS ONE (2010)

Bottom Line: Specifically, we found a temporal and spatial activation of nuclear factor (NF)kappaB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3/7 in infected 2B4 cells at 12-, 24-, and 48-hrs post infection (p.i.), resulting in the activation of many antiviral genes, including interferon (IFN)-beta, -lambdas, inflammatory mediators, and many IFN-stimulated genes (ISGs).We also showed, for the first time, that IFN-beta and IFN-lambdas were capable of exerting previously unrecognized, non-redundant, and complementary abilities to limit SARS-CoV replication, even though their expression could not be detected in infected 2B4 bronchial epithelial cells until 48 hrs p.i.Collectively, our results highlight the mechanics of the sequential events of antiviral signaling pathway/s triggered by SARS-CoV in bronchial epithelial cells and identify novel cellular targets for future studies, aiming at advancing strategies against SARS.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Human lung epithelial cells are likely among the first targets to encounter invading severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Not only can these cells support the growth of SARS-CoV infection, but they are also capable of secreting inflammatory cytokines to initiate and, eventually, aggravate host innate inflammatory responses, causing detrimental immune-mediated pathology within the lungs. Thus, a comprehensive evaluation of the complex epithelial signaling to SARS-CoV is crucial for paving the way to better understand SARS pathogenesis. Based on microarray-based functional genomics, we report here the global gene response of 2B4 cells, a cloned bronchial epithelial cell line derived from Calu-3 cells. Specifically, we found a temporal and spatial activation of nuclear factor (NF)kappaB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3/7 in infected 2B4 cells at 12-, 24-, and 48-hrs post infection (p.i.), resulting in the activation of many antiviral genes, including interferon (IFN)-beta, -lambdas, inflammatory mediators, and many IFN-stimulated genes (ISGs). We also showed, for the first time, that IFN-beta and IFN-lambdas were capable of exerting previously unrecognized, non-redundant, and complementary abilities to limit SARS-CoV replication, even though their expression could not be detected in infected 2B4 bronchial epithelial cells until 48 hrs p.i. Collectively, our results highlight the mechanics of the sequential events of antiviral signaling pathway/s triggered by SARS-CoV in bronchial epithelial cells and identify novel cellular targets for future studies, aiming at advancing strategies against SARS.

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Enriched entities of biological processes for those genes that were highly activated in 2B4 cells in response to SARS-CoV infection.While no enriched GO-annotated biological term could be identified for those genes whose expressions were significantly down-regulated, 13 enriched biological entities were readily revealed for those highly activated genes of SARS-CoV-infected 2B4 cells at 12, 24, and/or 48 hrs p.i.. The height of each individual bar represents the level of statistical significance of the enriched GO-annotated biological process. An adjusted p value of <0.05 was used as the minimal criterion for selecting the enriched GO-annotated biological functions.
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pone-0008729-g005: Enriched entities of biological processes for those genes that were highly activated in 2B4 cells in response to SARS-CoV infection.While no enriched GO-annotated biological term could be identified for those genes whose expressions were significantly down-regulated, 13 enriched biological entities were readily revealed for those highly activated genes of SARS-CoV-infected 2B4 cells at 12, 24, and/or 48 hrs p.i.. The height of each individual bar represents the level of statistical significance of the enriched GO-annotated biological process. An adjusted p value of <0.05 was used as the minimal criterion for selecting the enriched GO-annotated biological functions.

Mentions: To identify functional patterns that might allow us to better understand the biological relevance of the temporally regulated genes of infected 2B4 cells, all of the significantly up- and down-regulated genes were subjected to gene ontogeny (GO)-based annotation and functional analysis. Those that were applicable, namely the enriched GO terms of genes analyzed, are depicted as Figures 4 and 5, according to their molecular function and biological process, respectively.


Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection.

Yoshikawa T, Hill TE, Yoshikawa N, Popov VL, Galindo CL, Garner HR, Peters CJ, Tseng CT - PLoS ONE (2010)

Enriched entities of biological processes for those genes that were highly activated in 2B4 cells in response to SARS-CoV infection.While no enriched GO-annotated biological term could be identified for those genes whose expressions were significantly down-regulated, 13 enriched biological entities were readily revealed for those highly activated genes of SARS-CoV-infected 2B4 cells at 12, 24, and/or 48 hrs p.i.. The height of each individual bar represents the level of statistical significance of the enriched GO-annotated biological process. An adjusted p value of <0.05 was used as the minimal criterion for selecting the enriched GO-annotated biological functions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2806919&req=5

pone-0008729-g005: Enriched entities of biological processes for those genes that were highly activated in 2B4 cells in response to SARS-CoV infection.While no enriched GO-annotated biological term could be identified for those genes whose expressions were significantly down-regulated, 13 enriched biological entities were readily revealed for those highly activated genes of SARS-CoV-infected 2B4 cells at 12, 24, and/or 48 hrs p.i.. The height of each individual bar represents the level of statistical significance of the enriched GO-annotated biological process. An adjusted p value of <0.05 was used as the minimal criterion for selecting the enriched GO-annotated biological functions.
Mentions: To identify functional patterns that might allow us to better understand the biological relevance of the temporally regulated genes of infected 2B4 cells, all of the significantly up- and down-regulated genes were subjected to gene ontogeny (GO)-based annotation and functional analysis. Those that were applicable, namely the enriched GO terms of genes analyzed, are depicted as Figures 4 and 5, according to their molecular function and biological process, respectively.

Bottom Line: Specifically, we found a temporal and spatial activation of nuclear factor (NF)kappaB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3/7 in infected 2B4 cells at 12-, 24-, and 48-hrs post infection (p.i.), resulting in the activation of many antiviral genes, including interferon (IFN)-beta, -lambdas, inflammatory mediators, and many IFN-stimulated genes (ISGs).We also showed, for the first time, that IFN-beta and IFN-lambdas were capable of exerting previously unrecognized, non-redundant, and complementary abilities to limit SARS-CoV replication, even though their expression could not be detected in infected 2B4 bronchial epithelial cells until 48 hrs p.i.Collectively, our results highlight the mechanics of the sequential events of antiviral signaling pathway/s triggered by SARS-CoV in bronchial epithelial cells and identify novel cellular targets for future studies, aiming at advancing strategies against SARS.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT
Human lung epithelial cells are likely among the first targets to encounter invading severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Not only can these cells support the growth of SARS-CoV infection, but they are also capable of secreting inflammatory cytokines to initiate and, eventually, aggravate host innate inflammatory responses, causing detrimental immune-mediated pathology within the lungs. Thus, a comprehensive evaluation of the complex epithelial signaling to SARS-CoV is crucial for paving the way to better understand SARS pathogenesis. Based on microarray-based functional genomics, we report here the global gene response of 2B4 cells, a cloned bronchial epithelial cell line derived from Calu-3 cells. Specifically, we found a temporal and spatial activation of nuclear factor (NF)kappaB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3/7 in infected 2B4 cells at 12-, 24-, and 48-hrs post infection (p.i.), resulting in the activation of many antiviral genes, including interferon (IFN)-beta, -lambdas, inflammatory mediators, and many IFN-stimulated genes (ISGs). We also showed, for the first time, that IFN-beta and IFN-lambdas were capable of exerting previously unrecognized, non-redundant, and complementary abilities to limit SARS-CoV replication, even though their expression could not be detected in infected 2B4 bronchial epithelial cells until 48 hrs p.i. Collectively, our results highlight the mechanics of the sequential events of antiviral signaling pathway/s triggered by SARS-CoV in bronchial epithelial cells and identify novel cellular targets for future studies, aiming at advancing strategies against SARS.

Show MeSH
Related in: MedlinePlus