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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 molecular functions of those genes whose expressions in 2B4 cells were significantly altered by SARS-CoV.Expressions of both up- and down-regulated genes at 12, 24, and/or 48 hrs after SARS-CoV infection were analyzed against the entire human genome gene set. The enriched GO-annotated terms identified for those up-regulated and down-regulated genes are presented in A and B, respectively. The height of an individual bar represents the level of the statistical significance of the enriched GO-annotated term. An adjusted p value of <0.05 was used as the criterion for selecting enriched molecular functions.
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pone-0008729-g004: Enriched molecular functions of those genes whose expressions in 2B4 cells were significantly altered by SARS-CoV.Expressions of both up- and down-regulated genes at 12, 24, and/or 48 hrs after SARS-CoV infection were analyzed against the entire human genome gene set. The enriched GO-annotated terms identified for those up-regulated and down-regulated genes are presented in A and B, respectively. The height of an individual bar represents the level of the statistical significance of the enriched GO-annotated term. An adjusted p value of <0.05 was used as the criterion for selecting enriched molecular 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 molecular functions of those genes whose expressions in 2B4 cells were significantly altered by SARS-CoV.Expressions of both up- and down-regulated genes at 12, 24, and/or 48 hrs after SARS-CoV infection were analyzed against the entire human genome gene set. The enriched GO-annotated terms identified for those up-regulated and down-regulated genes are presented in A and B, respectively. The height of an individual bar represents the level of the statistical significance of the enriched GO-annotated term. An adjusted p value of <0.05 was used as the criterion for selecting enriched molecular functions.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0008729-g004: Enriched molecular functions of those genes whose expressions in 2B4 cells were significantly altered by SARS-CoV.Expressions of both up- and down-regulated genes at 12, 24, and/or 48 hrs after SARS-CoV infection were analyzed against the entire human genome gene set. The enriched GO-annotated terms identified for those up-regulated and down-regulated genes are presented in A and B, respectively. The height of an individual bar represents the level of the statistical significance of the enriched GO-annotated term. An adjusted p value of <0.05 was used as the criterion for selecting enriched molecular 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