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Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques.

de Lang A, Baas T, Teal T, Leijten LM, Rain B, Osterhaus AD, Haagmans BL, Katze MG - PLoS Pathog. (2007)

Bottom Line: The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity.As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques.Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT
The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis) that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL)-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS.

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Immune Response, Cell Cycle, and Lung Repair Genes with Strongly Induced or Reduced ExpressionA selection of genes, involved in the immune response, cell cycle, or lung repair processes, that showed an absolute fold change > 5 and p < 0.0001 in both day 1 animals and/or in at least two of the four day 4 animals was made. Genes with an absolute fold change > 5 in both day 1 animals and in at least two of the four day 4 animals are indicated with bold, underlined text. A full summary of genes that show an absolute fold change > 5 and p < 0.0001 after SARS-CoV infection is given in Figure S2.
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ppat-0030112-g004: Immune Response, Cell Cycle, and Lung Repair Genes with Strongly Induced or Reduced ExpressionA selection of genes, involved in the immune response, cell cycle, or lung repair processes, that showed an absolute fold change > 5 and p < 0.0001 in both day 1 animals and/or in at least two of the four day 4 animals was made. Genes with an absolute fold change > 5 in both day 1 animals and in at least two of the four day 4 animals are indicated with bold, underlined text. A full summary of genes that show an absolute fold change > 5 and p < 0.0001 after SARS-CoV infection is given in Figure S2.

Mentions: In order to investigate genes that are most strongly regulated after SARS-CoV infection, genes included in the Venn diagram (Figure 3A) that also held to an absolute fold change > 5 were queried (Figure S2). From this set, genes that were involved in the immune response and lung repair processes were used to generate a heat map (Figure 4). A number of genes that have been reported to be up-regulated in SARS patient sera, such as CCL2 (MCP-1), CXCL10 (IP-10), IL-6, and IL-8, were strongly (∼20-fold) induced in all animals. Many cell cycle and matrix genes indicative of tissue repair processes were also highly differentially expressed at day 4 (e.g., ANLN, AREG, CDC2, CDKN3, CKS2, FOSL1, and KIF2C). Likewise, tissue factor pathway inhibitor 2 (TFPI2), an anticoagulant, was strongly up-regulated during infection in all animals (averaging ∼20-fold), as well as PLSCR1, SERPINE1 (PAI1), and THBS1, all genes involved in pro-coagulation and platelet activation, were induced. Concomitant expression of TFPI2 with these pro-coagulation genes might function as an inhibitory response to restrain the activation of the coagulation pathway during acute inflammation.


Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques.

de Lang A, Baas T, Teal T, Leijten LM, Rain B, Osterhaus AD, Haagmans BL, Katze MG - PLoS Pathog. (2007)

Immune Response, Cell Cycle, and Lung Repair Genes with Strongly Induced or Reduced ExpressionA selection of genes, involved in the immune response, cell cycle, or lung repair processes, that showed an absolute fold change > 5 and p < 0.0001 in both day 1 animals and/or in at least two of the four day 4 animals was made. Genes with an absolute fold change > 5 in both day 1 animals and in at least two of the four day 4 animals are indicated with bold, underlined text. A full summary of genes that show an absolute fold change > 5 and p < 0.0001 after SARS-CoV infection is given in Figure S2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1941749&req=5

ppat-0030112-g004: Immune Response, Cell Cycle, and Lung Repair Genes with Strongly Induced or Reduced ExpressionA selection of genes, involved in the immune response, cell cycle, or lung repair processes, that showed an absolute fold change > 5 and p < 0.0001 in both day 1 animals and/or in at least two of the four day 4 animals was made. Genes with an absolute fold change > 5 in both day 1 animals and in at least two of the four day 4 animals are indicated with bold, underlined text. A full summary of genes that show an absolute fold change > 5 and p < 0.0001 after SARS-CoV infection is given in Figure S2.
Mentions: In order to investigate genes that are most strongly regulated after SARS-CoV infection, genes included in the Venn diagram (Figure 3A) that also held to an absolute fold change > 5 were queried (Figure S2). From this set, genes that were involved in the immune response and lung repair processes were used to generate a heat map (Figure 4). A number of genes that have been reported to be up-regulated in SARS patient sera, such as CCL2 (MCP-1), CXCL10 (IP-10), IL-6, and IL-8, were strongly (∼20-fold) induced in all animals. Many cell cycle and matrix genes indicative of tissue repair processes were also highly differentially expressed at day 4 (e.g., ANLN, AREG, CDC2, CDKN3, CKS2, FOSL1, and KIF2C). Likewise, tissue factor pathway inhibitor 2 (TFPI2), an anticoagulant, was strongly up-regulated during infection in all animals (averaging ∼20-fold), as well as PLSCR1, SERPINE1 (PAI1), and THBS1, all genes involved in pro-coagulation and platelet activation, were induced. Concomitant expression of TFPI2 with these pro-coagulation genes might function as an inhibitory response to restrain the activation of the coagulation pathway during acute inflammation.

Bottom Line: The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity.As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques.Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT
The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis) that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL)-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs) and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS.

Show MeSH
Related in: MedlinePlus