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Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology.

Wong TM, Boyapalle S, Sampayo V, Nguyen HD, Bedi R, Kamath SG, Moore ML, Mohapatra S, Mohapatra SS - PLoS ONE (2014)

Bottom Line: The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes.Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age.In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, James A. Haley Veterans Affairs Hospital, Tampa, Florida, United States of America ; Division of Translational Medicine and Nanomedicine Research Center, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.

ABSTRACT
Elderly persons are more susceptible to RSV-induced pneumonia than young people, but the molecular mechanism underlying this susceptibility is not well understood. In this study, we used an aged mouse model of RSV-induced pneumonia to examine how aging alters the lung pathology, modulates antiviral gene expressions, and the production of inflammatory cytokines in response to RSV infection. Young (2-3 months) and aged (19-21 months) mice were intranasally infected with mucogenic or non-mucogenic RSV strains, lung histology was examined, and gene expression was analyzed. Upon infection with mucogenic strains of RSV, leukocyte infiltration in the airways was elevated and prolonged in aged mice compared to young mice. Minitab factorial analysis identified several antiviral genes that are influenced by age, infection, and a combination of both factors. The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes. Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age. In addition to delays in cytokine signaling and pattern recognition receptor induction, we found TLR7/8 signaling to be impaired in alveolar macrophages in aged mice. In vivo, induction of IL-1β and OPN were delayed but prolonged in aged mice upon RSV infection compared to young. In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.

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Five significant genes identified after DOE analysis.Minitab design of experimental analysis identified candidate genes that are significantly associated with age and/or infection on either 1 dpi, 3 dpi, 5 dpi, or combination of all days (p<0.05). (A) A Venn diagram illustrates these relationships and the significant genes associated only with age, infection, a combination of both factors, and neither on 1 dpi, 3 dpi, or 5 dpi. (B) Genes found significantly influenced by age and infection were used to construct individual graphs at 3 dpi and illustrate differences in direction and magnitude of gene expression of the five significant genes (RIG-I, IFNAR1, IL-1β, OPN, and TLR8) associated with both age and RSV A2 infection between young (dotted) and aged (solid) mice.
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pone-0088764-g004: Five significant genes identified after DOE analysis.Minitab design of experimental analysis identified candidate genes that are significantly associated with age and/or infection on either 1 dpi, 3 dpi, 5 dpi, or combination of all days (p<0.05). (A) A Venn diagram illustrates these relationships and the significant genes associated only with age, infection, a combination of both factors, and neither on 1 dpi, 3 dpi, or 5 dpi. (B) Genes found significantly influenced by age and infection were used to construct individual graphs at 3 dpi and illustrate differences in direction and magnitude of gene expression of the five significant genes (RIG-I, IFNAR1, IL-1β, OPN, and TLR8) associated with both age and RSV A2 infection between young (dotted) and aged (solid) mice.

Mentions: To identify which genes are uniquely regulated by the contributing factors of age or infection, a Minitab design-of-experiments (DOE) was performed on the first delta Ct derived from the PCR array analysis. Age was found to be a statistically significant factor influencing the ΔCt in 15 genes and the Venn diagram illustrates the relationship of the contributing factors of age or infection for all 84 antiviral genes examined (Fig. 4A). Several of the identified genes are associated with Nod-like receptor signaling and activation of inflammasome complexes, such as Casp1, Casp9, and Nod2. Age and infection were found to be statistically associated with five genes, RIG-I, IFNAR1, IL-1β, OPN, and TLR8 and relative gene expressions from young and aged mice show age-related differences in the gene induction on day 3, when the change in ΔCt and subsequent relative gene expression was found to be statistically significant, often with contrasting trends between mock and 3 dpi (Fig. 4B). Of interest, 11 genes were not found to be significantly influenced by RSV infection over days 1, 3, or 5, including CD40, CD80, IFIH1, IL-18, JUN, MAPK3, MyD88, NFKB1, PYCARD, TBKBP1, and TRAF3. For the remainder of the study we focused on cytokines, OPN and IL-1β (upregulated >3-fold after infection in young mice) because of their associated roles in leukocyte migration and inflammasome activation, respectively.


Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology.

Wong TM, Boyapalle S, Sampayo V, Nguyen HD, Bedi R, Kamath SG, Moore ML, Mohapatra S, Mohapatra SS - PLoS ONE (2014)

Five significant genes identified after DOE analysis.Minitab design of experimental analysis identified candidate genes that are significantly associated with age and/or infection on either 1 dpi, 3 dpi, 5 dpi, or combination of all days (p<0.05). (A) A Venn diagram illustrates these relationships and the significant genes associated only with age, infection, a combination of both factors, and neither on 1 dpi, 3 dpi, or 5 dpi. (B) Genes found significantly influenced by age and infection were used to construct individual graphs at 3 dpi and illustrate differences in direction and magnitude of gene expression of the five significant genes (RIG-I, IFNAR1, IL-1β, OPN, and TLR8) associated with both age and RSV A2 infection between young (dotted) and aged (solid) mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3928298&req=5

pone-0088764-g004: Five significant genes identified after DOE analysis.Minitab design of experimental analysis identified candidate genes that are significantly associated with age and/or infection on either 1 dpi, 3 dpi, 5 dpi, or combination of all days (p<0.05). (A) A Venn diagram illustrates these relationships and the significant genes associated only with age, infection, a combination of both factors, and neither on 1 dpi, 3 dpi, or 5 dpi. (B) Genes found significantly influenced by age and infection were used to construct individual graphs at 3 dpi and illustrate differences in direction and magnitude of gene expression of the five significant genes (RIG-I, IFNAR1, IL-1β, OPN, and TLR8) associated with both age and RSV A2 infection between young (dotted) and aged (solid) mice.
Mentions: To identify which genes are uniquely regulated by the contributing factors of age or infection, a Minitab design-of-experiments (DOE) was performed on the first delta Ct derived from the PCR array analysis. Age was found to be a statistically significant factor influencing the ΔCt in 15 genes and the Venn diagram illustrates the relationship of the contributing factors of age or infection for all 84 antiviral genes examined (Fig. 4A). Several of the identified genes are associated with Nod-like receptor signaling and activation of inflammasome complexes, such as Casp1, Casp9, and Nod2. Age and infection were found to be statistically associated with five genes, RIG-I, IFNAR1, IL-1β, OPN, and TLR8 and relative gene expressions from young and aged mice show age-related differences in the gene induction on day 3, when the change in ΔCt and subsequent relative gene expression was found to be statistically significant, often with contrasting trends between mock and 3 dpi (Fig. 4B). Of interest, 11 genes were not found to be significantly influenced by RSV infection over days 1, 3, or 5, including CD40, CD80, IFIH1, IL-18, JUN, MAPK3, MyD88, NFKB1, PYCARD, TBKBP1, and TRAF3. For the remainder of the study we focused on cytokines, OPN and IL-1β (upregulated >3-fold after infection in young mice) because of their associated roles in leukocyte migration and inflammasome activation, respectively.

Bottom Line: The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes.Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age.In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, James A. Haley Veterans Affairs Hospital, Tampa, Florida, United States of America ; Division of Translational Medicine and Nanomedicine Research Center, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.

ABSTRACT
Elderly persons are more susceptible to RSV-induced pneumonia than young people, but the molecular mechanism underlying this susceptibility is not well understood. In this study, we used an aged mouse model of RSV-induced pneumonia to examine how aging alters the lung pathology, modulates antiviral gene expressions, and the production of inflammatory cytokines in response to RSV infection. Young (2-3 months) and aged (19-21 months) mice were intranasally infected with mucogenic or non-mucogenic RSV strains, lung histology was examined, and gene expression was analyzed. Upon infection with mucogenic strains of RSV, leukocyte infiltration in the airways was elevated and prolonged in aged mice compared to young mice. Minitab factorial analysis identified several antiviral genes that are influenced by age, infection, and a combination of both factors. The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes. Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age. In addition to delays in cytokine signaling and pattern recognition receptor induction, we found TLR7/8 signaling to be impaired in alveolar macrophages in aged mice. In vivo, induction of IL-1β and OPN were delayed but prolonged in aged mice upon RSV infection compared to young. In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.

Show MeSH
Related in: MedlinePlus