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Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33.

Saravia J, You D, Shrestha B, Jaligama S, Siefker D, Lee GI, Harding JN, Jones TL, Rovnaghi C, Bagga B, DeVincenzo JP, Cormier SA - PLoS Pathog. (2015)

Bottom Line: The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive.Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence.This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee, United States of America.

ABSTRACT
Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

No MeSH data available.


Related in: MedlinePlus

The percentage of ILC2s in the lungs of neonatal mice are further increased after RSV infection.(a) Gating strategy and (b) ILC2 marker expression on ILC2s at baseline and 1 dpi. (c) ILC2s as percent of total lung cells, and (d) MFI of ST2 expression of/on ILC2s at baseline and 1 dpi. ILC2s defined as lineage- CD45+ ICOS+ ST2+ with gating based on FMO controls. *P < 0.05 (Two-way ANOVA). Data are representative of four independent experiments (means ± s.e.m).
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ppat.1005217.g002: The percentage of ILC2s in the lungs of neonatal mice are further increased after RSV infection.(a) Gating strategy and (b) ILC2 marker expression on ILC2s at baseline and 1 dpi. (c) ILC2s as percent of total lung cells, and (d) MFI of ST2 expression of/on ILC2s at baseline and 1 dpi. ILC2s defined as lineage- CD45+ ICOS+ ST2+ with gating based on FMO controls. *P < 0.05 (Two-way ANOVA). Data are representative of four independent experiments (means ± s.e.m).

Mentions: Of note, neonatal mice displayed 3–4 fold more lung ILC2s (lineage- CD45+ ICOS+ ST2+; gating strategy in S1 Fig; raw numbers in S3 Fig) at baseline (i.e. prior to infection) compared to adults (Fig 2a–2c). After infection, lung ILC2 percentages at 1 dpi were significantly higher in RSV-infected neonates compared to adults. Furthermore, neonatal ILC2s expressed more ST2 (Fig 2d). There was no change in the frequency of ILC2s at baseline or at 1dpi (Fig 2c) or in ST2 levels on those ILC2s at baseline or at 1dpi (Fig 2d) in adults.


Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33.

Saravia J, You D, Shrestha B, Jaligama S, Siefker D, Lee GI, Harding JN, Jones TL, Rovnaghi C, Bagga B, DeVincenzo JP, Cormier SA - PLoS Pathog. (2015)

The percentage of ILC2s in the lungs of neonatal mice are further increased after RSV infection.(a) Gating strategy and (b) ILC2 marker expression on ILC2s at baseline and 1 dpi. (c) ILC2s as percent of total lung cells, and (d) MFI of ST2 expression of/on ILC2s at baseline and 1 dpi. ILC2s defined as lineage- CD45+ ICOS+ ST2+ with gating based on FMO controls. *P < 0.05 (Two-way ANOVA). Data are representative of four independent experiments (means ± s.e.m).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608776&req=5

ppat.1005217.g002: The percentage of ILC2s in the lungs of neonatal mice are further increased after RSV infection.(a) Gating strategy and (b) ILC2 marker expression on ILC2s at baseline and 1 dpi. (c) ILC2s as percent of total lung cells, and (d) MFI of ST2 expression of/on ILC2s at baseline and 1 dpi. ILC2s defined as lineage- CD45+ ICOS+ ST2+ with gating based on FMO controls. *P < 0.05 (Two-way ANOVA). Data are representative of four independent experiments (means ± s.e.m).
Mentions: Of note, neonatal mice displayed 3–4 fold more lung ILC2s (lineage- CD45+ ICOS+ ST2+; gating strategy in S1 Fig; raw numbers in S3 Fig) at baseline (i.e. prior to infection) compared to adults (Fig 2a–2c). After infection, lung ILC2 percentages at 1 dpi were significantly higher in RSV-infected neonates compared to adults. Furthermore, neonatal ILC2s expressed more ST2 (Fig 2d). There was no change in the frequency of ILC2s at baseline or at 1dpi (Fig 2c) or in ST2 levels on those ILC2s at baseline or at 1dpi (Fig 2d) in adults.

Bottom Line: The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive.Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence.This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee, United States of America.

ABSTRACT
Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

No MeSH data available.


Related in: MedlinePlus