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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

RSV induces robust, rapid IL-33 and IL-13 production in the lungs of neonates.(a) Cytokine protein levels of IL-33 and IL-13 in whole lung homogenates of RSV-infected neonate (5-day-old; NR) and adult (6-8-week-old; AR) mice (n = 4–10 per group) at different days (0–10) post-infection (dpi). (b) Cytokine protein levels of IL-33 detected in BAL at 1 dpi from NR and AR mice (n = 8–10 per group) compared to controls. (c) Gating strategy for determination of IL-33 expression by median fluorescence intensity (MFI) in epithelial cells (CD45- EpCam+) with representative IL-33 MFI histogram (quantified in inset vs. fluorescence-minus-one (FMO) control (dotted line)). (d) Representative micrographs of in situ hybridization for IL-33 mRNA with red arrows to indicate positive staining cells (top), magnified inset (bottom), and quantification of IL-33 mRNA positive cells per unit area of lung. Scale bar = 100 μm. (e) Cytokine protein levels of IL-33 in whole lung homogenates of neonates infected with RSV or UV-RSV compared to control at 1 dpi. *P < 0.05 (Student’s t-test; a, c, d) (Two-way ANOVA; b) (One-way ANOVA; e). Data are representative of two (a, c) or 2 pooled (b, d, e) independent experiments (means ± s.e.m).
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ppat.1005217.g001: RSV induces robust, rapid IL-33 and IL-13 production in the lungs of neonates.(a) Cytokine protein levels of IL-33 and IL-13 in whole lung homogenates of RSV-infected neonate (5-day-old; NR) and adult (6-8-week-old; AR) mice (n = 4–10 per group) at different days (0–10) post-infection (dpi). (b) Cytokine protein levels of IL-33 detected in BAL at 1 dpi from NR and AR mice (n = 8–10 per group) compared to controls. (c) Gating strategy for determination of IL-33 expression by median fluorescence intensity (MFI) in epithelial cells (CD45- EpCam+) with representative IL-33 MFI histogram (quantified in inset vs. fluorescence-minus-one (FMO) control (dotted line)). (d) Representative micrographs of in situ hybridization for IL-33 mRNA with red arrows to indicate positive staining cells (top), magnified inset (bottom), and quantification of IL-33 mRNA positive cells per unit area of lung. Scale bar = 100 μm. (e) Cytokine protein levels of IL-33 in whole lung homogenates of neonates infected with RSV or UV-RSV compared to control at 1 dpi. *P < 0.05 (Student’s t-test; a, c, d) (Two-way ANOVA; b) (One-way ANOVA; e). Data are representative of two (a, c) or 2 pooled (b, d, e) independent experiments (means ± s.e.m).

Mentions: We previously observed an increase in pulmonary IL-13 immediately following RSV infection of neonatal, but not, adult mice. Since this increase was prior to the induction of Th2 cells and responses, it suggested a role for ILC2s. To determine if there are age-dependent differences in the induction of ILC2s in response to RSV, we infected neonatal mice (5 d of age; NR) and adult mice (6–8 weeks of age; AR) then kinetically measured IL-33 and IL-13 cytokine levels in whole lung homogenates (Fig 1a). Highly elevated IL-33 levels were detected in neonates as early as 0.25 days post-infection (dpi) and peaking at 0.5 dpi. Although IL-33 could be detected in the lungs of adult mice, there was no significant change in expression following RSV infection. A similar trend was observed with IL-13 levels—increased expression in the lungs of mice infected as neonates, which peaked at 1 dpi, and no significant change in the lungs of mice infected as adults. An additional significant increase in IL-13 was observed at 6 dpi in mice infected as neonates. Significantly elevated levels of IL-33 were also observed in bronchoalveolar lavage (BAL) from infected neonates but not adults (Fig 1b). Investigation into the cellular sources of IL-33 at 1 dpi revealed significant expression in airway epithelial cells (CD45- EpCam+) of infected neonates (Fig 1c). A similar trend was observed with detection of IL-33 mRNA by in situ hybridization (Fig 1d). To determine if this rapid IL-33 increase in neonates requires live replicating virus, we “infected” neonates with UV-inactivated RSV (UV-RSV) and measured IL-33 in lung homogenates at 1 dpi (Fig 1e). IL-33 levels in the lungs following administration of UV-RSV was statistically no different than sham infected neonatal control mice and significantly lower than RSV infected neonatal mice.


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)

RSV induces robust, rapid IL-33 and IL-13 production in the lungs of neonates.(a) Cytokine protein levels of IL-33 and IL-13 in whole lung homogenates of RSV-infected neonate (5-day-old; NR) and adult (6-8-week-old; AR) mice (n = 4–10 per group) at different days (0–10) post-infection (dpi). (b) Cytokine protein levels of IL-33 detected in BAL at 1 dpi from NR and AR mice (n = 8–10 per group) compared to controls. (c) Gating strategy for determination of IL-33 expression by median fluorescence intensity (MFI) in epithelial cells (CD45- EpCam+) with representative IL-33 MFI histogram (quantified in inset vs. fluorescence-minus-one (FMO) control (dotted line)). (d) Representative micrographs of in situ hybridization for IL-33 mRNA with red arrows to indicate positive staining cells (top), magnified inset (bottom), and quantification of IL-33 mRNA positive cells per unit area of lung. Scale bar = 100 μm. (e) Cytokine protein levels of IL-33 in whole lung homogenates of neonates infected with RSV or UV-RSV compared to control at 1 dpi. *P < 0.05 (Student’s t-test; a, c, d) (Two-way ANOVA; b) (One-way ANOVA; e). Data are representative of two (a, c) or 2 pooled (b, d, e) independent experiments (means ± s.e.m).
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Related In: Results  -  Collection

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ppat.1005217.g001: RSV induces robust, rapid IL-33 and IL-13 production in the lungs of neonates.(a) Cytokine protein levels of IL-33 and IL-13 in whole lung homogenates of RSV-infected neonate (5-day-old; NR) and adult (6-8-week-old; AR) mice (n = 4–10 per group) at different days (0–10) post-infection (dpi). (b) Cytokine protein levels of IL-33 detected in BAL at 1 dpi from NR and AR mice (n = 8–10 per group) compared to controls. (c) Gating strategy for determination of IL-33 expression by median fluorescence intensity (MFI) in epithelial cells (CD45- EpCam+) with representative IL-33 MFI histogram (quantified in inset vs. fluorescence-minus-one (FMO) control (dotted line)). (d) Representative micrographs of in situ hybridization for IL-33 mRNA with red arrows to indicate positive staining cells (top), magnified inset (bottom), and quantification of IL-33 mRNA positive cells per unit area of lung. Scale bar = 100 μm. (e) Cytokine protein levels of IL-33 in whole lung homogenates of neonates infected with RSV or UV-RSV compared to control at 1 dpi. *P < 0.05 (Student’s t-test; a, c, d) (Two-way ANOVA; b) (One-way ANOVA; e). Data are representative of two (a, c) or 2 pooled (b, d, e) independent experiments (means ± s.e.m).
Mentions: We previously observed an increase in pulmonary IL-13 immediately following RSV infection of neonatal, but not, adult mice. Since this increase was prior to the induction of Th2 cells and responses, it suggested a role for ILC2s. To determine if there are age-dependent differences in the induction of ILC2s in response to RSV, we infected neonatal mice (5 d of age; NR) and adult mice (6–8 weeks of age; AR) then kinetically measured IL-33 and IL-13 cytokine levels in whole lung homogenates (Fig 1a). Highly elevated IL-33 levels were detected in neonates as early as 0.25 days post-infection (dpi) and peaking at 0.5 dpi. Although IL-33 could be detected in the lungs of adult mice, there was no significant change in expression following RSV infection. A similar trend was observed with IL-13 levels—increased expression in the lungs of mice infected as neonates, which peaked at 1 dpi, and no significant change in the lungs of mice infected as adults. An additional significant increase in IL-13 was observed at 6 dpi in mice infected as neonates. Significantly elevated levels of IL-33 were also observed in bronchoalveolar lavage (BAL) from infected neonates but not adults (Fig 1b). Investigation into the cellular sources of IL-33 at 1 dpi revealed significant expression in airway epithelial cells (CD45- EpCam+) of infected neonates (Fig 1c). A similar trend was observed with detection of IL-33 mRNA by in situ hybridization (Fig 1d). To determine if this rapid IL-33 increase in neonates requires live replicating virus, we “infected” neonates with UV-inactivated RSV (UV-RSV) and measured IL-33 in lung homogenates at 1 dpi (Fig 1e). IL-33 levels in the lungs following administration of UV-RSV was statistically no different than sham infected neonatal control mice and significantly lower than RSV infected neonatal mice.

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