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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

IL-33 signaling is required for neonatal RSV immunopathophysiology.(a) Number of Th1, Th2, and multifunctional mTh cells in the lungs of wild-type (WT) or ST2-deficient (Il1rl1-/-) mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6 per group), compared to naïve control mice of similar size and age. (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 5–8 per group). *P < 0.05 (Student’s t-test (a, c) or two-way ANOVA with Bonferroni post-hoc tests (b)). Data are representative of two independent experiments (means ± s.e.m).
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ppat.1005217.g006: IL-33 signaling is required for neonatal RSV immunopathophysiology.(a) Number of Th1, Th2, and multifunctional mTh cells in the lungs of wild-type (WT) or ST2-deficient (Il1rl1-/-) mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6 per group), compared to naïve control mice of similar size and age. (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 5–8 per group). *P < 0.05 (Student’s t-test (a, c) or two-way ANOVA with Bonferroni post-hoc tests (b)). Data are representative of two independent experiments (means ± s.e.m).

Mentions: To further demonstrate the role of IL-33 in promoting enhanced RSV disease in infected neonates, ST2 (IL-33 receptor, Il1rl1-/-)-deficient neonatal mice were infected with RSV as in Figs 4, 5 and 6. Compared to similarly-infected wild type mice (WT NRR), Il1rl1-/- NRR mice failed to develop significant Th2 or mTh adaptive responses (Fig 6a), did not exhibit AHR (Fig 6b), and had decreased total cells, lymphocytes, and eosinophils in BAL (Fig 6c).


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)

IL-33 signaling is required for neonatal RSV immunopathophysiology.(a) Number of Th1, Th2, and multifunctional mTh cells in the lungs of wild-type (WT) or ST2-deficient (Il1rl1-/-) mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6 per group), compared to naïve control mice of similar size and age. (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 5–8 per group). *P < 0.05 (Student’s t-test (a, c) or two-way ANOVA with Bonferroni post-hoc tests (b)). Data are representative of two independent experiments (means ± s.e.m).
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005217.g006: IL-33 signaling is required for neonatal RSV immunopathophysiology.(a) Number of Th1, Th2, and multifunctional mTh cells in the lungs of wild-type (WT) or ST2-deficient (Il1rl1-/-) mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6 per group), compared to naïve control mice of similar size and age. (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 5–8 per group). *P < 0.05 (Student’s t-test (a, c) or two-way ANOVA with Bonferroni post-hoc tests (b)). Data are representative of two independent experiments (means ± s.e.m).
Mentions: To further demonstrate the role of IL-33 in promoting enhanced RSV disease in infected neonates, ST2 (IL-33 receptor, Il1rl1-/-)-deficient neonatal mice were infected with RSV as in Figs 4, 5 and 6. Compared to similarly-infected wild type mice (WT NRR), Il1rl1-/- NRR mice failed to develop significant Th2 or mTh adaptive responses (Fig 6a), did not exhibit AHR (Fig 6b), and had decreased total cells, lymphocytes, and eosinophils in BAL (Fig 6c).

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