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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 levels during primary RSV infection determine disease severity after reinfection.(a) Number of Th1 (CD3+CD4+IFNγ+), Th2 (CD3+CD4+IL-4+), and multifunctional Th (CD3+CD4+IFNγ+IL-4+; mTh) cells in the lungs of mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group); prior to initial RSV infection, neonatal mice were pretreated with IL-33 neutralizing antibody (α-IL-33 + NRR) or control IgG antibody (Isotype + NRR) and adult mice pretreated with recombinant IL-33 (rIL-33 + ARR) or vehicle control (Control + ARR). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6–8 per group). (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 3–6 per group). *P < 0.05 vs. indicated group (one-way ANOVA with Bonferroni post-hoc tests; a, c) (two-way ANOVA with Bonferroni post-hoc tests; b). Data are representative of at least two independent experiments (means ± s.e.m).
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ppat.1005217.g004: IL-33 levels during primary RSV infection determine disease severity after reinfection.(a) Number of Th1 (CD3+CD4+IFNγ+), Th2 (CD3+CD4+IL-4+), and multifunctional Th (CD3+CD4+IFNγ+IL-4+; mTh) cells in the lungs of mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group); prior to initial RSV infection, neonatal mice were pretreated with IL-33 neutralizing antibody (α-IL-33 + NRR) or control IgG antibody (Isotype + NRR) and adult mice pretreated with recombinant IL-33 (rIL-33 + ARR) or vehicle control (Control + ARR). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6–8 per group). (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 3–6 per group). *P < 0.05 vs. indicated group (one-way ANOVA with Bonferroni post-hoc tests; a, c) (two-way ANOVA with Bonferroni post-hoc tests; b). Data are representative of at least two independent experiments (means ± s.e.m).

Mentions: In infants, severe RSV often causes bronchiolitis, recruitment of inflammatory cells (i.e., Th2 cells, eosinophils) to the lungs, and increased airway mucus, resulting in significant airway obstruction and airway hyperresponsiveness (AHR). A similar disease phenotype is readily observed (following reinfection) in mice initially infected with RSV as neonates, but not adults. To phenotypically recapitulate severe RSV infection seen clinically in human infants, mice from the same treatment groups as in Fig 3 were reinfected with RSV at 4 weeks post-primary infection (established neonatal mouse RSV infection + reinfection protocol [6, 7, 16]) and immune responses determined at 6 dpi (Fig 4). Neutralizing IL-33 during primary infection in neonates resulted in significant reductions in Th2 and multifunctional Th (mTh; IFNγ+, IL-4+) cells upon reinfection (α-IL-33+NRR) (Fig 4a). Conversely, administration of rIL-33 to adult mice during primary infection resulted in significant increases in Th2 and mTh cells upon reinfection (rIL-33+ARR), which were similar to levels induced in NRR 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)

IL-33 levels during primary RSV infection determine disease severity after reinfection.(a) Number of Th1 (CD3+CD4+IFNγ+), Th2 (CD3+CD4+IL-4+), and multifunctional Th (CD3+CD4+IFNγ+IL-4+; mTh) cells in the lungs of mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group); prior to initial RSV infection, neonatal mice were pretreated with IL-33 neutralizing antibody (α-IL-33 + NRR) or control IgG antibody (Isotype + NRR) and adult mice pretreated with recombinant IL-33 (rIL-33 + ARR) or vehicle control (Control + ARR). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6–8 per group). (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 3–6 per group). *P < 0.05 vs. indicated group (one-way ANOVA with Bonferroni post-hoc tests; a, c) (two-way ANOVA with Bonferroni post-hoc tests; b). Data are representative of at least two independent experiments (means ± s.e.m).
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ppat.1005217.g004: IL-33 levels during primary RSV infection determine disease severity after reinfection.(a) Number of Th1 (CD3+CD4+IFNγ+), Th2 (CD3+CD4+IL-4+), and multifunctional Th (CD3+CD4+IFNγ+IL-4+; mTh) cells in the lungs of mice at 6 dpi following reinfection with RSV (methods) (n = 5–6 per group); prior to initial RSV infection, neonatal mice were pretreated with IL-33 neutralizing antibody (α-IL-33 + NRR) or control IgG antibody (Isotype + NRR) and adult mice pretreated with recombinant IL-33 (rIL-33 + ARR) or vehicle control (Control + ARR). (b) Change in airway resistance in response to increasing doses of inhaled methacholine after treatment as in a (n = 6–8 per group). (c) Total cells (Total), monocytes/macrophages (Mo/MΦ), lymphocytes (Lymph), neutrophils (Neutro), and eosinophils (Eos) in BAL fluid after treatment as in a (n = 3–6 per group). *P < 0.05 vs. indicated group (one-way ANOVA with Bonferroni post-hoc tests; a, c) (two-way ANOVA with Bonferroni post-hoc tests; b). Data are representative of at least two independent experiments (means ± s.e.m).
Mentions: In infants, severe RSV often causes bronchiolitis, recruitment of inflammatory cells (i.e., Th2 cells, eosinophils) to the lungs, and increased airway mucus, resulting in significant airway obstruction and airway hyperresponsiveness (AHR). A similar disease phenotype is readily observed (following reinfection) in mice initially infected with RSV as neonates, but not adults. To phenotypically recapitulate severe RSV infection seen clinically in human infants, mice from the same treatment groups as in Fig 3 were reinfected with RSV at 4 weeks post-primary infection (established neonatal mouse RSV infection + reinfection protocol [6, 7, 16]) and immune responses determined at 6 dpi (Fig 4). Neutralizing IL-33 during primary infection in neonates resulted in significant reductions in Th2 and multifunctional Th (mTh; IFNγ+, IL-4+) cells upon reinfection (α-IL-33+NRR) (Fig 4a). Conversely, administration of rIL-33 to adult mice during primary infection resulted in significant increases in Th2 and mTh cells upon reinfection (rIL-33+ARR), which were similar to levels induced in NRR 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