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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

Modulation of IL-33 levels during primary RSV infection alters ILC2 numbers and IL-13 production at 1 dpi.(a) Number of ILC2s (lineage- CD45+ ICOS+ ST2+) expressed as percentage of total lung cells and MFI of surface ST2 on ILC2s at 1 dpi in neonatal mice pretreated with IL-33 neutralizing antibody (α-IL-33 + NR) or control IgG antibody (Isotype + NR) and adult mice pretreated with recombinant IL-33 (rIL-33 + AR) or vehicle control (Control + AR). (n = 5–7 per group). (b) IL-13 protein levels in whole lung homogenates. (c) Pulmonary viral loads measured at 4 dpi (peak) using the TCID50 method. *P < 0.05 vs. indicated group, (Student’s t-test). Data are representative of two independent experiments (means ± s.e.m).
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ppat.1005217.g003: Modulation of IL-33 levels during primary RSV infection alters ILC2 numbers and IL-13 production at 1 dpi.(a) Number of ILC2s (lineage- CD45+ ICOS+ ST2+) expressed as percentage of total lung cells and MFI of surface ST2 on ILC2s at 1 dpi in neonatal mice pretreated with IL-33 neutralizing antibody (α-IL-33 + NR) or control IgG antibody (Isotype + NR) and adult mice pretreated with recombinant IL-33 (rIL-33 + AR) or vehicle control (Control + AR). (n = 5–7 per group). (b) IL-13 protein levels in whole lung homogenates. (c) Pulmonary viral loads measured at 4 dpi (peak) using the TCID50 method. *P < 0.05 vs. indicated group, (Student’s t-test). Data are representative of two independent experiments (means ± s.e.m).

Mentions: Because our data showed increased IL-33 in the lungs of RSV-infected neonates, but not adults, we pretreated neonates with anti-IL-33 antibody (α-IL-33+NR) and pretreated adults with recombinant IL-33 (rIL-33+AR) prior to RSV infection (see methods). When IL-33 was neutralized during primary RSV infection in neonates, the number of ILC2s and ST2 expression by those ILC2s was decreased compared to controls, while the opposite effect was seen in adults given rIL-33 (Fig 3a). Additionally, lung levels of IL-13 were statistically decreased/increased depending upon IL-33 neutralization/augmentation, respectively (Fig 3b). To determine if IL-33 modulation had an impact on overall viral load, we compared the amount of infectious virus in the lungs of treated and control mice at the peak of infection (i.e. 4 dpi) (Fig 3c). Interestingly, IL-33 neutralization had no effect on RSV burden in neonates, but we observed a significant decrease in viral load in adult mice pre-treated with rIL-33.


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)

Modulation of IL-33 levels during primary RSV infection alters ILC2 numbers and IL-13 production at 1 dpi.(a) Number of ILC2s (lineage- CD45+ ICOS+ ST2+) expressed as percentage of total lung cells and MFI of surface ST2 on ILC2s at 1 dpi in neonatal mice pretreated with IL-33 neutralizing antibody (α-IL-33 + NR) or control IgG antibody (Isotype + NR) and adult mice pretreated with recombinant IL-33 (rIL-33 + AR) or vehicle control (Control + AR). (n = 5–7 per group). (b) IL-13 protein levels in whole lung homogenates. (c) Pulmonary viral loads measured at 4 dpi (peak) using the TCID50 method. *P < 0.05 vs. indicated group, (Student’s t-test). Data are representative of two independent experiments (means ± s.e.m).
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005217.g003: Modulation of IL-33 levels during primary RSV infection alters ILC2 numbers and IL-13 production at 1 dpi.(a) Number of ILC2s (lineage- CD45+ ICOS+ ST2+) expressed as percentage of total lung cells and MFI of surface ST2 on ILC2s at 1 dpi in neonatal mice pretreated with IL-33 neutralizing antibody (α-IL-33 + NR) or control IgG antibody (Isotype + NR) and adult mice pretreated with recombinant IL-33 (rIL-33 + AR) or vehicle control (Control + AR). (n = 5–7 per group). (b) IL-13 protein levels in whole lung homogenates. (c) Pulmonary viral loads measured at 4 dpi (peak) using the TCID50 method. *P < 0.05 vs. indicated group, (Student’s t-test). Data are representative of two independent experiments (means ± s.e.m).
Mentions: Because our data showed increased IL-33 in the lungs of RSV-infected neonates, but not adults, we pretreated neonates with anti-IL-33 antibody (α-IL-33+NR) and pretreated adults with recombinant IL-33 (rIL-33+AR) prior to RSV infection (see methods). When IL-33 was neutralized during primary RSV infection in neonates, the number of ILC2s and ST2 expression by those ILC2s was decreased compared to controls, while the opposite effect was seen in adults given rIL-33 (Fig 3a). Additionally, lung levels of IL-13 were statistically decreased/increased depending upon IL-33 neutralization/augmentation, respectively (Fig 3b). To determine if IL-33 modulation had an impact on overall viral load, we compared the amount of infectious virus in the lungs of treated and control mice at the peak of infection (i.e. 4 dpi) (Fig 3c). Interestingly, IL-33 neutralization had no effect on RSV burden in neonates, but we observed a significant decrease in viral load in adult mice pre-treated with rIL-33.

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