IL1RL1 Gene Variants and Nasopharyngeal IL1RL-a Levels Are Associated with Severe RSV Bronchiolitis: A Multicenter Cohort Study

Targets for intervention are required for respiratory syncytial virus (RSV) bronchiolitis, a common disease during infancy for which no effective treatment exists. Clinical and genetic studies indicate that IL1RL1 plays an important role in the development and exacerbations of asthma. Human IL1RL1 encodes three isoforms, including soluble IL1RL1-a, that can influence IL33 signalling by modifying inflammatory responses to epithelial damage. We hypothesized that IL1RL1 gene variants and soluble IL1RL1-a are associated with severe RSV bronchiolitis.We studied the association between RSV and 3 selected IL1RL1 single-nucleotide polymorphisms rs1921622, rs11685480 or rs1420101 in 81 ventilated and 384 non-ventilated children under 1 year of age hospitalized with primary RSV bronchiolitis in comparison to 930 healthy controls. Severe RSV infection was defined by need for mechanical ventilation. Furthermore, we examined soluble IL1RL1-a concentration in nasopharyngeal aspirates from children hospitalized with primary RSV bronchiolitis. An association between SNP rs1921622 and disease severity was found at the allele and genotype level (p = 0.011 and p = 0.040, respectively). In hospitalized non-ventilated patients, RSV bronchiolitis was not associated with IL1RL1 genotypes. Median concentrations of soluble IL1RL1-a in nasopharyngeal aspirates were >20-fold higher in ventilated infants when compared to non-ventilated infants with RSV (median [and quartiles] 9,357 [936-15,528] pg/ml vs. 405 [112-1,193] pg/ml respectively; p<0.001).We found a genetic link between rs1921622 IL1RL1 polymorphism and disease severity in RSV bronchiolitis. The potential biological role of IL1RL1 in the pathogenesis of severe RSV bronchiolitis was further supported by high local concentrations of IL1RL1 in children with most severe disease. We speculate that IL1RL1a modifies epithelial damage mediated inflammatory responses during RSV bronchiolitis and thus may serve as a novel target for intervention to control disease severity

Systemic Signature of the Lung Response to Respiratory Syncytial Virus Infection

Respiratory Syncytial Virus is a frequent cause of severe bronchiolitis in children. To improve our understanding of systemic host responses to RSV, we compared BALB/c mouse gene expression responses at day 1, 2, and 5 during primary RSV infection in lung, bronchial lymph nodes, and blood. We identified a set of 53 interferon-associated and innate immunity genes that give correlated responses in all three murine tissues. Additionally, we identified blood gene signatures that are indicative of acute infection, secondary immune response, and vaccine-enhanced disease, respectively. Eosinophil-associated ribonucleases were characteristic for the vaccine-enhanced disease blood signature. These results indicate that it may be possible to distinguish protective and unfavorable patient lung responses via blood diagnostics

Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze

Abstract Background Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis. Methods This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%). Results Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs. Conclusion The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.</p

<i>IL1RL1</i> SNP rs1921622 associated with severe RSV bronchiolitis.

<p>Subgroup analysis showed an association between severe RSV disease characterized by need for mechanical ventilation and <i>IL1RL1</i> SNP rs1921622 at both the allele level, and at the genotype level (p = 0.040).</p><p>RefSNP ID is the Reference SNP (rs) Number; SNP, single-nucleotide polymorphism.</p>1<p>Number of alleles and genotypes.</p>2<p>According to χ² distribution of a 2×2 table on allele or genotype frequencies.³</p

Subject characteristics of infants hospitalized for RSV bronchiolitis with IL1RL1-a measured in nasopharyngeal aspirate.

#<p>Fisher’s exact test.</p>*<p>Mann-Whitney U test.</p><p>n.a. = not applicable.</p><p>Analyses were performed in nasopharyngeal aspirates of hospitalized, non-ventilated infants with respiratory syncytial virus (RSV) infection and ventilated infants at the Pediatric Intensive Care Unit with RSV.</p><p><b>°</b>Excluded samples of poor quality had too little material to perform genotyping or an IL1RL1-a measurement.</p

<i>IL1RL1</i> SNPs not associated with RSV bronchiolitis.

<p><i>IL1RL1</i> selected genotypes rs1921622, rs11685480 and rs1420101 are not associated with RSV bronchiolitis in hospitalized infants when compared to healthy controls in the population.</p><p>RefSNP ID is the Reference SNP (rs) Number; SNP, single-nucleotide polymorphism.</p>1<p>Number of alleles and genotypes.</p>2<p>According to χ² distribution of a 2×2 table on allele or genotype frequencies.</p>3<p>Reference allele is the major allele.</p

Median concentrations of IL1RL1-a in nasopharyngeal aspirates of hospitalized infants with RSV were >20-fold higher in mechanically ventilated infants at the Pediatric Intensive Care Unit (n = 19) when compared to non-ventilated infants admitted to the general pediatric ward (n = 135) (median [and quartiles] 9,357 [936–15,528] pg/ml vs 405 [112–1,193] pg/ml respectively; Mann-Whitney U test p<0.0001).

<p>Median concentrations of IL1RL1-a in nasopharyngeal aspirates of hospitalized infants with RSV were >20-fold higher in mechanically ventilated infants at the Pediatric Intensive Care Unit (n = 19) when compared to non-ventilated infants admitted to the general pediatric ward (n = 135) (median [and quartiles] 9,357 [936–15,528] pg/ml vs 405 [112–1,193] pg/ml respectively; Mann-Whitney U test p<0.0001).</p

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection▿ †

Vaccine-induced immunity has been shown to alter the course of a respiratory syncytial virus (RSV) infection both in murine models and in humans. To elucidate which mechanisms underlie the effect of vaccine-induced immunity on the course of RSV infection, transcription profiles in the lungs of RSV-infected mice were examined by microarray analysis. Three models were used: RSV reinfection as a model for natural immunity, RSV challenge after formalin-inactivated RSV vaccination as a model for vaccine-enhanced disease, and RSV challenge following vaccination with recombinant RSV virus lacking the G gene (ΔG-RSV) as a model for vaccine-induced immunity. Gene transcription profiles, histopathology, and viral loads were analyzed at 1, 2, and 5 days after RSV challenge. On the first 2 days after challenge, all mice displayed an expression pattern in the lung similar of that found in primary infection, showing a strong innate immune response. On day 5 after RSV reinfection or after challenge following ΔG-RSV vaccination, the innate immune response was waning. In contrast, in mice with vaccine-enhanced disease, the innate immune response 5 days after RSV challenge was still present even though viral replication was diminished. In addition, only in this group was Th2 gene expression induced. These findings support a hypothesis that vaccine-enhanced disease is mediated by prolonged innate immune responses and Th2 polarization in the absence of viral replication

Gene expression changes upon RSV infection in mice for the shared set of 53 genes in lung, lymph node, and blood on days 1, 2, and 5.

<p>Blood data are indicated as follows: primary, primary RSV infection response; protective, secondary RSV infection response; adverse, FI-RSV vaccine-enhanced response. Data for lung and lymph node are all responses to primary RSV infection. Values are given as ratios between infected and control.</p