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

Dual role of interleukin‐10 in the regulation of respiratory syncitial virus ( RSV )‐induced lung inflammation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97500/1/cei12059.pd

Genetic Control of Resistance to Trypanosoma brucei brucei Infection in Mice

Trypanosoma brucei are extracellular protozoa transmitted to mammalian host by the tsetse fly. They developed several mechanisms that subvert host's immune defenses. Therefore analysis of genes affecting host's resistance to infection can reveal critical aspects of host-parasite interactions. Trypanosoma brucei brucei infects many animal species including livestock, with particularly severe effects in horses and dogs. Mouse strains differ greatly in susceptibility to T. b. brucei. However, genes controlling susceptibility to this parasite have not been mapped. We analyzed the genetic control of survival after T. b. brucei infection using CcS/Dem recombinant congenic (RC) strains, each of which contains a different random set of 12.5% genes of their donor parental strain STS/A on the BALB/c genetic background. The RC strain CcS-11 is even more susceptible to parasites than BALB/c or STS/A. In F2 hybrids between BALB/c and CcS-11 we detected and mapped four loci, Tbbr1-4 (Trypanosoma brucei brucei response 1–4), that control survival after T. b. brucei infection. Tbbr1 (chromosome 3) and Tbbr2 (chromosome 12) have independent effects, Tbbr3 (chromosome 7) and Tbbr4 (chromosome 19) were detected by their mutual inter-genic interaction. Tbbr2 was precision mapped to a segment of 2.15 Mb that contains 26 genes

Host response to respiratory syncytial virus : genetic associations and effect on disease severity

Respiratory syncytial virus (RSV) is the most frequent cause of severe respiratory tract infections in young children. Almost all children become infected with RSV during the first two years of life, and 1-3% needs hospitalization. Genetic determinants are believed to play a role in the risk of developing RSV infection in healthy infants. In this thesis, the functional role of the previously reported associated gene variants during RSV infection is studied. We aimed to determine the in vivo role of interleukin-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) at the time of hospitalization 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. We further studied the local immune response in NPAs during RSV infection. TIMP metallopeptidase inhibitor (TIMP)-1 was higher in the NPAs of hospitalized infants with severe RSV disease compared to the NPAs of infants at home with mild disease. Similar results were found for matrix metalloproteinase (MMP)-3. MMP-3 as a marker of disease severity was confirmed in a larger cohort and MMP3 gene polymorphism rs522616 was associated with severe RSV infection. Therefore, extracellular matrix proteinases play an important role in the pathogenesis of RSV bronchiolitis. Additionally, we reported transcription profiles in the lungs of RSV-infectedmice examined by microarray analysis to elucidate which mechanisms underliethe effect of vaccine-induced immunity on the course of RSVinfection. Three models wereused: RSV reinfection as a model for natural immunity, RSV challengeafter formalin-inactivated RSV vaccination as a model for vaccine-enhanceddisease, and RSV challenge following vaccination with recombinantRSV lacking the G gene (DG-RSV) as a model for vaccine-inducedimmunity. On the first days after challenge, all mice showed a strong innate immune response. On day 5 after RSVreinfection or after challenge following DG-RSV vaccination,the innate immune response was waning. In contrast, in micewith vaccine-enhanced disease, the innate immune response 5days after RSV challenge was still present even though viralreplication was diminished. These findings support a hypothesisthat vaccine-enhanced disease is mediated by prolonged innateimmune responses and Th2 polarization in the absence of viralreplication. Moreover, we described transcription profiles in the blood and bronchial lymph nodes of RSV-infectedmice to improve our understanding of systemic host responses to RSV. 53 interferon-associated and innate immunity genes were identified that give correlated responses in all three murine tissues. We identified blood gene signatures that are indicative of acute infection, secondary immune response, and vaccine-enhanced disease, respectively. These results indicate that it may be possible to distinguish protective and unfavorable patient lung responses via blood diagnostics. Finally, we discussed on the host response to RSV infection. To conclude, host genetic studies offer a complex but robust method to improve our understanding of disease pathogenesis and develop new targets for intervention for one of the most common diseases during early childhoo

Host response to respiratory syncytial virus : genetic associations and effect on disease severity

Respiratory syncytial virus (RSV) is the most frequent cause of severe respiratory tract infections in young children. Almost all children become infected with RSV during the first two years of life, and 1-3% needs hospitalization. Genetic determinants are believed to play a role in the risk of developing RSV infection in healthy infants. In this thesis, the functional role of the previously reported associated gene variants during RSV infection is studied. We aimed to determine the in vivo role of interleukin-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) at the time of hospitalization 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. We further studied the local immune response in NPAs during RSV infection. TIMP metallopeptidase inhibitor (TIMP)-1 was higher in the NPAs of hospitalized infants with severe RSV disease compared to the NPAs of infants at home with mild disease. Similar results were found for matrix metalloproteinase (MMP)-3. MMP-3 as a marker of disease severity was confirmed in a larger cohort and MMP3 gene polymorphism rs522616 was associated with severe RSV infection. Therefore, extracellular matrix proteinases play an important role in the pathogenesis of RSV bronchiolitis. Additionally, we reported transcription profiles in the lungs of RSV-infectedmice examined by microarray analysis to elucidate which mechanisms underliethe effect of vaccine-induced immunity on the course of RSVinfection. Three models wereused: RSV reinfection as a model for natural immunity, RSV challengeafter formalin-inactivated RSV vaccination as a model for vaccine-enhanceddisease, and RSV challenge following vaccination with recombinantRSV lacking the G gene (DG-RSV) as a model for vaccine-inducedimmunity. On the first days after challenge, all mice showed a strong innate immune response. On day 5 after RSVreinfection or after challenge following DG-RSV vaccination,the innate immune response was waning. In contrast, in micewith vaccine-enhanced disease, the innate immune response 5days after RSV challenge was still present even though viralreplication was diminished. These findings support a hypothesisthat vaccine-enhanced disease is mediated by prolonged innateimmune responses and Th2 polarization in the absence of viralreplication. Moreover, we described transcription profiles in the blood and bronchial lymph nodes of RSV-infectedmice to improve our understanding of systemic host responses to RSV. 53 interferon-associated and innate immunity genes were identified that give correlated responses in all three murine tissues. We identified blood gene signatures that are indicative of acute infection, secondary immune response, and vaccine-enhanced disease, respectively. These results indicate that it may be possible to distinguish protective and unfavorable patient lung responses via blood diagnostics. Finally, we discussed on the host response to RSV infection. To conclude, host genetic studies offer a complex but robust method to improve our understanding of disease pathogenesis and develop new targets for intervention for one of the most common diseases during early childhoo

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

Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: a opposite effect in boys and girls.

The predominance of severe respiratory syncytial virus (RSV) bronchiolitis in boys compared to girls is well known, but its mechanism is not yet understood. This is the first study focusing on gender-specific genetic factors affecting the risk of severe RSV infection using a previously described cohort. We determined 347 single-nucleotide polymorphisms (SNPs) in 470 children hospitalized for RSV infection, their parents, and 1,008 random population controls. We tested if these SNPs exerted a different effect in boys and girls by performing statistical interaction tests. Only one SNP (rs2069885) had a gender-specific significant association with RSV infection, severe enough to require hospitalization (P-value 0.00057). The major allele of this structural polymorphism in the interleukin (IL)-9 gene is associated with an increased susceptibility to severe RSV infection in boys, while there is a decreased susceptibility in girls. Haplotype analysis of two SNPs in the IL-9 gene (rs2069885 and rs1799962) showed overrepresentation of the TT haplotype in girls with severe RSV bronchiolitis requiring hospitalization indicating that this is the haplotype conferring the highest risk in girls. In conclusion, the IL-9 genetic polymorphism (rs2069885) has an opposite effect on the risk of severe RSV bronchiolitis in boys and girls. Although so far a difference in IL-9 production in boys and girls has not been reported, this study may help in explaining the different risks of severe RSV bronchiolitis in boys and girl