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 girls.

BackgroundTargets 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.Methodology/Principal FindingsWe 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).ConclusionsWe 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.

BackgroundRespiratory 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.MethodsThis 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%).ResultsLocal 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.ConclusionThe 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.

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 (⌬G-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 ⌬G-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.Respiratory syncytial virus (RSV) infection in infants can cause morbidity ranging from mild upper respiratory tract symptoms to severe bronchiolitis and even mortality (29). A small proportion of infected infants need hospitalization, whereas the majority develop only upper respiratory tract infection and recover in an outpatient setting (14). Known risk factors for more severe disease in children are age younger than 3 months, preterm birth, chronic lung disease of prematurity, congenital heart disease, Down's syndrome, cystic fibrosis, and immunodeficiency disorders (1,30,37). Besides infants, specific adult populations also are at risk to develop severe RSV infection, such as adults who are immunocompromised, aged, or institutionalized or have underlying diseases (8, 13). Both immunological mechanisms and virus-induced cytopathology may be keys to the variable severity of RSV bronchiolitis in infancy. The association between naturally occurring polymorphisms in innate immune response genes and the susceptibility to severe RSV bronchiolitis supports this theory (15,16,20,32).Murine models are widely used to study RSV-induced pathology. However, differences in RSV pathogenesis in relation to the genetic background of the mouse strain used have been described (19). These murine models have shown that a complex immune response is induced by RSV infection. However, high viral titers are needed to induce consistent histopathological changes in the lung (12). Generally, mice clear the virus without suffering severe lung pathology. Vaccination of mice with formalin-inac...

Severity of respiratory syncytial virus (RSV) infection ranges widely. To what extent the local immune response is involved in RSV disease pathogenesis and which markers of this response are critical in determining disease severity is still a matter of debate.The local immune response was studied in nasopharyngeal aspirates (NPAs) during RSV infection. 47 potential markers of disease severity were analysed in a screening cohort of RSVinfected infants with mild disease at home (n58), hospitalised infants (n510) and infants requiring mechanical ventilation (n57). Results were confirmed in a cohort of infants hospitalised for RSV infection (n5200). Finally, genetic validation was studied in a cohort of infants hospitalised for RSV infection (n5465) and healthy controls (n5930).The concentration of TIMP-1 (tissue inhibitor of metalloproteinase) was higher in the NPAs of hospitalised infants compared with the NPAs of infants at home (1,199 versus 568 ng?mL -1 ; p,0.0001). Similar results were found for matrix metalloproteinase (MMP)-3 (765 versus 370 pg?mL -1 ; p50.004). MMP-3 was confirmed as a marker of disease severity in a larger cohort and MMP3 gene polymorphism rs522616 was associated with severe RSV infection (OR 0.82, p,0.05).In conclusion, extracellular matrix proteinases play an important role in the pathogenesis of RSV bronchiolitis.

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.

Severity of respiratory syncytial virus (RSV) infection is subject to individual variation, and, accordingly, genetic determinants play a role in the risk of developing RSV lower respiratory tract infection (LRTI) in previously healthy infants. A twin study showed that 22% of the individual susceptibility to RSV LRTI is attributable to genetic factors. About half of the infants with RSV LRTI will develop post-bronchiolitis wheeze (PBW). It is unknown whether RSV LRTI and PBW have similar etiology. This systematic review aims to provide insight into the genetic factors influencing susceptibility to RSV LRTI and PBW. Published genetic associations of RSV LRTI with both single nucleotide polymorphisms (SNPs) and haplotypes are shown. Particularly SNPs in innate immunity genes are associated with the pathogenesis of RSV LRTI. However, no genetic variants associated with RSV LRTI have been exactly replicated in other cohorts. A limited number of studies have reported associations between SNPs and PBW, especially in chemokine and Th2 related genes. In conclusion, although RSV LRTI and PBW show similarities in clinical presentation, different genetic factors are important for the development of these diseases in young children.

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