SNPs in innate immune genes are important in determining susceptibility to RSV bronchiolitis.

The association of variants of genes encoding interleukin (IL)-4 and the IL-4 receptor alpha chain (IL-4Ralpha) with respiratory syncytial virus (RSV) bronchiolitis was examined in hospitalized infants. Polymorphisms in IL-4 (C-590T) and IL-4Ralpha (I50V and Q551R) were genotyped by restriction fragment-length polymorphism analysis. Control subjects included parents of the hospitalized children (for the transmission/disequilibrium test), and a random population sample (for the case-control study). Results were also analyzed in a combination of these 2 tests, using Fisher's method. The IL-4 590T allele was found more frequently among children hospitalized with RSV than expected in the case-control (odds ratio [OR], 1.43; P=.04) and combination (OR, 1.41; P=.02) tests. Among children who were >6 months old when they were hospitalized, compared with the control group or with the <6 months old who were hospitalized for RSV infection, higher frequencies of both the IL-4 590T allele and the IL-4Ralpha R551 allele were found. These results indicate that gain-of-function variants of T helper type 2 cytokine genes may play a role in increasing the severity of RSV disease, which appears more pronounced after the first half-year of life.

Previously, we reported genetic associations between severe respiratory syncytial virus (RSV) bronchiolitis in infants and polymorphisms in the interleukin (IL)-4 and IL-4 receptor alpha (IL-4Ralpha) genes, providing evidence for involvement of T helper type 2 cytokines in the pathogenesis of RSV bronchiolitis. We expanded our studies to polymorphisms in genes encoding IL-9, IL-10, and tumor necrosis factor (TNF)-alpha, using both a transmission/disequilibrium test and a case-control approach. Children homozygous for the IL-10 -592C or -592A allele had a higher risk of hospitalization for RSV bronchiolitis than did heterozygous carriers (odds ratio [OR], 1.73 vs. 2.55; 95% confidence interval [CI], 1.13-2.66 vs. 1.21-5.39). In children hospitalized at < or =6 months of age, a significant association between RSV bronchiolitis and the IL-10 -592C allele was found (OR, 1.61; 95% CI, 1.10-2.35). No significant associations of TNF-alpha and IL-9 polymorphisms with RSV bronchiolitis were observed. We also explored the interactions between different polymorphisms and found an interaction between the IL-4Ralpha Q551R and IL-10 C-592A polymorphisms.

Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in children.Severe RSV disease is related to an inappropriate immune response to RSV resulting in enhanced lung pathology which is influenced by host genetic factors. To gain insight into the early pathways of the pathogenesis of and immune response to RSV infection, we determined the transcription profiles of lungs and lymph nodes on days 1 and 3 after infection of mice. Primary RSV infection resulted in a rapid but transient innate, proinflammatory response, as exemplified by the induction of a large number of type I interferon-regulated genes and chemokine genes, genes involved in inflammation, and genes involved in antigen processing. Interestingly, this response is much stronger on day 1 than on day 3 after infection, indicating that the strong transcriptional response in the lung precedes the peak of viral replication. Surprisingly, the set of downregulated genes was small and none of these genes displayed strong down-regulation. Responses in the lung-draining lymph nodes were much less prominent than lung responses and are suggestive of NK cell activation. Our data indicate that at time points prior to the peak of viral replication and influx of inflammatory cells, the local lung response, measured at the transcriptional level, has already dampened down. The processes and pathways induced shortly after RSV infection can now be used for the selection of candidate genes for human genetic studies of children with severe RSV infection.The severity of respiratory syncytial virus (RSV) infection in young children varies from a nonclinical or mild upper respiratory tract infection to severe lower respiratory tract infection that may lead to hospitalization and occasionally to death. Some children are more prone to a severe course of disease, such as premature-born children, children younger than 3 months of age, children with chronic lung disease or congenital heart disease, and immunocompromised children (27,35). However, the biological mechanisms underlying the highly variable disease course in children are still poorly understood. The current belief is that children with severe RSV disease suffer from enhanced inflammatory lesions rather than from virus-induced cytopathology (25). In line with this, naturally occurring polymorphisms in genes affecting the inflammatory immune response influence the severity of RSV-induced disease (5,11,12,15).Immune responses to viral pathogens are initiated among others via the recognition of pathogen-associated molecular patterns by various Toll-like receptors (TLR), leading to the induction of innate immune responses, proinflammatory cytokines, and the Th1 pathway (reviewed in references 18 and 26). Innate immunity to RNA viruses is initiated by TLR3 and murine TLR7 or human TLR8, which are important for the responses to double-stranded and single-stranded RNAs, and through intracellular RNA recognition molecules, such as RIG-I and Mda5 (reviewed in reference 21). Both TLR3 and R...

Using a human study and an experimental model, we show that opioid receptor signaling has a potential beneficial role in the outcome of respiratory viral disease. We show that opioid receptor signaling is required to control respiratory syncytial virus replication and thereby to control disease severity. However, we also show that caution is required before using pharmaceutical opioids as anti-inflammatory or antiviral treatment of patients with viral respiratory infection.

Prematurity is a risk factor for severe respiratory syncytial virus bronchiolitis. We show that genetic factors in innate immune genes (IFNA13, IFNAR2, STAT2, IL27, NFKBIA, C3, IL1RN, TLR5), in innate and adaptive immunity (IFNG), and in airway remodeling genes (ADAM33 and TGFBR1), affect disease susceptibility to a different extent in preterm children, born with underdeveloped lungs, than in term children.

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.

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