Influence of Promoter Variants of Interleukin‐10, Interleukin‐9, and Tumor Necrosis Factor–α Genes on Respiratory Syncytial Virus Bronchiolitis

Hoebee, Barbara; Bont, Louis; Rietveld, Edwin; Oosten, Marijke van; Hodemaekers, Hennie M.; Nagelkerke, Nico; Neijens, H. J.; Kimpen, Jan L. L.; Kimman, Tjeerd G.

doi:10.1086/380908

Cited by 97 publications

(95 citation statements)

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“…Several studies focused on the role of genetic variation in the IL10 gene locus in the pathophysiology of acute RSV LRTI. Overall, the frequency of IL10 polymorphisms in infants with RSV LRTI did not differ from controls (22)(23)(24)(25). However, in infants hospitalized Յ6 mo of age, the IL10 -592C allele was related to RSV LRTI hospitalization (23).…”

Section: Discussionmentioning

confidence: 74%

“…Overall, the frequency of IL10 polymorphisms in infants with RSV LRTI did not differ from controls (22)(23)(24)(25). However, in infants hospitalized Յ6 mo of age, the IL10 -592C allele was related to RSV LRTI hospitalization (23). In addition, genetic variation at the IL10 gene locus was associated with the need for mechanical ventilation (24) and with the frequency of pneumonia (25) in RSV LRTI-hospitalized infants.…”

Section: Discussionmentioning

confidence: 87%

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IL10 Family Member Genes IL19 and IL20 Are Associated With Recurrent Wheeze After Respiratory Syncytial Virus Bronchiolitis

et al. 2011

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Mechanisms underlying the increased risk of recurrent wheeze after respiratory syncytial virus lower respiratory tract infection (RSV LRTI) are unclear. Specifically, information about genetic determinants of recurrent wheeze after RSV LRTI is limited. We performed a candidate gene association study to identify genetic determinants of recurrent wheeze after RSV LRTI. We investigated 346 single nucleotide polymorphisms (SNPs) in 220 candidate genes in 166 Dutch infants hospitalized for RSV LRTI. Logistic regression analysis was used to study associations between genotypes and haplotypes and recurrent wheeze after RSV LRTI. We found associations with recurrent wheeze for SNPs in IL19, IL20, MUC5AC, TNFRSF1B, C3, CTLA4, CXCL9, IL4R, and IL7 genes. Haplotype analysis of the combined IL19/IL20 genotyped polymorphisms demonstrated an inverse association between the TGG haplotype and recurrent wheeze after RSV LRTI. IL19 and IL20 genes were notably associated with recurrent wheeze in infants without asthmatic parents. The association of IL20 SNP rs2981573 with recurrent wheeze was confirmed in a healthy birth cohort. We concluded that genetic variation in adaptive immunity genes and particularly in IL19/IL20 genes associates with the development of recurrent wheeze after RSV LRTI, suggesting a role for these IL10 family members in the etiology of airway disease during infancy. (Pediatr Res 70: 518-523, 2011) R espiratory syncytial virus lower respiratory tract infection (RSV LRTI) during infancy is an independent risk factor for subsequent recurrent wheeze, at least within the first years of childhood (1). Mechanisms underlying the increased incidence of wheeze during the first years after RSV LRTI are unclear. Recurrent wheeze after RSV LRTI was related to signs of airflow limitation during RSV LRTI (2), eosinophilia during RSV LRTI (3), and monocyte IL10-production during the convalescent phase of RSV LRTI (4).To date, only two studies aimed to identify genetic determinants of recurrent wheeze after RSV LRTI. In one association study of 134 RSV hospitalized infants, a variant of the IL8 gene was related to the development of subsequent wheeze (5). We previously demonstrated an association between a functional IL13 polymorphism and wheeze at age 6, whereas no association was found between the IL13 polymorphism and recurrent wheeze during the first year after RSV LRTI (6).The availability of analytic tools to study larger numbers of genes and a larger cohort of RSV LRTI-hospitalized infants in whom recurrent wheeze was evaluated enabled us to extend our previous studies. Herein, we describe the results of 346 genotyped single nucleotide polymorphisms (SNPs) on 210 genes, including IL10 family genes. METHODS Subjects and design.The infants included in this study participated in previous studies (4,6 -8). In brief, they were hospitalized for RSV LRTI during the winter seasons of 1995-1996 or 2004 -2006. Infants included in the winter season of 1995-1996 participated in an observational study investigating the ...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 87%

IL10 Family Member Genes IL19 and IL20 Are Associated With Recurrent Wheeze After Respiratory Syncytial Virus Bronchiolitis

et al. 2011

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confidence: 63%

“…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).…”

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confidence: 82%

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

Schuurhof

Bont

Pennings³

et al. 2010

J Virol

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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...

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“…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).…”

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confidence: 97%

Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

Janssen¹,

Pennings²,

Hodemaekers³

et al. 2007

J Virol

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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...

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Influence of Promoter Variants of Interleukin‐10, Interleukin‐9, and Tumor Necrosis Factor–α Genes on Respiratory Syncytial Virus Bronchiolitis

Cited by 97 publications

References 53 publications

IL10 Family Member Genes IL19 and IL20 Are Associated With Recurrent Wheeze After Respiratory Syncytial Virus Bronchiolitis

IL10 Family Member Genes IL19 and IL20 Are Associated With Recurrent Wheeze After Respiratory Syncytial Virus Bronchiolitis

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

Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

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