The Interleukin 6 −174 C/C Genotype Predicts Greater Rhinovirus Illness

Doyle, William J.; Casselbrant, Margaretha L.; Li-Korotky, Ha-Sheng; Doyle, Allison P Cullen; Lo, Chia-Yee; Turner, Ronald B.; Cohen, Sheldon

doi:10.1086/649559

Cited by 50 publications

(35 citation statements)

References 41 publications

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“…Donor 1 had a G/C genotype, while donor 2 (with higher levels of IL-6 in the apical compartment) had a G/G genotype (data not shown). The C allele at -174 has been associated with lower IL-6 expression, more severe symptoms following rhinovirus and RSV infection, and an increased frequency of otitis media (Alper et al, 2009; Doyle et al, 2010). In general, HAE from donor 2 secreted higher levels of most of the cytokines examined than HAE from donor 1 did, suggesting a stronger pro-inflammatory response by donor 2.…”

Section: Resultsmentioning

confidence: 99%

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

et al. 2012

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Human parainfluenza viruses (PIVs) cause acute respiratory illness in children, the elderly, and immunocompromised patients. PIV3 is a common cause of bronchiolitis and pneumonia, whereas PIV1 and 2 are frequent causes of upper respiratory tract illness and croup. To assess how PIV1, 2, and 3 differ with regard to replication and induction of type I interferons, interleukin-6, and relevant chemokines, we infected primary human airway epithelium (HAE) cultures from the same tissue donors and examined replication kinetics and cytokine secretion. PIV1 replicated to high titer yet did not induce cytokine secretion until late in infection, while PIV2 replicated less efficiently but induced an early cytokine peak. PIV3 replicated to high titer but induced a slower rise in cytokine secretion. The T cell chemoattractants CXCL10 and CXCL11 were the most abundant chemokines induced. Differences in replication and cytokine secretion might explain some of the differences in PIV serotype-specific pathogenesis and epidemiology.

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Section: Resultsmentioning

confidence: 99%

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

et al. 2012

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“…In contrast, low production polymorphisms in the Il6 gene are actually associated with increased risk of disease in both rhinovirus and RSV infection [27]. Clinical targeting of the IL-6 pathway is used to treat a number of inflammatory disorders, in particular rheumatoid arthritis [1].…”

Section: Discussionmentioning

confidence: 99%

Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology

et al. 2017

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Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific TH1 and cytotoxic CD8+ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate TH1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27.

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“…Each of these mediators has been identified in clinical studies in association with disease severity [Tabarani et al, 2013; Sow et al, 2011; Lee et al, 2011; Ichikawa et al, 2013; Doyle et al, 2010]. …”

Section: Discussionmentioning

confidence: 99%

Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection

Percopo¹,

Rice²,

Brenner³

et al. 2015

Antiviral Research

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We reported previously that priming of the respiratory tract with immunobiotic Lactobacillus prior to virus challenge protects mice against subsequent lethal infection with pneumonia virus of mice (PVM). We present here the results of gene microarray which document differential expression of proinflammatory mediators in response to PVM infection alone and those suppressed in response to Lactobacillus plantarum. We also demonstrate for the first time that intranasal inoculation with live or heat-inactivated L. plantarum or Lactobacillus reuteri promotes full survival from PVM infection when administered within 24 h after virus challenge. Survival in response to L. plantarum administered after virus challenge is associated with suppression of proinflammatory cytokines, limited virus recovery, and diminished neutrophil recruitment to lung tissue and airways. Utilizing this post-virus challenge protocol, we found that protective responses elicited by L. plantarum at the respiratory tract were distinct from those at the gastrointestinal mucosa, as mice devoid of the anti-inflammatory cytokine, interleukin (IL)-10, exhibit survival and inflammatory responses that are indistinguishable from those of their wild-type counterparts. Finally, although L. plantarum interacts specifically with pattern recognition receptors TLR2 and NOD2, the respective gene-deleted mice were fully protected against lethal PVM infection by L. plantarum, as are mice devoid of type I interferon receptors. Taken together, L. plantarum is a versatile and flexible agent that is capable of averting the lethal sequelae of severe respiratory infection both prior to and post-virus challenge via complex and potentially redundant mechanisms.

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The Interleukin 6 −174 C/C Genotype Predicts Greater Rhinovirus Illness

Cited by 50 publications

References 41 publications

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology

Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection

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