Abstract
High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups.
Highlights
Rhinovirus infections are important triggers of severe asthma exacerbations among children [1, 2], in particular those who are sensitized to perennial aeroallergens [3]
In a preliminary study focusing on bronchoalveolar lavage (BAL) we found that naïve Piebald Virol Glaxo (PVG) and Brown Norway (BN) rats elicit dichotomous responses to infection mirroring to some extent the IRF7hi (PVG) and IRF7lo (BN) phenotypes we observed in children
The acute inflammatory response to virus in PVG rats was dominated by neutrophil influx in BAL, in contrast to the acute eosinophilic response observed in BN rats (Figure 1B)
Summary
Rhinovirus infections are important triggers of severe asthma exacerbations among children [1, 2], in particular those who are sensitized to perennial aeroallergens [3]. Very few treatment options exist, and drug development programs to redress this deficiency are currently stalled because the underlying immunobiology is incompletely understood [2]. Frontiers in Immunology | www.frontiersin.org de Jong et al. IRF7 Dependent Asthma Immunomodualtion employed gene expression profiling to elucidate upper airway responses in children who present to emergency departments with severe exacerbations of asthma or wheeze. We found that the response patterns were heterogeneous and could be divided into IRF7hi versus IRF7lo immunophenotypes [4]. Expression of the IRF7lo immunophenotype was associated with more prolonged symptoms during exacerbations and shorter intervals between exacerbation events [4]
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