Abstract
Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/β interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations.
Highlights
Rhinovirus (RV) infections in healthy individuals manifest as common colds but in asthma are strongly associated with acute exacerbations [1,2]
We previously reported deficiency in interferon production in asthma, which correlated with disease severity and viral load during experimental rhinovirus infection
We show that macrophages produce IL-15 upon rhinovirus infection and that IFN-b plays an important role in IL-15 production
Summary
Rhinovirus (RV) infections in healthy individuals manifest as common colds but in asthma are strongly associated with acute exacerbations [1,2]. Type I (a/b), II (c) and III (l) interferon (IFN) responses are important in anti-viral immunity and increased susceptibility to RV infection has been demonstrated in asthma in vivo [2,3]. Since (i) a/bIFNs are reported to induce IL-15 in dendritic cells and monocytes [14,15], (ii) RV induction of IFN-b is reported deficient in asthma [4], (iii) IL-15 is important in innate and acquired antiviral immunity and (iv) there is increased susceptibility to RV infection in asthma [1,2,3] we hypothesized that IL-15 production may be deficient in asthma and related to asthma exacerbation pathogenesis
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