Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

Abstract

Rationale: The mechanism by which viruses cause exacerbations of chronic airway disease and the capacity of patients with cystic fibrosis (CF) to respond to viral infection are not precisely known.Objectives: To determine the antiviral response to infection in patients with CF.Methods: Sputum was collected from patients with CF with respiratory exacerbation. Viruses were detected in multiplex polymerase chain reaction (PCR)-based assays. Gene expression of 84 antiviral response genes was measured, using a focused quantitative PCR gene array. Measurements and Main Results:We examined 36 samples from 23 patients with respiratory exacerbation. Fourteen samples tested virus-positive and 22 virus-negative. When we compared exacerbations associated with rhinovirus (RV, n = 9) and influenza (n = 5) with virus-negative specimens, we found distinct patterns of antiviral gene expression. RV was associated with greater than twofold induction of five genes, including those encoding the monocyte-attracting chemokines CXCL10, CXCL11, and CXCL9. Influenza was associated with overexpression of 20 genes, including those encoding the cytokines tumor necrosis factor and IL-12; the kinases MEK, TBK-1, and STAT-1; the apoptosis proteins caspase-8 and caspase-10; the influenza doublestranded RNA receptor RIG-I and its downstream effector MAVS; and pyrin, an IFN-stimulated protein involved in influenza resistance. Conclusions:We conclude that virus-induced exacerbations of CF are associated with immune responses tailored to specific infections. Influenza induced a more potent response consisting of inflammation, whereas RV infection had a pronounced effect on chemokine expression. As far as we are aware, this study is the first to compare specific responses to different viruses in live patients with chronic airway disease.

The prevalence of viral infections in children with cystic fibrosis in a tertiary care center in Saudi Arabia

“…exacerbations associated with rhinovirus and influenza virus with virus-negative specimens which showed that viruses were associated with immune responses tailored to specific infections [19]. In our study, we showed that rhinovirus was the most prevalent virus.…”

Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection

“…All these viruses are inducing distinct pathogenesis in the lung and it is therefore conceivable that the mechanisms of virus-induced CF exacerbation are at least in part virus-specific. In line with this hypothesis, a recent study by Ramirez et al demonstrated that CF exacerbations triggered by RV or influenza virus led to a distinct antiviral response [37]. Therefore, it would be interesting to test our in vitro system with other clinically relevant respiratory viruses such as influenza and respiratory syncytial virus.…”

Acute effects of viral respiratory tract infections on sputum bacterial density during CF pulmonary exacerbations

“…Although 50% of exacerbations were associated with a viral respiratory tract infection, viral infections had no acute effect on changes in P. aeruginosa sputum bacterial density. Given the significance of CF exacerbations, further work is needed to determine if viral infections elicit an immune response that leads to exacerbation that may be independent of P. aeruginosa bacterial load in CF patients [29]. As well, further investigation is required to understand the etiology of exacerbations in patients who do not have viral infections, since increased P. aeruginosa bacterial density in sputum does not appear to be responsible.…”