Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells

Abstract

Background Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF. Methods Early innate immune responses towards rhinoviruses (RV-16, major-type and RV-1B, minor-type) in CF and non-CF bronchial epithelial cell lines and primary nasal and bronchial epithelial cells from patients with CF (n¼13) and healthy controls (n¼24) were studied. Results Rhinovirus RNA expression and virus release into supernatants was increased more than tenfold in CF cells compared with controls. CF cells expressed up to 1000 times less interferon (IFN) type I (b) and type III (l) mRNA and produced less than half of IFN-b and IFN-l protein compared with controls. In contrast, interleukin 8 production was not impaired, indicating a selective deficiency in the innate antiviral defence system. Deficient IFN production was paralleled by lower expression of IFN-stimulated genes including myxovirus resistance A, 2 9 ,5 9 -oligoadenylate synthetase, viperin and nitric oxide synthase 2. Addition of exogenous type I and III IFNs, particularly IFN-b, restored antiviral pathways and virus control in CF cells, underscoring the crucial role of these molecules. Conclusions This study describes a novel mechanism to explain the increased susceptibility of patients with CF to rhinovirus infections. A profound impairment of the antiviral early innate response in CF airway epithelial cells was identified, suggesting a potential use of IFNs in the treatment of rhinovirus-induced CF exacerbations.

Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

“…3). Collectively, these observations confirm previous studies showing that IFN-␣ and IFN-s have overlapping effects (7)(8)(9). Moreover, they suggest that the different subtypes of IFN-s may exert similar, though not identical, effects on human pancreatic islet cells.…”

“…Moreover, they suggest that the different subtypes of IFN-s may exert similar, though not identical, effects on human pancreatic islet cells. It has been hypothesized that IFN-and IFN-␣ exert similar functions due to the fact that they use the same signaling molecules (7)(8)(9). Our data on a selected number of genes affirm this notion, although future studies with a broadened approach are needed to determine if other genes may be regulated differentially by IFN-␣ and IFN-, as well as by the different IFN-s.…”

“…Type III IFN is known to become expressed during infection of mammalian cells with viruses both in vitro and in vivo (7)(8)(9). Here, we show that human pancreatic islets express both IFN-1 and IFN-2 in response to infection with CVB3.…”

“…The accumulation of newly synthesized virus particles in the culture supernatant was 22-to 53-fold lower in type III IFN-treated islets than in untreated islets. Previous studies have shown a protective effect of type III IFN in other picornavirus infections, including those with foot-and-mouth disease virus (33,34) and rhinovirus (9). To our knowledge, this is, however, the first time that type III IFN has been shown to promote antiviral activity against CVB.…”

“…Type III IFNs have been described as being functionally similar to type I IFNs, since both display antiviral properties and can, for example, induce an antiviral state in responsive cells (2,6,7). In support of this, type III IFNs have been shown to mediate an antiviral response against several human pathogens, including hepatitis B virus, hepatitis C virus, rhinovirus, and human immunodeficiency virus (7)(8)(9). The restricted receptor expression, however, suggests that type III IFNs may exert this specialized antiviral defense role in only certain cell types (10,11).…”