Efficacy of IFN-λ1 to Protect Human Airway Epithelial Cells against Human Rhinovirus 1B Infection

Abstract

Impaired interferon (IFN) production has been observed in various obstructive respiratory diseases. This contributes to enhanced sensitivity towards viral infections triggering acute exacerbations. To compensate for this impaired host IFN response, there is need to explore new therapeutic strategies, like exogenous administration of IFNs as prophylactic treatment. In the present study, we examined the protective potential of IFN-λ1 and compared it with the previously established protecting effect of IFN-β. A549 cells and human primary bronchial epithelial cells were first treated with either IFN-β (500 IU/ml) or IFN-λ1 (500 ng/ml) for 18 h. For infection, two approaches were adopted: i) Continuous scenario: after pre-treatment, cells were infected immediately for 24 h with human rhinovirus 1B (HRV1B) in IFN-containing medium, or were cultured for another 72 h in IFN-containing medium, and then infected for 24 h with HRV1B, ii) Pre-treatment scenario: IFN-containing medium was replaced after 18 h and cells were infected for 4 h either immediately after pre-treatment or after additional culturing for 72 h in IFN-free medium. The protective effect was evaluated in terms of reduction in the number of viral copies/infectious progeny, and enhanced expression of IFN-stimulated genes (ISGs). In both cell types and in both approaches, IFN-λ1 and IFN-β treatment resulted in pronounced and long-lasting antiviral effects exemplified by significantly reduced viral copy numbers and diminished infectious progeny. This was associated with strong up-regulation of multiple ISGs. However, in contrast to the IFN-β induced expression of ISGs, which decreased over time, expression of ISGs induced by IFN-λ1 was sustained or even increased over time. Here we demonstrate that the protective potential of IFN-λ1 is comparable to IFN-β. Yet, the long-lasting induction of ISGs by IFN-λ1 and most likely less incitement of side effects due to more localized expression of its receptors could make it an even more promising candidate for prophylactic treatment than IFN-β.

Conditional reprogramming of pediatric airway epithelial cells: A new human model to investigate early‐life respiratory disorders

“…We did not have enough donors to make conclusions about the relevance of atopy or history of prematurity in AEC immune responses or to examine the effect of CRC methods in the success/failure rates of AEC cultures. However, our experiments demonstrate that CRC derived from AEC of neonates and infants have significantly increased proliferative capacity and life extension, and are capable of mounting an innate immune response that resembles that seen in primary human AEC in vitro and in vivo during viral respiratory infections in children . Accordingly, pediatric nasal CRC might potentially represent a valuable research approach to investigate the molecular mechanisms that control airway epithelial immune responses in early life.…”

“…Notably, IFN regulatory transcription factor 7 (IRF‐7), which regulates transcriptional activation of virus‐inducible IFN genes in AEC, was also overexpressed. IRF‐7 induction was coupled with the expression of IFNL (Figure A), the gene that encodes the IFN λ1 protein (also known as IL‐29), an epithelial type III IFN secreted by AEC during viral respiratory infections . CRC also showed a robust production of IFN λ1 after exposure to dsRNA with basically identical IFN λ1 production in nasal and bronchial infant CRC paired cultures from the same donor (Figure B).…”

“…As expected, pediatric nasal CRC exposed to dsRNA showed upregulation of canonical antiviral AEC signaling pathways activated by innate receptors including TLR‐3, RIG‐I, and MDA‐5, and downstream transcription of IFN genes and other NFκβ‐related pro‐inflammatory genes. In addition, dsRNA induced CRC production of IFN λ1, a signature molecule for epithelial IFN responses during viral respiratory infections . Importantly, the fact that antiviral and inflammatory genes are upregulated under CRC conditions is promising, but it does not prove that these responses are the same as the in vivo AEC responses.…”

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection

“…In a normal setting, RV-induced host pro-inflammatory (e.g., IL-8 production) and anti-viral (e.g., expression of IFN-λ1) responses are necessary to contain the viral infection [3, 4]. IFN-λ1 is critical to host defense against RV infection [5, 6]. Impaired IFN-λ1 expression has been reported in cultured asthmatic airway epithelial cells [5, 6].…”

“…IFN-λ1 is critical to host defense against RV infection [5, 6]. Impaired IFN-λ1 expression has been reported in cultured asthmatic airway epithelial cells [5, 6]. While the appropriate pro-inflammatory response such as neutrophil recruitment/activation is beneficial during the viral infection, excessive airway inflammation may be responsible for asthma exacerbations [7].…”