Rhinovirus species/genotypes and interferon-λ: subtypes, receptor and polymorphisms – missing pieces of the puzzle of childhood asthma?

Abstract

We agree about the importance of rhinovirus-C in asthma pathogenesis. In fact, rhinovirus genotyping is currently underway and the results of all Predicta cohorts will be published in a separate manuscript. Moreover, we agree with C. Scagnolari and co-workers that IFN-λ and IFN-λR distribution in the airways are relevant to asthma, so they require separate study. Moreover, beside epithelial cells, we have recently reported that IFN-λR is also expressed in pulmonary CD11c+ dendritic cells [1]. In our original manuscript we analysed IFN-λ in the serum of preschool children with and without asthma considering the presence of respiratory viruses in their airways [2], and detected higher levels of IFN-λ in serum in association with rhinovirus in the airways. This indicates the importance of evaluating systemic IFN-λ, especially during exacerbation of the disease, without diminishing its relevance in the airways. In conclusion, we thank C. Scagnolari and co-workers for their analysis of our work and we absolutely agree that the complex puzzle of childhood asthma regarding rhinovirus and type I and III interferons is still far from being completed and thus needs further investigations.

Respiratory infections regulated blood cells IFN‐β‐PD‐L1 pathway in pediatric asthma

“…Two cohorts of preschool children (age 4-6 years) with and without asthma were analyzed. The recruitment of the subjects, inclusion and exclusion criteria as well as the timescale for clinical visits and data collection were exactly described recently 1,2,5,6 along with the clinical aspects and characteristics and reported in other form in Tables 1 and 2. For gene expression analysis, we isolated messenger RNA (mRNA) from total blood cells of the children as previously described and performed quantitative real-time polymerase chain reaction (PCR) as described below. 1 The levels of C-reactive-protein (CRP) in the serum samples of the children were measured by turbidimetry on a Roche Integra 800 Analyzer (CRPL2 reagent, limit of detection 1.0 mg/L, interday CV 1.4% [8.1 mg/L]; Roche Diagnostics, Basel, Switzerland).…”

“…We recently described that acute in vitro infection of PBMCs from preschool children with and without asthma with RV, a single-stranded RNA picornavirus, is associated with the upregulation of IFN-regulated genes like STAT1, STAT2, and IFN regulatory factor 1. 1,2 Moreover, paradoxically, IFNγ upregulates also PD-L1, a factor involved in silencing/ exhausting of activated T cells by ligating PD1 on the surface of T cells. 10 Consistently, we found that acute RV infection ex vivo induced PD-L1 and CTLA4 in the PBMCs of asthmatic children.…”

“…6 We thus wanted to follow up these in vitro observations in the two cohorts of our study and analyzed 21 control children and 24 children with asthma ( Figure 1A). The clinical data of these cohorts of children were recently reported 2,5,6 and are summarized in Tables 1 and 2. By looking at the PD-L1 mRNA expression in blood, we found that PD-L1 mRNA expression was induced in children with a virus-induced asthma phenotype (in accordance to PRACTALL guidelines 2008 11 ) compared to healthy control children ( Figure 1B).…”

“…The immune responses of the host to respiratory infections, in general, and to rhinovirus (RV) infection in particular, are associated with upregulation of type I interferon (IFN) pathways 1,2 in the airways and systemically in the blood cells 3 . Deficient systemic IFN responses to respiratory infections have been observed in patients with noncontrolled asthma, 1,2,4,5 suggesting that type I IFN could be used to improve lung function in asthma.…”

“…The immune responses of the host to respiratory infections, in general, and to rhinovirus (RV) infection in particular, are associated with upregulation of type I interferon (IFN) pathways 1,2 in the airways and systemically in the blood cells 3 . Deficient systemic IFN responses to respiratory infections have been observed in patients with noncontrolled asthma, 1,2,4,5 suggesting that type I IFN could be used to improve lung function in asthma. IFN response of the host can be suppressed by infectious agents by upregulation of programmed cell death protein 1 ligand (PD‐L1), 2,6 which then inhibit T cell proliferation via binding to programmed cell death protein 1 (PD1), considered as an immune checkpoint because it downregulates the immune responses 7 …”