PREDICTA

Post-infectious immune reprogramming and its association with persistence and chronicity of respiratory allergic diseases

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 Obiettivo del progetto (Objective)

'Chronic inflammatory diseases associated with allergy, including asthma and rhinitis, constitute a major and continuously growing public health concern for Europe. However, the causative factors and mechanisms converting a physiological inflammatory reaction to a chronic response triggering allergic disease remain elusive. Viral infections, particularly those caused by human rhinoviruses (RV) are the most frequent triggers of acute asthma exacerbations. RV infections have more recently been associated with asthma initiation; there is evidence suggesting that such infections may also contribute to respiratory allergy persistence. The strategic aims of PreDicta are to evaluate the hypothesis that repeated infections reprogram the immune system towards a persistent inflammatory pattern leading to respiratory allergies by (i) dissecting the molecular and cellular mechanisms involved in the lack of resolution of inflammation in the context of a human disease, (ii) identifying specific infectious agents and underlying altered host-pathogen interactions, and develop relevant prognostic and therapeutic strategies. PreDicta follows three interconnected workflows: models, mechanisms and translational output. Models include a longitudinal cohort in children, mouse models of repeated virus infection, primary epithelial cultures from patients, viral-bacterial interaction models, and models of epithelial-T-cell-dendritic cell interactions. These will be used to look into disease persistence, inflammation patterns, dysbiosis, immune regulation and resolution of inflammation. Translational outputs include prognostic use of subtype-specific antiviral antibodies, DNAZymes for therapeutic use and delivery technologies targeted to the bronchial epithelium. This interdisciplinary Consortium with strong track record, unique resources and strong translational focus, aims to produce new knowledge and technologies that can rapidly and effectively reach clinical care.'

Introduzione (Teaser)

Accurate prediction of the predisposing risk factors for the persistence of asthma and rhinitis could help alleviate and hopefully treat such respiratory allergies. Leading European scientists in the field are teaming up to investigate the relationship between recurrent infections and asthma development.

Descrizione progetto (Article)

Asthma and rhinitis are allergy-related diseases caused by chronic inflammations affecting millions of people globally. Despite the growing health concern, the causative factors and mechanisms converting a physiological inflammatory reaction to a chronic response triggering allergic disease remain elusive.

Based on the observation that childhood asthma usually follows a viral respiratory tract infection, the EU-funded Predicta project partners are hypothesising that such infections could reprogramme the immune system and predispose individuals towards chronic inflammation. To this end, they aim to advance the understanding of the pathogenesis of respiratory allergies and to suggest new prevention and innovative treatment strategies.

Viral infections, particularly those caused by human rhinoviruses (RVs) are the most frequent triggers of acute asthma. Project partners have set out to associate asthma/rhinitis persistence with the number and type of respiratory infections, with a particular emphasis on respiratory viruses, such as RV-C.

In an ex vivo model of interactions between viruses (RVs) and bacterial (Staphylococcus Aureus) infections, scientists have found that consecutive infection by these pathogens causes acute inflammation. Work into the active mechanisms of inflammation resolution indicates that mediators of the protectin family (PD1, PDX) control the duration and magnitude of inflammation. They are the first to be generated in the early phase of the allergic response, while their levels increase as the response proceeds into the resolution phase.

Experiments in mouse models of repeated RV infections will reveal how neutralising antibodies are generated and form the basis for the design of future vaccines. By studying these antibody responses to RV, the Predicta consortium provides evidence that misdirected responses could potentially fail to protect against recurrent RV infections. Furthermore, central to the unresponsiveness of the immune system are regulatory T lymphocytes and the interleukin-23 that normally functions to defend against viral or bacterial pathogens.

The Predicta project expects to establish diagnostic and therapeutic strategies to predict and if possible avoid respiratory allergy persistence. Towards this end, a diagnostic chip, able to recognise antibodies against RVs, is being developed. Collectively, the project outcomes will improve understanding of asthma and rhinitis and contribute to national, European and international prevention programmes.