Complex interplay between host immunity and pathogenic organisms has been proposed in Cystic fibrosis (CF) disease progression. Type I and III interferon (IFN) are involved in tuning antimicrobial and inflammation response as well as emerging negative modifier of respiratory infections. The use of IFN therapies or targeting the IFN pathway has been pursued in other diseases, but the IFN expression profiling in CF patients accordingly to the clinical and microbiological status is less well understood. The following aims will be pursued: i) to characterize viral and bacterial infections in CF mild or severe disease; to uncover the role of rhinovirus (HRV) species, viral load, genotype specific persistence; to assess airway type I/III IFN signature, according to bacterial/viral infections and patient data. We will collect about 1800 samples from the respiratory tract of patients. Respiratory samples will be analyzed for common and emerging microorganisms. Besides the bacteriological analysis, detection and typing of respiratory viruses will be performed. Gene expression evaluation of type I ¿III IFN profiling will be evaluated in CF patients accordingly to the bacteriological, virological and clinical data. The following output will be obtained: i) To delineate the presence and demonstrate the clinical value of the type I and III IFN-signature in CF disease; ii) To better understand the dynamics between bacteria and respiratory viruses in CF patients; iii) To ascertain whether virus¿bacteria coinfection compromise the IFN response. An improved understanding of the positive and/or negative effects of IFN response will enable clinicians and public health officials to identify which CF patients are at risk of developing this potentially fatal complication, and aid in the development of new therapeutic immunological approaches aimed at mitigating the severity of CF.
The clinical impact of viral infections is greater in patients with CF and they are associated with a longer duration and more severe course of lower respiratory symptoms, and deterioration in pulmonary function [Lipuma J. 2010]. Studies have linked respiratory tract viral infections with the acquisition and/or persistence of the bacterial opportunistic pathogen P. aeruginosa by CF patients and viceversa. Indeed, P. aeruginosa pre-infection inhibited HRV clearance by suppressing the antiviral response [Chattoraj SS et al. 2011]. On the other hand, the exposure to secondary infection, while the airway epithelium is responding to ongoing primary infection, may affect the early innate defense mechanisms of the airway epithelium in multiple ways, depending on the types of infection during CF disease. In this regard, the innate response to respiratory syncytial virus (RSV) creates a microenvironment particularly favorable for biofilm establishment [Bouvier NM 2016;]. Given the pervasive influence of type I and III IFN responses and data revealing both positive as well as negative effects of these complex cytokines system in the respiratory tract infection, it is also imperative to critically delineate the impact of a specific IFN signatures on CF disease settings. An increased expression of IFN-responding genes, the so-called IFN signature, has been reported in several chronic diseases including CF [Andreakos E et al 2017, Bouvier NM 2016; Jiang K et al 2015; Bergauer A et al 2017; da Silva Jet al 2017]. However, controversy exists concerning its clinical relevance in airway chronic diseases. Therefore during this project the expression of the IFN-mediated signatures to respiratory pathogens in a large cohort of CF patients in relation with P. aeruginosa colonization, the principal pathogen in CF, or with other persistent bacterial or viral infections will be characterized. This following aims will be persuaded: i) to characterize viral and bacterial infections in CF mild or severe disease; to uncover the role of HRV species, viral load, genotype specific persistence in determining clinical conditions; ii) to assess type I and III IFN signature, according to bacterial/viral infections and patient data. Overall, the rationale behind these research is to understand whether enhanced type I or III IFN signaling in a patient group may eventually keep the viral infection under control and/or may have effects on the battle against P. aeruginosa or detrimental effects for the host. Matching participants with CF for infection status should allow to discriminate the real differences in specific IFN genes raised by specific viral species. Then, trough this project will be able to delineate whether activation of IFN signaling exert opposing effects, protective or deleterious, in relation to the clinical/microbiological status of CF patients. We retain that the elucidation of the interplay between bacteria, respiratory viruses and IFN immunity will shed light on pathogenesis and will elucidate avenues to potentially develop more effective and targeted treatment options [e.g. IFN or anti-IFN therapies] for CF disease. Moreover, it will allow to identify patients suffering from CF more at risk of developing severe respiratory disease according to the IFN profiling and bacterial/viral coinfection.