This project hypothesizes candidate modifier genes within the identified QTL(Quantitative Trait Locus) in murine models and aims to validate them as risk factors for P. aeruginosa infection and disease severity. Validation of candidate modifier genes was carried out: 1) in model system including gene editing with CRISPR/Cas9 of cell lines; 2) in CF patients cohorts by exploring available BIO-banks. Fourteen protein-coding genes were candidates for involvement in P. aeruginosa pneumonia. Among others, the sphingosine 1-phosphate receptor 1 (S1PR1) ranked as one of the most promising candidates. To translate these results to humans, first, a genotyped cohort (Canadian CF Gene Modifier) with clinical microbiological data for P. aeruginosa infection was used for identification of candidate genes. Genetic-association analysis on the syntenic human locus on chromosome 1 identified two single-nucleotide polymorphisms annotated to the dihydropyrimidine dehydrogenase (DPYD) gene that were significantly associated with age at first P. aeruginosa infection. DPYD encoded a pyrimidine catabolic enzyme and has never been described in infection and inflammation processes. Other CF patients cohorts are under evaluation.

 Pubblications

– Lorè NI, Cigana C, Sipione B et al. “The impact of host genetic background in the Pseudomonas aeruginosa respiratory infections” Mammalian Genome 2018 Jun 12.

Congress abstracts

– Lorè NI, Sipione B, Mott R et al. “Host genetic traits influence the severity of respiratory infections by Pseudomonas
aeruginosa” 30th Annual North American Cystic Fibrosis Conference – Orlando, October 27-29, 2016
– Lorè NI, Sipione B, Mott R et al. “Novel disease models to capture pathological complexity of Pseudomonas aeruginosa respiratory infection “ ECFS 2017 – The 40th European Cystic Fibrosis Conference– Siviglia, June 18-21, 2017
– Lorè NI, Iraqi F, Bragonzi A “Novel genetically-diverse mouse models to unravel the complexity of the lung infections” 2017 ECFS Basic Science Conference – Albufeira 29-1 April, 2017
– Lorè NI, Sipione B, Mott R et al. “Novel disease models to capture pathological complexity of Pseudomonas aeruginosa respiratory infection “ CFF Research Conference – Stevenson, June 18-21, 2017
– Lorè NI, Sipione B, He G et al. “Novel genetically-diverse mouse models to unravel genetic modifiers for Pseudomonas aeruginosa infection” North American Cystic Fibrosis Conference (NACFC), November 2-4, 2017, Indianapolis