Abstract
Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.
Highlights
Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; the contributions of disease modifiers remain underappreciated
P. aeruginosa infections are associated with bacterial pneumonia in patients with a range of pathological and clinical phenotypes owing to different etiologies and underlying conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD)
Systematic screening for susceptibility to P. aeruginosa infection was carried out in 39 Collaborative Cross (CC) lines, which included a total of 221 mice (100 female and 121 male) aged between 7 and 14 weeks
Summary
Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; the contributions of disease modifiers remain underappreciated. Disease outcomes range from fatal pneumonia to chronic lifethreatening infection and inflammation leading to the progressive deterioration of pulmonary function The development of these respiratory infections is mediated by multiple causes. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. Novel approaches and improved disease models are required to move the field forward Among respiratory infections, those caused by the opportunistic pathogen Pseudomonas aeruginosa retain critical roles in clinical settings [1, 2]. P. aeruginosa infections are associated with bacterial pneumonia in patients with a range of pathological and clinical phenotypes owing to different etiologies and underlying conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Identifying genetic disease modifiers by genome-wide association studies (GWASs) in humans requires a very large cohort of subjects with detailed phenotypes in order to achieve statistical significance [6]
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