Cystic Fibrosis Mice Are Highly Susceptible to Repeated Acute Pseudomonas aeruginosa Pneumonia after Intranasal Inoculation

TL;DR

Mice with cystic fibrosis are more vulnerable to repeated lung infections with Pseudomonas aeruginosa compared to healthy mice.

Contribution

This study reveals that CF mice have impaired immune responses during repeated acute Pseudomonas infections.

Findings

CF mice showed increased susceptibility to Pseudomonas aeruginosa after a second infection compared to non-CF mice.

Non-CF mice exhibited better neutrophil recruitment and function during repeated infections.

Non-CF neutrophils had higher ICAM-1 expression compared to CF neutrophils.

Abstract

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that controls chloride current. A number of different CFTR transgenic mouse lines have been developed and subjected to both acute and chronic infection models. However, prior studies showed no substantial differences in bacterial clearance between CF and non-CF mice after single inoculations. Here, using F508del transgenic CF mice, we examined the role of repeated acute Pseudomonas aeruginosa (PA) infection, with the second inoculation 7 days after the first. We found that CF mice were more susceptible to PA infection than non-CF mice following the second inoculation, with non-CF mice showing better neutrophil recruitment and effector functions. We further investigated the characteristics of lung immune cells using single-cell RNA sequencing, finding that non-CF lung neutrophils had more prominent upregulation of adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) compared to CF lung neutrophils. Although people with CF are often colonized with bacteria and have high numbers of neutrophils in the airways during chronic infection, these data suggest that CF neutrophils have deficient effector functions in the setting of repeated acute infection.

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