The Effects of CFTR and Mucoid Phenotype on Susceptibility and Innate Immune Responses in a Mouse Model of Pneumococcal Lung Disease.

Evida A Dennis,Mamie T Coats,Marilyn J Crain,David E Briles,Lea Novak,Joanetha Y Hale,Sarah E Griffin,Bernard Beall

doi:10.1371/journal.pone.0140335

Evida A Dennis, Mamie T Coats + Show 6 more

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https://doi.org/10.1371/journal.pone.0140335

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Abstract

Recent studies have reported the isolation of highly mucoid serotype 3 Streptococcus pneumoniae (Sp) from the respiratory tracts of children with cystic fibrosis (CF). Whether these highly mucoid Sp contribute to, or are associated with, respiratory failure among patients with CF remains unknown. Other mucoid bacteria, predominately Pseudomonas aeruginosa, are associated with CF respiratory decline. We used a mouse model of CF to study pneumococcal pneumonia with highly mucoid serotype 3 and non-mucoid serotype 19A Sp isolates. We investigated susceptibility to infection, survival, and bacterial counts from bronchoaviolar lavage samples and lung homogenates, as well as associated inflammatory cytokines at the site of infection, and lung pathology. Congenic CFTR–/– mice and wild-type (WT)-mice were infected intranasally with CHB756, CHB1126, and WU2 (highly mucoid capsular serotype 3, intermediately mucoid serotype 3, and less mucoid serotype 3, respectively), or CHB1058 (non-mucoid serotype 19A). BAL, lung homogenates, and blood were collected from mice 5 days post-infection. Higher CFU recovery and shorter survival were observed following infection of CFTR–/– mice with CHB756 compared to infection with CHB1126, WU2, or CHB1058 (P≤0.001). Additionally, CFTR–/– mice infected with CHB756 and CHB1126 were more susceptible to infection than WT-mice (P≤0.05). Between CFTR–/– mice and WT-mice, no significant differences in TNF-α, CXCL1/KC concentrations, or lung histopathology were observed. Our results indicate that highly mucoid type 3 Sp causes more severe lung disease than non-mucoid Sp, and does so more readily in the lungs of CFTR–/– than WT-mice.

Highlights

Streptococcus pneumoniae (Sp) is a leading cause of morbidity and mortality worldwide, especially in children, the elderly, and those with underlying diseases
It is clear that the fundamental cause of cystic fibrosis (CF) is the lack of functional CFTR protein, the mechanisms leading to chronic lung disease associated with infection need further study
The observation that mucoid Sp were isolated from the sputum of CF patients more frequently than from patients without CF [Coats et al in preparation] prompted the question of whether mice with a CFTR defect are more susceptible to infection with highly mucoid Sp compared to their congenic WT littermates since other mucoid bacteria, most notably Pseudomonas aeruginosa (Pa), are associated with progression of CF lung disease [9, 14,15,16,17,18,19, 29,30,31]

Summary

Introduction

Streptococcus pneumoniae (Sp) is a leading cause of morbidity and mortality worldwide, especially in children, the elderly, and those with underlying diseases. Sp has been reported in the sputum of CF patients in a few previous studies, little is known about its specific role in cystic fibrosis (CF) lung disease [2,3,4,5,6]. Pulmonary infection with an exaggerated inflammatory response is a major cause of morbidity and mortality in CF [11]. CF patients often fail to eradicate bacteria despite a high influx of neutrophils, and it is thought that the resultant inflammation plays a major role in the deterioration of lung function, and in subsequent morbidity and mortality [11,12]

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