Abstract
BackgroundChronic lung infection with Pseudomonas aeruginosa is a major contributor to morbidity, mortality and premature death in cystic fibrosis. A new paradigm for managing such infections is needed, as are relevant and translatable animal models to identify and test concepts. We sought to improve on limitations associated with existing models of infection in small animals through developing a lung segmental model of chronic Pseudomonas infection in sheep.Methodology/Principal FindingsUsing local lung instillation of P. aeruginosa suspended in agar beads we were able to demonstrate that such infection led to the development of a suppurative, necrotising and pyogranulomatous pneumonia centred on the instilled beads. No overt evidence of organ or systemic compromise was apparent in any animal during the course of infection. Infection persisted in the lungs of individual animals for as long as 66 days after initial instillation. Quantitative microbiology applied to bronchoalveolar lavage fluid derived from infected segments proved an insensitive index of the presence of significant infection in lung tissue (>104 cfu/g).Conclusions/SignificanceThe agar bead model of chronic P. aeruginosa lung infection in sheep is a relevant platform to investigate both the pathobiology of such infections as well as novel approaches to their diagnosis and therapy. Particular ethical benefits relate to the model in terms of refining existing approaches by compromising a smaller proportion of the lung with infection and facilitating longitudinal assessment by bronchoscopy, and also potentially reducing animal numbers through facilitating within-animal comparisons of differential therapeutic approaches.
Highlights
With about 80% of CF adults being chronically infected with Pseudomonas aeruginosa in the respiratory and conducting zones of the lungs [1] this pathogen is recognized as being a major contributor to morbidity, mortality and premature death in this disease
Whilst new antibiotics that exploit novel mechanisms of action are largely conspicuous by their absence from the current drug development pipeline, the use of adjunct therapies that promote the effectiveness of existing antibiotics hold clinical potential
Median [range] total cell counts (6106) in BALF from the agar-instilled segments in these sheep were 6.27 [4.64–7.90], 5.35 [4.16–6.54], 5.60 [4.02–7.18] and 7.62 [5.74–9.44] at day 3, 7, 14 and 21 after instillation, which compared with values of 4.83 [4.04–5.62], 5.04 [3.60–6.48], 4.93 [4.00–5.86] and 5.34 [3.66–7.02] obtained at the same time points from non-instilled control lung segments
Summary
With about 80% of CF adults being chronically infected with Pseudomonas aeruginosa in the respiratory and conducting zones of the lungs [1] this pathogen is recognized as being a major contributor to morbidity, mortality and premature death in this disease. Whilst new antibiotics that exploit novel mechanisms of action are largely conspicuous by their absence from the current drug development pipeline, the use of adjunct therapies that promote the effectiveness of existing antibiotics hold clinical potential. Such adjuncts include quorum sensing inhibitors, lectin inhibitors and iron chelators – all directed towards controlling the expression of virulence factors, efflux pump modulators, resistance gene expression inhibitors, bacteriophages and endolysins – all directed towards limiting the development of resistance, and lastly immunisation and immunotherapeutic strategies [4]. We sought to improve on limitations associated with existing models of infection in small animals through developing a lung segmental model of chronic Pseudomonas infection in sheep
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