Differential post-transcriptional activation of human phagocytes by different Pseudomonas aeruginosa isolates
Andrew J Pollard1, Andrew Currie, Carrie M Rosenberger
1Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, British Columbia's Research Institute for Children's and Women's Health, Vancouver, BC, Canada. andrew.pollard@paediatrics.ox.ac.uk
Abstract:
Pseudomonas aeruginosa is a pulmonary pathogen in individuals with impaired mucociliary clearance such as cystic fibrosis or mechanical ventilation. Non-opsonic phagocytosis of P. aeruginosa can be mediated by either CR3 or CD14 and different strains appear to have a bias towards one or the other receptor. Strain Fc808 is ingested through CD14 whereas P1 (Fc194) uses CR3. In an in vitro culture system, the inflammatory response of macrophages to these two different strains of P. aeruginosa was divergent at the protein level, with higher IL-6 and tumour necrosis factor (TNF)-alpha production generated in response to strain P1 and higher IL-1 beta production in response to strain Fc808. Interaction of macrophages with these two bacterial strains induced distinct gene expression patterns as detected by gene array analysis, with prominence of genes encoding pro-inflammatory cytokines, surface receptors, transcription factors and proteins involved in phagocytosis. However, comparison of gene expression data and cytokine response data with the two bacterial strains indicated that production of IL-1 beta, IL-6 and TNF-alpha was under differential post-transcriptional control. Interestingly, this effect did not correlate with receptor bias but instead was related to the different LPSs of the two strains. The use of specific mitogen-activated protein kinase (MAPK) inhibitors suggested a role for extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in the differential cytokine production by strains P1 and Fc808. These results indicate that strains of the same species of bacteria may induce differential macrophage phagocytic and inflammatory responses with likely consequence for bacterial clearance and host injury.
Insights
Different Pseudomonas aeruginosa strains trigger distinct macrophage responses. This study reveals variations in inflammatory cytokine production and gene expression, influenced by bacterial LPS and MAPK pathways, impacting bacterial clearance and host injury.
Area of Science:
- Immunology
- Microbiology
- Pulmonary Medicine
Background:
- Pseudomonas aeruginosa is a significant pulmonary pathogen, particularly in vulnerable populations like cystic fibrosis patients.
- Non-opsonic phagocytosis of P. aeruginosa by macrophages involves either complement receptor 3 (CR3) or CD14, with different strains exhibiting receptor bias.
- Strain Fc808 utilizes CD14, while strain P1 (Fc194) employs CR3 for phagocytosis.
Purpose of the Study:
- To investigate the differential inflammatory and phagocytic responses of macrophages to distinct P. aeruginosa strains (Fc808 and P1).
- To elucidate the underlying mechanisms, including gene expression patterns, post-transcriptional control, and signaling pathways, that govern these strain-specific responses.
Main Methods:
- In vitro macrophage culture system exposed to P. aeruginosa strains Fc808 and P1.
- Analysis of protein-level inflammatory markers (IL-6, TNF-alpha, IL-1 beta) and gene expression profiles using gene arrays.
- Investigation of post-transcriptional regulation and the role of mitogen-activated protein kinase (MAPK) pathways (ERK, JNK) using specific inhibitors.
Main Results:
- Macrophages exhibited divergent inflammatory protein production: higher IL-6 and TNF-alpha for strain P1, and higher IL-1 beta for strain Fc808.
- Distinct gene expression patterns were observed, with significant regulation of genes involved in inflammation, phagocytosis, and immune signaling.
- Differential cytokine production was linked to bacterial lipopolysaccharides (LPSs) and post-transcriptional control, rather than initial receptor bias.
- Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were implicated in the differential cytokine responses.
Conclusions:
- P. aeruginosa strains can elicit distinct macrophage phagocytic and inflammatory responses.
- Bacterial LPS and post-transcriptional mechanisms, modulated by MAPK signaling, play crucial roles in determining the host immune outcome.
- Understanding these strain-specific interactions is vital for predicting bacterial clearance and host-induced injury in pulmonary infections.
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