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Interaction between Pseudomonas aeruginosa and host defenses in cystic fibrosis
1Intermountain Cystic Fibrosis Center, University of Utah Medical Center, Salt Lake City 84132.
Abstract:
The major causes of morbidity and mortality in cystic fibrosis are chronic pulmonary obstruction and infection. Mucoid Pseudomonas aeruginosa is the primary pathogen in up to 90% of these patients. Once Pseudomonas organisms colonize the airways, they are virtually never eradicated. No defect in systemic host defense has been elucidated, however, several mechanisms contribute to the breakdown in host defenses that allow persistence of this organism in the endobronchial space. These mechanisms involve both bacterial adaptation to an unfavorable host environment and impaired host response. P aeruginosa adapts to the host by expressing excessive mucoid exopolysaccharide and a less virulent form of lipopolysaccharide. These features make it less likely to cause systemic infection, yet still enable it to resist local host defenses. Mucociliary clearance becomes impaired due to abnormal viscoelastic properties of sputum, squamous metaplasia of the respiratory epithelium, and bronchiectasis. Despite a brisk antibody response to a variety of Pseudomonas antigens, several defects in antibody-mediated opsonophagocytosis have been identified. These include (1) development of antibody isotypes that are suboptimal at promoting phagocytosis, (2) formation of immune complexes that inhibit phagocytosis, and (3) proteolytic fragmentation of immunoglobulins in the endobronchial space. Complement-mediated opsonophagocytosis is also compromised by proteolytic cleavage of complement receptors from the cell surface of neutrophils and complement opsonins from the surface of Pseudomonas. The resultant chronic inflammation and infection lead to eventual obliteration of the airways.
Insights
Cystic fibrosis lung infections by Pseudomonas aeruginosa are persistent due to bacterial adaptation and impaired host defenses. Understanding these mechanisms is key to combating chronic pulmonary obstruction and mortality.
Area of Science:
- Pulmonary Medicine
- Microbiology
- Immunology
Background:
- Cystic fibrosis (CF) is primarily characterized by chronic pulmonary obstruction and infection.
- Mucoid Pseudomonas aeruginosa (P. aeruginosa) is the predominant pathogen in up to 90% of CF patients, establishing persistent airway colonization.
- Eradication of P. aeruginosa once colonized is extremely difficult.
Purpose of the Study:
- To elucidate the mechanisms contributing to the breakdown of host defenses that allow P. aeruginosa persistence in the endobronchial space.
- To understand how bacterial adaptation and impaired host response facilitate chronic infection in CF.
Main Methods:
- The study reviews mechanisms of bacterial adaptation and host response in the context of P. aeruginosa infection in CF.
- Analysis of bacterial virulence factors, including mucoid exopolysaccharide and lipopolysaccharide.
- Evaluation of host defense defects, focusing on impaired mucociliary clearance and antibody- and complement-mediated opsonophagocytosis.
Main Results:
- P. aeruginosa adapts by expressing mucoid exopolysaccharide and altered lipopolysaccharide, enhancing resistance to local host defenses.
- Impaired mucociliary clearance, altered sputum properties, and respiratory epithelium changes contribute to pathogen persistence.
- Defects in antibody-mediated opsonophagocytosis include suboptimal antibody isotypes, inhibitory immune complexes, and immunoglobulin fragmentation.
- Complement-mediated opsonophagocytosis is compromised by proteolytic cleavage of complement receptors and opsonins.
Conclusions:
- Chronic inflammation and infection, driven by bacterial adaptation and host defense failures, lead to progressive airway obliteration in cystic fibrosis.
- Understanding these complex interactions is crucial for developing effective therapeutic strategies against P. aeruginosa in CF patients.