Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response

Abstract

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.

Keywords: Pseudomonas aeruginosa; adaptive immune response; chronic lung disease; inflammation; innate immune response; neutrophils.

Figure 1

Comparison between healthy airway and chronic lung disease. Chronic lung disease is characterized by mucociliary defects (i.e., mucus dehydration, ciliary dysfunction) which impair initial clearance of pathogens from the airway. Reduced pathogen clearance promotes immune cell recruitment and activation, resulting in a cascade of inflammation and tissue damage which renders the airway more susceptible to infection. Some chronic lung diseases are characterized by pre-existing inflammation which heightens this effect. Prolonged unresolving inflammation leads to tissue remodeling and fibrosis, which affects gas exchange in the alveoli, ultimately leading to lung failure. Figure created with BioRender.com.

Figure 2

Overview of the transition from initial colonizing P. aeruginosa to chronic lung-adapted P. aeruginosa. P. aeruginosa generally enters the lung as a motile planktonic bacterium expressing flagella and pili and producing high levels of virulence factors and exoproducts such as secreted proteases which are immunogenic and damage the lung tissue. This prototypical acute phenotype is outlined on the left. Initial infection can occur with environmental isolates or clonal strains which may already have some degree of lung adaptation. As P. aeruginosa adapts to the lung environment in chronic lung diseases such as cystic fibrosis, it genetically diversifies and then converges on a population level toward a set of chronicity-associated phenotypes highlighted on the right. It loses key virulence factors and becomes less immunogenic. Transition to a sessile biofilm lifestyle as well as mucoidy increase resistance to both immune and antibiotic clearance. Biofilm communities undergo clonal diversification to give rise to hypermutators and persisters which further increase P. aeruginosa resilience within the lung niche. Created with BioRender.com.

Figure 3

Overview of the immune response to chronic P. aeruginosa infection within the lung. (A) Summary of the timeline of chronic P. aeruginosa infection establishment and key immune players involved. Following initial potentially intermittent colonization, P. aeruginosa adapts to the diseased lung environment and establishes a biofilm community. (B) Overview of the primary pattern recognition receptors and pathogen-associated molecular patterns associated with initial recognition of P. aeruginosa by sentinel airway epithelial cells and alveolar macrophages. (C) Following pathogen recognition, innate immune cells are recruited to the site of infection. Chronic P. aeruginosa infection is characterized by neutrophilia and extensive neutrophil-mediated lung damage because of degranulation, NETosis, and cytokine production. Monocyte-derived macrophages are recruited from circulation and polarized into inflammatory “M1” macrophages at the site of infection. Interstitial macrophages and alveolar macrophages also contribute to the macrophage involvement in infection. Macrophages also contribute to production of pro-inflammatory cytokines. Phagocytosis by both macrophages and neutrophils is thwarted by chronic bacterial adaptations. (D) Antigen-presenting cells such as dendritic cells are activated within the lung and travel to local draining lymph nodes to activate adaptive T and B-cell mediated immunity. Naïve CD4+ T cells are predominantly polarized into Th2 and Th17 populations in chronic P. aeruginosa infection. Th2 cells produce characteristic cytokines IL-4, IL-5, and IL-13 and support the formation of the B cell antibody response. Robust IgG and IgA antibody production occurs in response to chronic P. aeruginosa infection but is largely ineffectual at clearing infection or protecting against re-infection and may contribute to further inflammation by immune complex formation. Th17 cells produce Il-17 family cytokines which indirectly support neutrophil maturation and recruitment, further contributing to detrimental neutrophil-mediated lung damage. Figure created using BioRender.com.

Figure 4

Immunomodulatory therapies available and under development for chronic P. aeruginosa infection in the context of chronic lung diseases, particularly CF. Beginning with non-specific therapies, corticosteroids have broad anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects that can reduce the progression of inflammation-driven lung damage in chronic lung disease, but also increase the risk of infections such as P. aeruginosa. High-dose ibuprofen acts on the COX-1 and COX-2 receptors to inhibit prostaglandin (ex. PGE2) and leukotriene (ex. LTB4) synthesis, reducing immune cell migration into the airways. Azithromycin is a macrolide antibiotic which, in addition to directly inhibiting bacterial growth, has been reported to have various immunomodulatory functions on innate immune cells like macrophages and neutrophils. Moving into more targeted therapies, alpha-1-antitrypsin is an antiprotease naturally produced in the human lung which restricts neutrophil elastase activity and can be given supplementarily to reduce lung damage. Recombinant human DNAse (rhDNAse) targets enhanced DNA concentrations in sputum because of NET release by neutrophils to reduce sputum viscosity and improve pulmonary function. LTB4 antagonists block the neutrophil chemoattractant and activator LTB4 but caused pulmonary exacerbations in clinical trials. Anti-CXCR2 monoclonal antibodies (mAbs) block the CXCR2 receptor on neutrophils preventing binding of the neutrophil chemoattractant and activator CXCL8. Anti-IL-17 mAbs block IL-17 function to limit neutrophil proliferation and activation. Finally, CFTR modulators, by correcting CFTR dysfunction indirectly modulate the immune system by improving overall lung function, reducing pathogen burden, and reducing inflammation. Figure created in BioRender.com.