Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection

Abstract

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

Keywords: Host defense; Inflammasome; Inflammation; Innate immunity; Pneumonia; Pseudomonas aeruginosa.

Fig. 1

Responses of epithelial and immune cells to Pseudomonas aeruginosa. Trachea: Defenses of the tracheal pseudostratified epithelium. Mucociliary flow driven by ciliated tracheal epithelial cells is critical to bacterial clearance. Mucin contains secreted IgA, as well as antimicrobial peptides (AMP) and defensins whose production is induced by epithelial recognition of P. aeruginosa via multiple Toll-like receptors (TLR). Lipopolysaccharide and other pathogen-associated molecular patterns stimulate TLR2 and TLR4; basolateral TLR5 responds to flagellin; TLR9 mediates recognition of unmethylated CpG in bacterial DNA. Dendritic cells can sample bacterial antigens for subsequent presentation in the lymph nodes. Bacterially mediated damage to epithelial cells results in the release of IL-1α and other alarmins, stimulating host inflammatory responses. Bronchiole: The interferon (IFN) response is differentially expressed between immune cells and epithelial cells. The type I IFN response has been shown to repress IL-1β-dependent recruitment of PMN. The type III IFN response results in increased production of the proinflammatory peptide PDCD4 and has been correlated with increased P. aeruginosa biofilm formation. Alveolus: Inflammasome-mediated recognition of P. aeruginosa. The innate immune response in the lower airways and alveoli (depicted) includes NLRC4 and NLRP3 inflammasome activation in alveolar macrophages, leading to production and secretion of proinflammatory IL-1β and IL-18. In addition to responding directly to bacterial products and actions, epithelial cells also amplify IL-1β signals, resulting in the release of CXC chemokines (IL-6, IL-8, and MIP-2). Recruited neutrophils aid in bacterial clearance via phagocytic killing and NETosis, but they also cause tissue damage and compromised gas-exchange in the lung. The anatomical location of insets depicted in the trachea, bronchiole, and alveolus is diagrammed at the bottom left.