Abstract
Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.
Highlights
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with a remarkable and threatening ability to thrive and adapt to various ecological niches (Stover et al, 2000)
The LasB elastolytic activities of culture supernatants from P. aeruginosa reference strain PAO1 and clinical isolates RP45 and RP73, collected from a cystic fibrosis (CF) patient at different periods following the onset of lung colonization, were investigated by the ECR method (Figure 1)
The loss of LasB activity is in accordance to the pathoadaptation of P. aeruginosa previously observed for some strains during development of chronic infection in CF (Bianconi et al, 2015)
Summary
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with a remarkable and threatening ability to thrive and adapt to various ecological niches (Stover et al, 2000). LasB can degrade components of the extracellular matrix, such as elastin, collagen, fibronectin, and mucins and components of the cellular junctions, such as vascular endothelial cadherin, inducing tissue injury, and bacterial dissemination (Golovkine et al, 2014; Flynn et al, 2017; Galdino et al, 2019b). It can alter epithelial integrity and repair efficiency (Ruffin and Brochiero, 2019), favoring the spread of infection. LasB can inactivate components of the complement system, such as C3 (Bastaert et al, 2018), degrade other components of the immune defenses (e.g., interleukin 6 – IL-6; Saint-Criq et al, 2018), and interfere with bacterial killing by alveolar macrophages (Kuang et al, 2011; Bastaert et al, 2018), manipulating the host response to P. aeruginosa
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