Pseudomonas aeruginosa adaptation in cystic fibrosis patients increases C5a levels and promotes neutrophil recruitment

Abstract

Cystic fibrosis (CF) disease is characterized by an intense airway inflammatory response mediated by neutrophils and chronic respiratory infections caused by P. aeruginosa . High levels of the complement component C5a, the strongest neutrophil chemoattractant molecule, are commonly found in the CF lung and have been associated with a worsening of the disease. In this study, we investigated how the isolates from CF patients modulate the levels of C5a and identified the bacterial factors involved. We demonstrated that most isolates from airway chronic infections induce the production and accumulation of C5a, an effect attributable to the loss of C5a cleavage by the exoproteases alkaline protease (AprA) and elastase B (LasB). Furthermore, we found that lack of the bacterial protease-dependent C5a degradation is due to mutations in the master regulator LasR. Thus, complementation of a non-C5a-cleaving CF isolate with a functional wild-type LasR restored its ability to express both proteases, cleave C5a and reduce neutrophil recruitment in vitro. These findings suggest that the non-cleaving C5a phenotype acquired by the LasR variants frequently isolated in CF patients may account for the strong neutrophilia and general neutrophil dysfunction predisposing toward increased inflammation and reduced bacterial clearance described in CF patients.

SARS-CoV-2 Spike- and Nucleoprotein-Specific Antibodies Induced After Vaccination or Infection Promote Classical Complement Activation

“…Limiting any inflammation or immunopathology associated with complement activation may be beneficial for maintaining barrier integrity. Nevertheless, significant levels of complement and its breakdown components are found in the respiratory tract after many different infections (58)(59)(60). This means that complement can be activated in the respiratory tract and so in some circumstances may have negative impacts on the host.…”

Immunity of turbot Induced by inactivated vaccine of Aeromonas salmonicida from the perspective of DNA methylation

“…Two immune-related negative regulatory genes, C5ar1-Like and EPX-Like , were screened from the immune-related genes in the combined analysis of DMRs-DEGs. C5a anaphylatoxin as a potent soluble mediator triggered chemotactic inflammation and the innate immune response via effecting inflammatory cell chemotaxis, chemokine release, phagocytosis as well as recruiting neutrophils and macrophages ( 35 , 36 ). As a specific receptor of C5a, C5ar could cause pro-inflammatory activation after specific binding with C5a in grass carp and zebrafish ( 37 , 38 ).…”

Pseudomonas aeruginosa and the Complement System: A Review of the Evasion Strategies

“…It has been reported that, in vitro, LasB cleaves C1q and C3, both in the soluble phase and bound to bacterial surfaces [ 79 , 80 , 81 ]. In addition, LasB inactivates the purified components C5a [ 82 ], C5, C8, and C9 [ 79 ].…”

“…Degradation of the second complement component by AprA inhibits C3b formation and, subsequently, reduces bacterial opsonization, C5a formation, and neutrophil recruitment, allowing the bacteria to elude phagocytes [ 85 ]. Moreover, AprA cleaves C1q [ 80 , 85 ], C3 [ 81 , 85 ], and C5a [ 82 ].…”