Pseudomonas aeruginosaLasB protease impairs innate immunity in mice and humans by targeting a lung epithelial cystic fibrosis transmembrane regulator–IL-6–antimicrobial–repair pathway

Abstract

Background Pseudomonas aeruginosa lung infections are a huge problem in ventilator-associated pneumonia, cystic fibrosis (CF) and in chronic obstructive pulmonary disease (COPD) exacerbations. This bacterium secretes virulence factors that may subvert host innate immunity.ObjectiveWe evaluated the effect of P. aeruginosa elastase LasB, an important virulence factor secreted by the type II secretion system, on ion transport, innate immune responses and epithelial repair, both in vitro and in vivo.MethodsWild-type (WT) or cystic fibrosis transmembrane conductance regulator (CFTR)-mutated epithelial cells (cell lines and primary cells from patients) were treated with WT or ΔLasB pseudomonas aeruginosa O1 (PAO1) secretomes. The effect of LasB and PAO1 infection was also assessed in vivo in murine models.ResultsWe showed that LasB was the most abundant protein in WT PAO1 secretomes and that it decreased epithelial CFTR expression and activity. In airway epithelial cell lines and primary bronchial epithelial cells, LasB degraded the immune mediators interleukin (IL)-6 and trappin-2, an important epithelial-derived antimicrobial molecule. We further showed that an IL-6/STAT3 signalling pathway was downregulated by LasB, resulting in inhibition of epithelial cell repair. In mice, intranasally instillated LasB induced significant weight loss, inflammation, injury and death. By contrast, we showed that overexpression of IL-6 and trappin-2 protected mice against WT-PAO1-induced death, by upregulating IL-17/IL-22 antimicrobial and repair pathways.ConclusionsOur data demonstrate that PAO1 LasB is a major P. aeruginosa secreted factor that modulates ion transport, immune response and tissue repair. Targeting this virulence factor or upregulating protective factors such as IL-6 or antimicrobial molecules such as trappin-2 could be beneficial in P. aeruginosa-infected individuals.

Cladodionen Is a Potential Quorum Sensing Inhibitor Against Pseudomonas aeruginosa

“…Elastase is the most abundant protein in P. aeruginosa secretomes; it modulates ion transport, immune response and tissue repair. The genes coding for the synthesis of elastase are regulated by the las system [6,20]. The production of elastase decreased in a dose dependent manner when the bacterial cultures were incubated with cladodionen at 100-400 μM ( Figure 3A).…”

MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3

“…For instance, TNFa, induced by the recruited monocytes, was required for the production of IL-17, macrophage phagocytosis, and bacterial clearance, and hence recovery from pneumonia (Xiong et al, 2016). Likewise, IL-6 exhibited the ability to promote IL-17/IL-22-mediated anti-microbial responses through stimulating STAT3 signaling (Saint-Criq et al, 2018). The defective production of IL-6, induced by pathogenic component LasB of Pseudomonas aeruginosa, resulted in defective STAT3 activation and compromised anti-bacterial reactivity.…”

Review of the British Thoracic Society Winter Meeting 2018, 5–7 December 2018, London, UK

“…Four notable studies published in Thorax were showcased at this year's symposium. Dr Jean-Michel Sallenave's group (Paris, France) highlighted that Pseudomonas aeruginosa elastase LasB is a secreted virulence factor that can downregulate CFTR and degrade anti-bacterial immune mediators IL-6 and Trappin-2, important epithelial derived antimicrobial factors 6 . Intranasal administration of LasB in mice also induced inflammation, weight loss and death, effects that were rescued by overexpression of IL6 and Trappin2.…”