oprC Impairs Host Defense by Increasing the Quorum-Sensing-Mediated Virulence of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa, found widely in the wild, causes infections in the lungs and several other organs in healthy people but more often in immunocompromised individuals. P. aeruginosa infection leads to inflammasome assembly, pyroptosis, and cytokine release in the host. OprC is one of the bacterial porins abundant in the outer membrane vesicles responsible for channel-forming and copper binding. Recent research has revealed that OprC transports copper, an essential trace element involved in various physiological processes, into bacteria during copper deficiency. Here, we found that oprC deletion severely impaired bacterial motility and quorum-sensing systems, as well as lowered levels of lipopolysaccharide and pyocyanin in P. aeruginosa. In addition, oprC deficiency impeded the stimulation of TLR2 and TLR4 and inflammasome activation, resulting in decreases in proinflammatory cytokines and improved disease phenotypes, such as attenuated bacterial loads, lowered lung barrier damage, and longer mouse survival. Moreover, oprC deficiency significantly alleviated pyroptosis in macrophages. Mechanistically, oprC gene may impact quorum-sensing systems in P. aeruginosa to alter pyroptosis and inflammatory responses in cells and mice through the STAT3/NF-κB signaling pathway. Our findings characterize OprC as a critical virulence regulator, providing the groundwork for further dissection of the pathogenic mechanism of OprC as a potential therapeutic target of P. aeruginosa.

Transcriptomic Analysis of Pseudomonas aeruginosa Response to Pine Honey via RNA Sequencing Indicates Multiple Mechanisms of Antibacterial Activity

“…In contrast, the genes mexF and E , encoding putative RND efflux transporter and RND efflux membrane fusion protein precursor, were up-regulated (log 2 FC, 2.25 and 2.42, respectively). OprC is a porin abundant in the outer membrane vesicles involved in channel-forming and copper binding [ 62 ]. OprC transports copper, an essential trace element implicated in several physiological processes, into bacteria during copper deficiency.…”

“…In a very recent study the authors showed that oprC deletion inhibited bacterial motility and quorum-sensing systems, as well as decreased lipopolysaccharide and pyocyanin levels in P . aeruginosa [ 62 ]. Interestingly, a previous study has shown that manuka honey decreased pyocyanin production in P .…”

Host cystathionine-γ lyase derived hydrogen sulfide protects against Pseudomonas aeruginosa sepsis

“…However, the exact mechanism by which H 2 S regulates the expression of the quorum sensing genes of P. aeruginosa still remains unclear. AHLs have been shown to reduce the activation of the nuclear factor-kappa β (NF-κΒ) pathway, which in term leads to a deficient innate immune response [45,46]. On the contrary, H 2 S produced by CSE has been found to up-regulate the expression and actions of NF-κΒ, through sulfhydration [47].…”

Acquisition of ionic copper by a bacterial outer membrane protein

“…In this model, bacterial virulence would be attenuated by mutations, particularly in transporters, that cause copper sensitivity (49). However, recent data suggest that deletion of oprC results in reduced quorum sensing, impaired motility and lower virulence of P. aeruginosa, leading to the proposal that the presence of OprC is critical for virulence (36). In addition, another recent study reported decreased virulence of an A. baumannii oprC knockout (37).…”

“…A recent study (36) suggested that OprC increases the virulence of P. aeruginosa, but did not provide a measure of the abundance of the transporter in vivo. To determine the abundance of OprC in P. aeruginosa UCBPP-PA14 and Acinetobacter baumannii ATCC 19606 in infected lung tissues, we employed a sensitive targeted proteomics approach with parallel reaction monitoring, with absolute quantification using heavy-isotope labeled reference peptides (Methods).…”