Dynorphin activates quorum sensing quinolone signaling in Pseudomonas aeruginosa.
There is now substantial evidence that compounds released during host stress directly activate the virulence of certain opportunistic pathogens. Here, we considered that endogenous opioids might function as such compounds, given that they are among the first signals to be released at multiple tissue sites during host stress. We tested the ability of various opioid compounds to enhance the virulence of Pseudomonas aeruginosa using pyocyanin production as a biological readout, and demonstrated enhanced virulence when P. aeruginosa was exposed to synthetic (U-50,488) and endogenous (dynorphin) kappa-agonists. Using various mutants and reporter strains of P. aeruginosa, we identified involvement of key elements of the quorum sensing circuitry such as the global transcriptional regulator MvfR and the quorum sensing-related quinolone signaling molecules PQS, HHQ, and HQNO that respond to kappa-opioids. The in vivo significance of kappa-opioid signaling of P. aeruginosa was demonstrated in mice by showing that dynorphin is released from the intestinal mucosa following ischemia/reperfusion injury, activates quinolone signaling in P. aeruginosa, and enhances the virulence of P. aeruginosa against Lactobacillus spp. and Caenorhabditis elegans. Taken together, these data demonstrate that P. aeruginosa can intercept opioid compounds released during host stress and integrate them into core elements of quorum sensing circuitry leading to enhanced virulence.
Zaborina
Olga
O
Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Lepine
Francois
F
Xiao
Gaoping
G
Valuckaite
Vesta
V
Chen
Yimei
Y
Li
Terry
T
Ciancio
Mae
M
Zaborin
Alex
A
Petrof
Elaine O
EO
Petroff
Elaine
E
Turner
Jerrold R
JR
Rahme
Laurence G
LG
Chang
Eugene
E
Alverdy
John C
JC
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D011710:Pyocyanine / Q000096:biosynthesis; D015363:Quinolones / Q000378:metabolism*; D053038:Quorum Sensing / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D014774:Virulence
C407944:2-heptyl-3-hydroxy-4-quinolone; D015363:Quinolones; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D011710:Pyocyanine