Nitrosative stress inhibits production of the virulence factor alginate in mucoid Pseudomonas aeruginosa.
Alginate is a critical virulence factor contributing to the poor clinical prognosis associated with the conversion of Pseudomonas aeruginosa to mucoid phenotypes in cystic fibrosis (CF). An important mechanism of action is its ability to scavenge host innate-immune reactive species. We have previously analyzed the bacterial response to nitrosative stress by S-nitrosoglutathione (GSNO), a physiological NO radical donor with diminished levels in the CF lung. GSNO substantially increased bacterial nitrosative and oxidative defenses and so we hypothesized a similar increase in alginate production would occur. However, in mucoid P. aeruginosa, there was decreased expression of the majority of alginate synthetic genes. This microarray data was confirmed both by RT-PCR and at the functional level by direct measurements of alginate production. Our data suggest that the lowered levels of innate-immune nitrosative mediators (such as GSNO) in the CF lung exacerbate the effects of mucoid P. aeruginosa, by failing to suppress alginate biosynthesis.
Wood
Simon R
SR
College of Pharmacy, Toxicology Program, Health Sciences Center, University of New Mexico, Albuquerque, NM 87131, USA.
Firoved
Aaron M
AM
Ornatowski
Wojciech
W
Mai
Tricia
T
Deretic
Vojo
V
Timmins
Graham S
GS
D000464:Alginates; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D003550:Cystic Fibrosis / Q000382:microbiology* / Q000473:pathology; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D020723:Glucuronic Acid / Q000096:biosynthesis; D006025:Glycosaminoglycans / Q000378:metabolism*; D006603:Hexuronic Acids; D006801:Humans; D008168:Lung / Q000382:microbiology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D015538:Nitrosation; D020411:Oligonucleotide Array Sequence Analysis; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects
D000464:Alginates; D001426:Bacterial Proteins; D006025:Glycosaminoglycans; D006603:Hexuronic Acids; D020030:Nitric Oxide Donors; C046129:mucoid exopolysaccharide (P aeruginosa); D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D020723:Glucuronic Acid; D052247:Nitric Oxide Synthase Type II