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Targeting the Pseudomonas aeruginosa Virulence Factor Phospholipase C With Engineered Liposomes

Authors
  • Wolfmeier, Heidi1, 2
  • Wardell, Samuel J. T.3
  • Liu, Leo T.1
  • Falsafi, Reza1
  • Draeger, Annette4
  • Babiychuk, Eduard B.4
  • Pletzer, Daniel1, 3
  • Hancock, Robert E. W.1
  • 1 Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC , (Canada)
  • 2 Institute of Anatomy and Cell Biology, Paracelsus Medical University, Salzburg , (Austria)
  • 3 Department of Microbiology and Immunology, University of Otago, Dunedin , (New Zealand)
  • 4 Institute of Anatomy, University of Bern, Bern , (Switzerland)
Type
Published Article
Journal
Frontiers in Microbiology
Publisher
Frontiers Media SA
Publication Date
Mar 18, 2022
Volume
13
Identifiers
DOI: 10.3389/fmicb.2022.867449
Source
Frontiers
Keywords
Disciplines
  • Microbiology
  • Original Research
License
Green

Abstract

Engineered liposomes composed of the naturally occurring lipids sphingomyelin (Sm) and cholesterol (Ch) have been demonstrated to efficiently neutralize toxins secreted by Gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus. Here, we hypothesized that liposomes are capable of neutralizing cytolytic virulence factors secreted by the Gram-negative pathogen Pseudomonas aeruginosa. We used the highly virulent cystic fibrosis P. aeruginosa Liverpool Epidemic Strain LESB58 and showed that sphingomyelin (Sm) and a combination of sphingomyelin with cholesterol (Ch:Sm; 66 mol/% Ch and 34 mol/% Sm) liposomes reduced lysis of human bronchial and red blood cells upon challenge with the Pseudomonas secretome. Mass spectrometry of liposome-sequestered Pseudomonas proteins identified the virulence-promoting hemolytic phospholipase C (PlcH) as having been neutralized. Pseudomonas aeruginosa supernatants incubated with liposomes demonstrated reduced PlcH activity as assessed by the p-nitrophenylphosphorylcholine (NPPC) assay. Testing the in vivo efficacy of the liposomes in a murine cutaneous abscess model revealed that Sm and Ch:Sm, as single dose treatments, attenuated abscesses by >30%, demonstrating a similar effect to that of a mutant lacking plcH in this infection model. Thus, sphingomyelin-containing liposome therapy offers an interesting approach to treat and reduce virulence of complex infections caused by P. aeruginosa and potentially other Gram-negative pathogens expressing PlcH.

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