Journal
FRONTIERS IN MICROBIOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2022.867449
Keywords
cholesterol; sphingomyelin; plcH; abscess; dermonecrosis; anti-virulence
Categories
Funding
- Canadian Institutes for Health Research [FDN-154287]
- UBC Killam Professorship
- Swiss National Science Foundation [P2BEP3_165401]
- Cystic Fibrosis Canada postdoctoral fellowship
- Swiss National Science Foundation (SNF) [P2BEP3_165401] Funding Source: Swiss National Science Foundation (SNF)
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Engineered liposomes containing sphingomyelin and cholesterol can effectively neutralize toxins secreted by Gram-negative bacteria Pseudomonas aeruginosa, reducing the cytolytic effects and attenuating the infection in vivo. The liposomes sequester and neutralize the virulence-promoting hemolytic phospholipase C (PlcH), offering a potential therapy to treat complex infections caused by P. aeruginosa and other Gram-negative pathogens expressing PlcH.
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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