Pseudomonas Aeruginosa Theft Biofilm Require Host Lipids of Cutaneous Wound
Mithun Sinha1, Nandini Ghosh1, Dayanjan S Wijesinghe2
1Indiana Center for Regenerative Medicine and Engineering, Department, of Surgery, IU Heath Comprehensive Wound Center, Indiana University, School of Medicine, Indianapolis, IN.
Objective:
This work addressing complexities in wound infection, seeks to test the reliance of bacterial pathogen Pseudomonas aeruginosa (PA) on host skin lipids to form biofilm with pathological consequences.
Background:
PA biofilm causes wound chronicity. Both CDC as well as NIH recognizes biofilm infection as a threat leading to wound chronicity. Chronic wounds on lower extremities often lead to surgical limb amputation.
Methods:
An established preclinical porcine chronic wound biofilm model, infected with PA or Pseudomonas aeruginosa ceramidase mutant (PA ∆Cer ), was used.
Results:
We observed that bacteria drew resource from host lipids to induce PA ceramidase expression by three orders of magnitude. PA utilized product of host ceramide catabolism to augment transcription of PA ceramidase. Biofilm formation was more robust in PA compared to PA ∆Cer . Downstream products of such metabolism such as sphingosine and sphingosine-1-phosphate were both directly implicated in the induction of ceramidase and inhibition of peroxisome proliferator-activated receptor (PPAR)δ, respectively. PA biofilm, in a ceram-idastin-sensitive manner, also silenced PPARδ via induction of miR-106b. Low PPARδ limited ABCA12 expression resulting in disruption of skin lipid homeostasis. Barrier function of the wound-site was thus compromised.
Conclusions:
This work demonstrates that microbial pathogens must co-opt host skin lipids to unleash biofilm pathogenicity. Anti-biofilm strategies must not necessarily always target the microbe and targeting host lipids at risk of infection could be productive. This work may be viewed as a first step, laying fundamental mechanistic groundwork, toward a paradigm change in biofilm management.
Insights
Pseudomonas aeruginosa (PA) exploits host skin lipids for biofilm formation, a key factor in chronic wound development. Targeting host lipids, not just the microbe, may offer new anti-biofilm strategies.
Area of Science:
- Microbiology
- Dermatology
- Wound Healing Research
Background:
- Bacterial biofilm infections, particularly by Pseudomonas aeruginosa (PA), are recognized by the CDC and NIH as major contributors to chronic wound development.
- Chronic wounds, often on lower extremities, can lead to severe outcomes such as limb amputation.
- Understanding the mechanisms of PA biofilm formation is critical for developing effective wound management strategies.
Purpose of the Study:
- To investigate the reliance of Pseudomonas aeruginosa (PA) on host skin lipids for biofilm formation and its pathological consequences in wound infections.
- To elucidate the molecular mechanisms by which PA co-opts host lipids to promote biofilm development and pathogenicity.
Main Methods:
- Utilized a preclinical porcine chronic wound biofilm model infected with PA and a PA ceramidase mutant (PA ∆Cer).
- Analyzed bacterial utilization of host lipids and its impact on PA ceramidase expression and biofilm formation.
- Investigated the role of downstream lipid metabolites and microRNAs in regulating host pathways like PPARδ.
Main Results:
- PA significantly upregulated its ceramidase expression by utilizing host ceramide catabolism products.
- Biofilm formation was more robust in PA compared to the PA ∆Cer mutant.
- PA biofilm induced ceramidase expression and silenced PPARδ via miR-106b, disrupting skin lipid homeostasis and barrier function.
Conclusions:
- Microbial pathogens like PA hijack host skin lipids to drive biofilm pathogenicity.
- Anti-biofilm strategies could be enhanced by targeting host lipid pathways, in addition to or instead of directly targeting the microbe.
- This research provides fundamental mechanistic insights for a paradigm shift in biofilm management for chronic wounds.
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