Hemolytic phospholipase C inhibition protects lung function during Pseudomonas aeruginosa infection

Matthew J Wargo1, Maegan J Gross, Sathish Rajamani

  • 1Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT 05405, USA. Matthew.Wargo@med.uvm.edu

Abstract

Insights

Pseudomonas aeruginosa PlcHR damages lung function by impairing surfactant. The drug miltefosine inhibits PlcHR, protecting lung function during P. aeruginosa infection.

Area of Science:

  • Microbiology
  • Pulmonary Physiology
  • Pharmacology

Background:

  • Pseudomonas aeruginosa is an opportunistic pathogen causing severe lung infections, especially in cystic fibrosis patients.
  • P. aeruginosa virulence factors significantly contribute to lung function decline, increasing morbidity and mortality.
  • Understanding specific bacterial factors and their impact on host physiology is crucial for developing effective treatments.

Purpose of the Study:

  • To elucidate the direct role of the phospholipase C/sphingomyelinase, PlcHR, in altering lung physiology during P. aeruginosa infection.
  • To evaluate miltefosine as a potential therapeutic agent to protect lung function against PlcHR-mediated damage.

Main Methods:

  • Mice were infected with wild-type or ΔplcHR P. aeruginosa strains.
  • Lung function was assessed using computer-controlled mechanical ventilation.
  • Miltefosine was administered intraperitoneally post-infection to evaluate its protective effects.

Main Results:

  • P. aeruginosa wild-type infection severely impaired lung function, while the ΔplcHR strain caused significantly less damage.
  • PlcHR was shown to reduce pulmonary surfactant function in bronchoalveolar lavage fluid.
  • Miltefosine inhibited PlcHR's lipid cleavage activity in vitro and protected lung function in vivo.

Conclusions:

  • This study directly links the P. aeruginosa virulence factor PlcHR to impaired lung function.
  • Miltefosine effectively protects lung function by inhibiting PlcHR-dependent surfactant dysfunction.

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