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A Porcine Ex Vivo Lung Perfusion Model To Investigate Bacterial Pathogenesis
Amy Dumigan1, Marianne Fitzgerald1, Joana Sá-Pessoa Graca Santos1
1Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
Mbio
|December 5, 2019
Summary
A novel ex vivo lung perfusion (EVLP) model using pig lungs effectively mimics Klebsiella pneumoniae pneumonia, offering a better preclinical model for respiratory infections than traditional methods.
Area of Science:
- Infectious Diseases
- Pulmonology
- Microbial Pathogenesis
Background:
- Current animal models for studying respiratory infections, such as rodents, often fail to accurately predict human outcomes due to physiological differences.
- Alternative models like insects and 2D/3D tissue cultures are being explored but raise concerns about recapitulating complex host-pathogen interactions.
- There is a critical need for advanced preclinical models that better approximate human respiratory disease for understanding infections and testing therapeutics.
Purpose of the Study:
- To develop and validate an ex vivo lung perfusion (EVLP) model using porcine lungs to study Klebsiella pneumoniae-induced pneumonia.
- To assess the utility of the porcine EVLP model in recapitulating key features of pneumonia, including lung injury and inflammatory responses.
- To evaluate the model's capability in characterizing pathogen virulence and host immune cell modulation at a single-cell level.
Main Methods:
- Developed a porcine ex vivo lung perfusion (EVLP) model.
- Infected porcine lungs with wild-type and a capsule mutant strain of Klebsiella pneumoniae.
- Analyzed lung injury, bacterial burden, inflammatory markers (IL-10, IFN-γ), and macrophage polarization (STAT6, p38, ERK signaling) in vitro and in vivo.
Main Results:
- The porcine EVLP model successfully recapitulated features of K. pneumoniae-induced pneumonia, including lung injury and inflammatory responses.
- The attenuated capsule mutant strain caused less damage and bacterial burden compared to the wild type, demonstrating the model's ability to assess virulence.
- Wild-type K. pneumoniae induced M2-like macrophage polarization, dependent on the capsule, with IL-10 production regulated by p38 and ERK signaling.
Conclusions:
- The porcine EVLP model serves as a valuable platform for investigating the infection biology of respiratory pathogens like K. pneumoniae.
- This model effectively mimics host-pathogen interactions and immune responses, offering a more relevant alternative to traditional animal models.
- The findings support the utility of the porcine EVLP model for preclinical assessment of respiratory infections and potential therapeutic interventions.
