Project description
Uncovering the molecular events leading to the development of Legionnaires' disease
An ageing population and the increasing use of immunomodulators result in a growing incidence of opportunistic infections. Legionella bacteria, mainly Legionella pneumophila, cause respiratory infections with a range of symptoms from mild flu to severe pneumonia, called Legionnaires' disease. The molecular mechanisms of the susceptibility for the disease are poorly understood. To tackle this, the EU-funded OPTIMISE project aims to establish human precision-cut lung tissue slices and perfused whole human lungs as infection models for Legionella. It will examine the clinical relevance of the models, analyse the transcriptional responses of cells in the infected human tissues, and employ histology and state-of-the-art microscopy to visualise infection dynamics and host responses.
Objective
Aging populations and the increasing use of immune modulatory medical treatments have given rise to a growing incidence of opportunistic infections. Legionella species are Gram-negative environmental bacteria, which after accidental inhalation can cause respiratory infections with symptoms reaching from a mild flu to a severe pneumonia, called Legionnaires’ disease. Disease progression, i.e. clearance or exacerbation of infection, is determined by the immune status of the host and acute pneumonia usually associated with immune suppression and/or underlying pulmonary conditions, but the molecular mechanisms enhancing susceptibility are poorly understood.
The infection biology of Legionella has been studied mostly in cellular infection models and mice, which do not develop human-like disease. As patients typically present only at late stages of infection, it is unclear to which extent findings from these models reflect the early processes which occur in the human lung during infection and how these drive the clinical outcomes. Similarly, these models fail to explain, why L. pneumophila serogroup 1 strains are the predominant cause of more than 90% of Legionnaires’ disease cases.
In this project I, the applicant Dr. Flavia Viana, will tackle these knowledge gaps by establishing and using human precision cut lung tissue slices (hPCLS) and excorporeal perfused whole human lungs (Ex vivo lung perfusion (EVLP)) as infection models for Legionella. I will determine if and how virulence of different Legionella isolates in these models correlates with their relevance in the clinical practice, analyse the transcriptional responses of all cell types in the infected human tissue using single cell transcriptomics and employ histology, state-of-the-art confocal and light sheet live microscopy, to visualise infection dynamics and host responses, providing unprecedented insight into the molecular events leading to the development of Legionnaires’ disease.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
BT7 1NN Belfast
United Kingdom