H2020Индивидуална стипендия2019–2021

OPTIMISE · Dissecting the molecular pathogenesis of Legionella spp. in human lung models

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-08-01 → 2021-07-31
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Бактериите от вида Legionella и начинът, по който заразяват човешкия белодроб, се анализират чрез тънки срезове от истинска човешка тъкан. Това помага за по-доброто разбиране на механизмите на болестта, тъй като животните и клетъчните модели често не отразяват точно човешката реакция.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Dissecting the molecular pathogenesis of Legionella spp. in human lung models

The Marie Skłodowska Curie Action (MSCA) OPTIMISE “Dissecting the molecular pathogenesis of Legionella spp. in human lung models” aimed to establish human Precision-Cut Lung Slices (hPCLS) as physiologically relevant model to study infection by the human bacterial pathogen Legionella pneumophila and related species. Legionella spp. are environmental bacteria that can infect susceptible individuals and cause a lethal pneumonia known as Legionnaires’ Disease. Aging populations and the increasing use of immune modulatory therapies have given rise to a growing incidence of opportunistic infections caused by pathogens such as Legionella spp.. As for many other infectious diseases, most of our knowledge about the mechanisms driving the outcome of the Legionella-host interaction, originates from studies in cellular and surrogate animal models, which often fail to recapitulate key aspects of human disease. The mechanisms underlying the susceptibility to disease and the virulence of different Legionella isolates in the human lung remain largely elusive. However, as also strikingly highlighted by the current COVID-19 pandemic, understanding disease mechanisms and rapid translation from mechanistic research into new therapies, requires information about the processes occurring in human tissue. The MSCA OPTIMISE aimed to address this gap in knowledge by 1) optimizing the generation of hPCLS, small uniform slices of human lung tissue from donated human lungs, 2) characterizing their viability, architecture and cellular composition and 3) measuring tissue invasion, growth and pathology induced by different Legionella isolates. Hundreds of these slices can be generated from one human lung, allowing comparison of many bacteria or treatments at the same time in the laboratory. The specific objectives of OPTIMISE were to reveal more about the mechanisms driving 1) host-susceptibility to Legionnaire’s Disease and 2) the virulence of different strains of these environmental bacteria by analyzing the response of the whole tissue, but also of individual lung cells to infection with Legionella.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

THE QUEEN'S UNIVERSITY OF BELFAST · BELFASTКоординаторОбединеното кралство