Descripción del proyecto
Dilucidar los procesos moleculares que conducen al desarrollo de la legionelosis neumófila
El envejecimiento de la población y el aumento del uso de inmunomoduladores están provocando una incidencia cada vez mayor de infecciones oportunistas. Las bacterias del género «Legionella», principalmente «L. pneumophila», provocan infecciones respiratorias con una variedad de síntomas que van desde una gripe leve a una neumonía grave, denominada legionelosis neumófila. Los mecanismos moleculares de la susceptibilidad a esta enfermedad son poco conocidos. Para abordar esta carencia, el objetivo del proyecto financiado con fondos europeos OPTIMISE es crear cortes histológicos precisos de tejido pulmonar humano y pulmones humanos enteros perfundidos como modelos de infección por legionela. Se examinará la pertinencia clínica de los modelos, se analizarán las respuestas transcripcionales de las células de los tejidos humanos infectados y se emplearán técnicas de histología y microscopia punteras para observar la dinámica de la infección y las respuestas del hospedador.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
BT7 1NN Belfast
Reino Unido