Pathogenèse | EPFL Graph Search

La pathogenèse, pathogénésie ou pathogénie (du grec ancien, pathos, « maladie », et genesis, « origine, création ») désigne le ou les processus responsable(s) du déclenchement et du développement d'une maladie donnée. On l'utilise aussi pour désigner les évènements ayant conduit à l'apparition d'une maladie et le déroulement de cette dernière. Description La pathogenèse peut impliquer les gènes, le mode de vie, l'environnement ainsi que tout autre facteur de risque spécifique à un individu (tant sur le plan physique que psychologique) ou non. L'identification de la pathogenèse d'une maladie insiste donc sur le déroulement et les processus physiopathologiques mis en jeu par l'organisme et le psychisme au cours d'une maladie. Sa valeur médicale demeure centrale pour le clinicien lorsqu'il effectue un diagnostic et surtout un pronostic. En homéopathie, la pathogénésie est l'ensemble des signes (ou symptômes) provoqués par une substance quelconque, dynamisée ou pas, sur plusi

Integrative transcriptome analyses of Transposable Elements (TEs) and genes contribute to a better understanding of colorectal cancer

Eunji Shin

Cancer is the second leading cause of death worldwide. Cancer develops through multiple hallmark functions including apoptosis evasion, unlimited replicative potential, metastasis, and immune avoidance. Over the past few decades, researchers have reported a substantial amount of information about the role of gene expression dysregulation in cancer, whereas transposable elements (TEs) have been overlooked despite the fact they constitute nearly half of the human genome. TEs are DNA repetitive sequences that spread across the genome of living organisms throughout the evolution of species, contributing to genomic diversity and shaping the epigenomic landscape. The vast majority of TEs appear to be transcriptionally silent in adult tissues, thus avoiding deleterious mutational insertions and recombination events in somatic tissues. Due to the global epigenetic dysregulation that occurs during tumorigenesis, some TEs lose repressive marks and become transcriptionally active in cancer cells. Consequently, TE insertions into oncogenes and tumor suppressor genes may occur, thereby contributing to cancer development and disease progression. It is also widely accepted that some TEs harbor transcription factor recognition sites and have regulatory functions on gene expression. Some transcriptionally active TEs can give rise to alternative TE-derived chimeric gene products. Given these facts, integrative transcriptome analysis of TEs and genes may contribute to a better understanding of complex traits of cancer and help to better classify cancer subtypes with clinical implications for patients.To gain insights into the underlying mechanisms of cancer pathogenesis, we constructed a co-expression network based on the similarity in expression levels of TEs and genes. We focused on colorectal cancer (CRC), a heterogeneous disease with different genetic and molecular backgrounds, contributing to patient outcomes and response to therapy. We investigated the coordinated activity of TEs and genes in view of recurrent CRC chromosomal aberrations, genome organization, and functional significance. We further examined co-expression changes in network structure under the contrasting conditions of cancerous versus matched healthy colic mucosal tissues. We found that the cancer network was associated with a dramatic decrease in the number of gene interactions as opposed to an increase in TE interactions. Physical chromosomal distance affects the degree of co-expression, where the proximal distance effect of TE is contrasted with the distant effect of the gene. Our study sheds light on the complex interplay between TEs and genes and how they coordinately shape cancer and normal co-expression networks. Furthermore, we integrated gene and TE expression to develop a new consensus molecular subtype (CMS) classifier derived from multiple layers of TE and gene signatures. We demonstrated that our new approach led to better identification of CRC patients of the former CMS3 subtype, the most heterogeneous subtype with mixed biological characteristics, and a global reduction of the expected misclassification of other CMS subtypes. We further optimized our classifier for potential clinical use and obtained a set of 50 genes and 20 TE integrants with the best ability to identify CMS subtypes. Our integrative model could be a major add on for the development of future clinical trials by improving patient stratification over current gene-restricted molecular classifications.

EPFL2022

Mechanisms protecting host cells against bacterial pore-forming toxins

Francisco De Magalhães Sarmento R De Mesquita

Pore-forming toxins (PFTs) are key virulence determinants produced and secreted by a variety of human bacterial pathogens. They disrupt the plasma membrane (PM) by generating stable protein pores, which allow uncontrolled exchanges between the extracellular and intracellular milieus, dramatically disturbing cellular homeostasis. In recent years, many advances were made regarding the characterization of conserved repair mechanisms that allow eukaryotic cells to recover from mechanical disruption of the PM membrane. However, the specificities of the cell recovery pathways that protect host cells against PFT-induced damage remain remarkably elusive. During bacterial infections, the coordinated action of such cell recovery processes defines the outcome of infected cells and is, thus, critical for our understanding of bacterial pathogenesis. Here, we review the cellular pathways reported to be involved in the response to bacterial PFTs and discuss their impact in single-cell recovery and infection.

SPRINGER BASEL AG2019

Quantitative Single-Cell Analysis of Host-Pathogen Interactions

Matthieu Jean-Hubert Delincé

During infection, microbial pathogens encounter phagocytic cells of the host innate immune system, such as macrophages and neutrophils. These encounters typically lead to uptake and killing of the bacteria by the host cell or, conversely, parasitization of the host cell by the bacteria. Microscopic analysis of these host-microbe interactions is complicated by the fact that phagocytic cells are motile and tend to stray out of the field of view. Most host-pathogen studies have therefore been undertaken at the population level. However, the success of many pathogens likely lies in their ability to generate heterogeneity within the population, facilitating adaptation to every host micro-environment and to environmental perturbations (such as application of an antibiotic). We believe that studying host-pathogen interactions at the single-cell level can reveal not only new mechanisms of pathogenesis but also why current treatments are not always successful. This thesis presents a novel microfluidic device for the long-term co-culturing of phagocytic cells and bacteria within spatially confining microchambers. Each device is patterned with thousands of microchambers, permitting high-throughput fluorescence timelapse microscopy of host-microbe interactions at single-cell resolution. We demonstrate the utility of this approach by co-culturing an established host-cell model, Dictyostelium discoideum, with the extracellular pathogen Klebsiella pneumoniae. We observed that K. pneumoniae is readily taken up and killed by D. discoideum but some events can take ten times as long as others. The capsule, a polysaccharide layer present at the surface at the bacterial cell wall, reduces the phagocytosis efficiency by 1.5 fold, but does not influence the killing time. The opportunistic human pathogen Mycobacterium marinum was then used to study intracellular bacterial virulence. As expected, bacteria could infect host cells, replicate inside, and eventually lyse them. However, surprisingly, in the majority of the infections, the bacteria were actually released from the host, with no apparent harm to either the host or the bacteria. Less frequently, bacteria were even seen being killed. The timing of these events was highly heterogeneous, ranging from a couple of hours to several days. In summary, the tools presented in this thesis provide a new and simple approach for following individual host-microbe interactions at high spatiotemporal resolution from the onset to the end of infections. This work unveiled that the timing and outcome of host-microbe interactions are unexpectedly heterogeneous, which may have important consequences for the bacterial pathogenesis and ultimately for the development of future treatment of microbial infections.