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Les protéines sécrétées par le système de sécrétion de type VII de Mycobacterium abscessus : leur rôle dans la virulence et la réponse de l’hôte

Abstract : Mycobacteria possess type VII secretion systems (T7SS), also known as ESX. Recently, our laboratory has demonstrated that the ESX-4 system of M. abscessus is an essential actor in the intracellular survival of M. abscessus Furthermore, mutation of the gene coding for a structural protein of ESX-4 leads to a decrease in the secretion of several proteins, two belonging to the esx-4 locus, EsxU and EsxT. For this project, we studied the role of EsxU and EsxT proteins in M. abscessus. We first demonstrated the localization of these proteins in M. abscessus, EsxU and EsxT are associated with the bacterial membrane and are also secreted. Furthermore, EsxU and EsxT form a complex characteristic of proteins secreted by mycobacterial T7SS. EsxU and EsxT proteins are able to interact with artificial membranes to form pore-like structures in vitro. In an intramacrophage context, esxU and esxT absence does not influence the intracellular behaviour of the ΔesxUT mutated strain, but prevents the disruption of the phagosomal membrane, keeping M. abscessus ΔesxUT in an unacidified phagosome. Finally, we identify a hypervirulent phenotype associated with ΔesxUT deletion characterized by increased animal mortality and bacterial growth in mice and zebrafish. All our results suggest that the absence of both substrates improves the survival and persistence of M. abscessus in animals. We also wanted to study the immunogenic potential of these proteins. The T cell response to synthetic peptides of the EsxU and EsxT proteins did not identify epitopes that induce a T response. This suggests that EsxU and T are not immunogenic after subcutaneous inoculation of M. abscessus in the mouse model suggesting that EsxU and EsxT are not good markers of infection. The secretome and a bioinformatics analysis based on the search for secretion patterns identified other potential substrates of SST7 in M. abscessus. Two proteins with a proline-glutamate (PE) an d proline-glutamate-glutamate (PPE) motif have peptides that induce a Th1-type immune response. However, further experiments are needed to determine whether these proteins represent good diagnostic targets in patients and whether they are able to discriminate M. abscessus infections from infections caused by other mycobacteria.
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Submitted on : Monday, May 23, 2022 - 8:21:55 AM
Last modification on : Friday, October 14, 2022 - 9:09:54 AM

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  • HAL Id : tel-03675222, version 1

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Marion Lagune. Les protéines sécrétées par le système de sécrétion de type VII de Mycobacterium abscessus : leur rôle dans la virulence et la réponse de l’hôte. Bactériologie. Université Paris-Saclay, 2022. Français. ⟨NNT : 2022UPASL021⟩. ⟨tel-03675222⟩

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