Year: 2022
Type: article
Abstract: ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.
Source: PLoS Pathogens
Institutions: Inserm, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Infection et inflammation, Centre National de la Recherche Scientifique, Université de Montpellier, Institut de Recherche en Infectiologie de Montpellier, Research Center Borstel - Leibniz Lung Center, European Molecular Biology Laboratory, European Molecular Biology Laboratory, University Medical Center Hamburg-Eppendorf, Hôpital Raymond-Poincaré
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,659
Awards: G102179115, G2337407410, G2465067033, G434337789, G4463643225, G7240651115, G7376787254, From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow, Structure/function of a prototypic type VII secretion system from a fast-growing pathogenic mycobacteria
OpenAlex ID: W4290852192