Current genetic studies (e.g. gene knockout) have suggested that EsxA and EsxB function as secreted virulence factors that are essential for Mycobaterium tuberculosis (Mtb) virulence, specifically in mediating phagosome rupture and translocation of Mtb to the cytosol of host cells, which further facilitates Mtb intracellular replicating and cell-to-cell spreading. The EsxA-mediated virulence is presumably achieved by its pH-dependent membrane-permeabilizing activity (MPA). However, the data from recent studies have generated a discrepancy regarding to the role of EsxA MPA in mycobacterial virulence with a major concern that genetic manipulations, such as deletion of esxB-esxA operon, may stimulate genetic compensation to produce artifacts and/or affect other co-dependently secreted factors that could be directly involved cytosolic translocation. To avoid the drawbacks of gene knockout, we first engineered a Mycobacterium marinum (Mm) strain, in which a DAS4+ tag was fused to the C-terminus of EsxB to allow inducible knockdown of EsxB (also EsxA) at the post-translational level. We also engineered a Mm strain by fusing a SpyTag to the C-terminus of EsxA, which allows inhibition of EsxA-ST MPA at the post-secretional level through a covalent linkage to SpyCatcher-GFP. Both post-translational knockdown and post-secretional inhibition of EsxA resulted in attenuation of Mm intracellular survival and virulence in macrophages and lung epithelial cells, which unambiguously confirms the role of EsxA MPA in mycobacterial virulence.
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