Fig. 7: Effects of ESX-3 and ESX-4 depletion on M. abscessus pathogenesis.

Mab possesses two T7SSs, ESX-3 and ESX-4. EccC3 and EccC4 are major membrane components of these machineries and are involved in substrate recognition. Following infection, WT bacilli are internalized in macrophage phagosomes and block fusion with acidic compartments. In these non-acidified compartments, ESX-secreted effectors, such as EsxU/EsxT, contribute to phagosomal membrane damage, allowing Mab to escape the phagosome and enter the cytosol. Here, the bacilli trigger the inflammasome, multiply, disseminate, and induce pathology, ultimately leading to the killing of the infected host. In this study, we show that both single and double eccC mutants most likely fail to block the phagolysosomal fusion process. In these mature phagosomes, ESX-3 and ESX-4 mutants cannot withstand the acidic pH and are eliminated by the macrophage, which can be linked to the incapacity to secrete effectors and/or to the inability to maintain metal homeostasis (for ESX-3). In mice, this translates into highly attenuated strains unable to colonize the lungs, thereby prolonging mice survival.