Background. The pathogenesis of Mycobacterium tuberculosis largely depends on the secretion of the 6-kD early secreted antigenic target ESAT-6 (EsxA) and the 10-kD culture filtrate protein CFP-10 (EsxB) via the ESX-1/typeVII secretion system. Although gene products from the core RD1 region have been shown to be deeply implicated in this process, less is known about proteins encoded further upstream in the 5′ region of the ESX-1 cluster, such as the ESX-1 secretion–associated proteins (Esps) EspF or EspG₁. Methods. To elucidate the role of EspF/G₁, whose orthologs in Mycobacterium marinum and Mycobacterium smegmatis are reportedly involved in EsxA/B secretion, we constructed 3 M. tuberculosis knockout strains deleted for espF, espG₁ or the segment corresponding to the combined RD1^bcg-RD1^mic region of bacille Calmette-Guérin (BCG) and Mycobacterium microti, which also contains espF and espG₁. Results. Analysis of these strains revealed that, unlike observations with the model organisms M. smegmatis or M. marinum, disruption of espF and espG₁ in M. tuberculosis did not impact the secretion and T cell recognition of EsxA/B but still caused severe attenuation. Conclusions. The separation of the 2 ESX-1–connected phenotypes (ie, EsxA/B secretion and virulence) indicates that EsxA/B secretion is not the only readout for a functional ESX-1 system and suggests that other processes involving EspF/G₁ also play important roles in ESX-1–mediated pathogenicity.

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