Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition

Abstract

The Esx secretion pathway is conserved across Gram-positive bacteria. Esx-1, the best-characterized system, is required for virulence of Mycobacterium tuberculosis, although its precise function during infection remains unclear. Esx-3, a paralogous system present in all mycobacterial species, is required for growth in vitro. Here, we demonstrate that mycobacteria lacking Esx-3 are defective in acquiring iron. To compete for the limited iron available in the host and the environment, these organisms use mycobactin, high-affinity iron-binding molecules. In the absence of Esx-3, mycobacteria synthesize mycobactin but are unable to use the bound iron and are impaired severely for growth during macrophage infection. Mycobacteria thus require a specialized secretion system for acquiring iron from siderophores.secretion ͉ siderophore

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

“…However, the uptake of transferrin iron observed in our experiments was rapid with increased cellular iron levels observed within 6 h for M.tb H37Ra and within 1 h for M. smegmatis strains. Crucially, the M. smegmatis Desx-3 strain that is unable to utilize mycobactin 35 retained its ability to acquire transferrin iron to levels comparable with that of the wild-type strain. Siderophore synthesis occurs only after culture in iron-free media.…”

“…GAPDH was also identified in various fractions of M. smegmatis. To assess whether (i) transferrin-mediated uptake exists across mycobacterial species and (ii) whether mycobactin is essential for iron uptake from transferrin, we utilized the M. smegmatis Desx-3 that lacks the esx-3 secretion system and is therefore incapable of mycobactin-mediated iron uptake 35 . M. smegmatis wild-type and M. smegmatis Desx-3 strains demonstrated no difference in binding of transferrin ( Supplementary Fig.…”

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

“…46 However, esxH has been the only antigen of the TB10.4 esx subfamily targeted as a vaccine candidate because it is strongly recognized by BCG-vaccinated individuals and by 70% of TB patients. 23 Nevertheless, we show immunological evidence that simultaneously targeting all members of this subfamily in future vaccine approaches may provide better efficacy against TB.…”

Smegmatis meets tuberculosis

“…3,4 The locus is essential for the growth of M. tuberculosis and the attenuated M. bovis strain used in BCG. 5 The team found that unlike M. tuberculosis and BCG, the more distant relative M. smegmatis could grow normally when esx-3 was deleted, and thus they selected the strain to study the locus' role.In mouse models of M. smegmatis infection, an esx-3-deleted strain was unable to evade the host innate immune system, whereas wildtype and esx-1-deleted strains did not elicit a strong innate immune response. Moreover, the esx-3-deleted strain had attenuated virulence.…”

“…3,4 The locus is essential for the growth of M. tuberculosis and the attenuated M. bovis strain used in BCG. 5 The team found that unlike M. tuberculosis and BCG, the more distant relative M. smegmatis could grow normally when esx-3 was deleted, and thus they selected the strain to study the locus' role.…”