Iron homeostasis in Mycobacterium tuberculosis is essential for persistence

Abstract

Tuberculosis, caused by the obligate intracellular pathogen Mycobacterium tuberculosis (Mtb), is responsible for 2–3 million deaths annually worldwide. Intracellular adaptability, which is critical for long-term persistence, requires the pathogen to neutralize host-mediated insults. The iron–sulphur (Fe–S) cofactor is essential for many enzymes critical for such ‘adaptation’. The Mtb genome harbors only one putative iron–sulphur cluster (ISC) operon (rv1460-66) predicted to be involved in the generation of the Fe–S cofactor. Except for rv1460, all other genes in this operon are anticipated to be essential. The current study investigated the role of rv1460, an sufR homologue of Mtb (sufRTB), in maintaining intracellular Fe homeostasis and its implications on mycobacterial pathogenesis. We found that Mtb ISC locus (rv1461–66) was transcribed as a single multigene transcript. We successfully generated the sufRTB null mutant strain (ΔsufRTB) of Mtb, suggesting nonessentiality of the gene under normal growth conditions. The mutant strain demonstrated enhanced biofilm generation and failed to grow under a low-Fe condition. Growth characterization studies indicated that SufRTB-mediated intracellular Fe homeostasis is essential for Mtb to persist in the host. Targeting mycobacterial persistence by inhibiting SufRTB protein activity may be a novel intervention strategy in tuberculosis treatment.

Population genomics provides insights into the evolution and adaptation to humans of the waterborne pathogen Mycobacterium kansasii

“…Two additional genes that encode the iron-dependent repressor (IdeR) and the subunit B of the SUF system (SufB) for Fe–S cluster biosynthesis also showed evidence of potential positive selection. Mutations in these genes may augment the ability of the bacilli to maintain iron homeostasis in the iron-limited environment encountered during infection 58 , 61 (Supplementary Fig. 16 ).…”

Cellular responses to reactive oxygen species are predicted from molecular mechanisms

“…In principle, switching from ISC to SUF is not the only mechanism for sustaining Fe-S assembly under ROS stress. For example, Mycobacterium tuberculosis possesses only the ISC operon, yet this pathogen is able to grow under oxidative stress including inside macrophages, presumably by up-regulating its ISC operon (32). A possible explanation is that M. tuberculosis's ISC scaffold proteins are less sensitive to ROS than those in E. coli or are repaired.…”

Mycobacterium tuberculosisSufR Responds to Nitric oxide via its 4Fe-4S cluster and Regulates Fe-S cluster Biogenesis for Persistence in Mice

“…These observations prompted us to investigate the NO-dependent phenotype of Mtb Δ sufR in vivo . Previous studies have reported the requirement of SufR for persistence of Mtb in mice [22, 53]. However, it remains to be addressed if SufR coordinates pathogen’s persistence in response to NO.…”