Abstract
Tuberculosis remains one of the deadliest diseases. Emergence of drug-resistant and multidrug-resistant M. tuberculosis strains makes treating tuberculosis increasingly challenging. In order to develop novel intervention strategies, detailed understanding of the molecular mechanisms behind the success of this pathogen is required. Here, we review recent literature to provide a systems level overview of the molecular and cellular components involved in divalent metal homeostasis and their role in regulating the three main virulence strategies of M. tuberculosis: immune modulation, dormancy and phagosomal rupture. We provide a visual and modular overview of these components and their regulation. Our analysis identified a single regulatory cascade for these three virulence strategies that respond to limited availability of divalent metals in the phagosome.
Highlights
Mycobacterium tuberculosis (Mtb) is the most successful known intracellular pathogen infecting roughly one third of the world population and killing about 1.3 million people in 2017 alone [1]
We review recent literature to provide a systems level overview of the molecular and cellular components involved in divalent metal homeostasis and their role in regulating the three main virulence strategies of M. tuberculosis: immune modulation, dormancy and phagosomal rupture
This was shown in a knockout study of the mmpS4/5 siderophore secretion, which resulted in limited intracellular availability of iron as well as intracellular accumulation of siderophores toxic to Mtb [57]
Summary
Mycobacterium tuberculosis (Mtb) is the most successful known intracellular pathogen infecting roughly one third of the world population and killing about 1.3 million people in 2017 alone [1]. Iron homeostasis is an essential process for bacterial survival, its cellular components are interesting drug targets This was shown in a knockout study of the mmpS4/5 siderophore secretion, which resulted in limited intracellular availability of iron as well as intracellular accumulation of siderophores toxic to Mtb [57]. Six putative IdeR binding sites upstream of the phoP-phoR operon were located, of which five were observed to bind IdeR in the presence of iron [63] This points to a possible link between iron homeostasis and PhoPR regulation of the oxidative stress response and virulence genes. IdeR, FurA, Acn, WhiB7, Lsr and SigE are all involved in the response to the oxidative conditions encountered in the phagosome and subsequent adaption through expression of a vast repertoire of molecules involved in iron homeostasis as well as genes involved in modulation of the immune response
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