Zinc limitation triggers formation of a distinct subpopulation of Mycobacterium tuberculosis
Allexa Dow, Endrei Marcantonio, Sladjana Prisic
University of Hawaii at Mānoa
While Mycobacterium tuberculosis (Mtb) infect macrophages, they are also found extracellularly in necrotic granulomas. These extracellular bacteria are notoriously difficult to eradicate during treatment, but the reason for this phenomenon is unclear. We hypothesize that zinc ion (Zn2+) limitation is a simple environmental cue that leads to complex physiological changes in the extracellular Mtb. Zn2+ sequestration is a part of the host’s nutritional immunity, which is achieved by accumulation of neutrophil derived protein calprotectin. However, in contrast to many other pathogens, Mtb can overcome this severe Zn2+ limitation. In order to identify changes caused by Zn2+ depletion, we used multi-omics approach and functional assays to compare Zn2+-replete and Zn2+-limited cultures of Mtb. Surprisingly, Zn2+ limitation causes physiological changes that go well beyond Zn2+ conservation. We identified multiple pathways involved in maintenance of redox homeostasis, DNA repair, and carbon/lipid metabolism that are differentially expressed in Zn2+- depleted Mtb. This Mtb subpopulation has extensively remodeled proteome and lipidome, altered utilization of redox cofactors, distinct cell surface morphology, and is more resistant to oxidative stress compared to Zn2+-replete Mtb. Strikingly, Zn2+-limited Mtb trigger a unique transcriptional signature and more killing of macrophages they infect. Together, our findings provide an insight into dramatic physiological changes that may allow survival of Mtb in necrotic granulomas and modulation of the immune response. These unique characteristics of the Zn2+-depleted subpopulation may be essential for development of a more effective TB therapy.