using-mycobacterium-smegmatis-as-bioindicator-for-zinc-limited-growth

Using <i>Mycobacterium smegmatis</i> as a Bioindicator for Zinc-Limited Growth Conditions in Mycobacteria

Many bacteria build alternative ribosomes in Zn2+-limiting growth conditions by replacing Zn2+-binding ribosomal proteins with Zn2+-independent paralogs. ...

University of Hawaiʻi at Mānoa

Mycobacterium tuberculosis (Mtb) has complex and dynamic interactions with the human host, and subpopulations of Mtb that emerge during infection can influence disease outcomes. This study implicates zinc ion (Zn2+) availability as a likely driver of bacterial phenotypic heterogeneity in vivo. Zn2+ sequestration is part of "nutritional immunity", where the immune system limits micronutrients to control pathogen growth, but this defense mechanism seems to be ineffective in controlling Mtb infection. Nonetheless, Zn2+-limitation is an environmental cue sensed by Mtb, as calprotectin triggers the zinc uptake regulator (Zur) regulon response in vitro and co-localizes with Zn2+-limited Mtb in vivo. Prolonged Zn2+ limitation leads to numerous physiological changes in vitro, including differential expression of certain antigens, alterations in lipid metabolism and distinct cell surface morphology. Furthermore, Mtb enduring limited Zn2+ employ defensive measures to fight oxidative stress, by increasing expression of proteins involved in DNA repair and antioxidant activity, including well described virulence factors KatG and AhpC, along with altered utilization of redox cofactors. Here, we propose a model in which prolonged Zn2+ limitation defines a population of Mtb with anticipatory adaptations against impending immune attack, based on the evidence that Zn2+-limited Mtb are more resistant to oxidative stress and exhibit increased survival and induce more severe pulmonary granulomas in mice. Considering that extracellular Mtb may transit through the Zn2+-limited caseum before infecting naïve immune cells or upon host-to-host transmission, the resulting phenotypic heterogeneity driven by varied Zn2+ availability likely plays a key role during early interactions with host cells.

Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis.

Zinc ion (Zn) is an essential micronutrient and a potent antioxidant. However, Zn is often limited in the environment. Upon Zn limitation,  (basonym: )  undergoes a morphogenesis, which relies on alternative ribosomal proteins (AltRPs); i.e., Zn-independent paralogues of Zn-dependent ribosomal proteins. However, the underlying physiological changes triggered by Zn limitation and how AltRPs contribute to these changes were not known. In this study, we expand the knowledge of mechanisms utilized by  to endure Zn limitation, by comparing the transcriptomes and proteomes of Zn-limited and Zn-replete . We further compare, corroborate and contrast our results to those reported for the pathogenic mycobacterium, , which highlighted conservation of the upregulated oxidative stress response when Zn is limited in both mycobacteria. By comparing the multi-omics analysis of a knockout mutant lacking AltRPs (Δ) to the  wild type strain, we specify the involvement of AltRPs in the response to Zn limitation. Our results show that AltRP expression in  does not affect the conserved oxidative stress response during Zn limitation observed in mycobacteria, but AltRPs do significantly impact expression patterns of numerous genes that may be involved in morphogenesis or other adaptive responses. We conclude that AltRPs are not only important as functional replacements for their Zn-dependent paralogues; they are also involved in the transcriptomic response to the Zn-limited environment.

Article	Year
Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis. PLoS pathogens\| PubMed ID: 33989345	2021
Multi-Omics Profiling Specifies Involvement of Alternative Ribosomal Proteins in Response to Zinc Limitation in . Frontiers in microbiology\| PubMed ID: 35222334	2022

Endrei Marcantonio

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