Glycine Betaine Uptake by the ProXVWZ ABC Transporter Contributes to the Ability ofMycobacterium tuberculosisTo Initiate Growth in Human Macrophages

Abstract

Mycobacterium tuberculosis maintains a large genetic capacity necessary for growth in different environments during infection and survival upon aerosol transmission to new hosts. Screening for bacterial RNAs produced in response to host interactions produced candidate lists where we noted proXVWZ, annotated as encoding a putative glycine betaine or proline transporter. As high surface-to-volume ratios make bacterial cells particularly vulnerable to changes in water availability, we investigated the contributions of this transporter to the ability of M. tuberculosis to colonize macrophages. An H37Rv proXVWZ mutant was impaired for initial survival and intracellular growth and exhibited reduced growth at elevated medium osmolarity. This defect could be complemented by restoring proXVWZ and was attributable to a failure to accumulate the compatible solute glycine betaine. We then demonstrated that ProXVWZ allows M. tuberculosis to obtain betaine from host macrophages and thereby contributes to early steps in colonizing this niche.

Osmosensory signaling in Mycobacterium tuberculosis mediated by a eukaryotic-like Ser/Thr protein kinase

“…Our focus on osmotic stress was motivated by the fact that Mtb adapts to changes in environmental osmolarity as it transitions between airborne droplet nuclei, mucosal epithelia, alveolar macrophages, necrotic cells, and caseous granulomas (28). Osmotic fluctuations alter turgor pressure, which can impair protein folding and metabolic activity (29).…”

How to manage stress: Lessons from an intracellular pathogen

“…6 Similarly, the uropathogenic E. coli ProP osmoregulatory system is observed to promote growth of this pathogen within human urine and the murine urinary tract, 7 while the expression of the Mycobacterium tuberculosis proXVWZ operon, which encodes a betaine glycine ABC transporter, mediates osmolyte uptake and promotes bacterial replication within infected macrophages. 8 In recent work, Mahmoud et al, report another advance, which points to the importance of osmoregulation during intracellular infection. 1 Following up on an earlier observation with Shigella flexneri, 9 an intracellular gastrointestinal pathogen, the investigators demonstrate that the closely related Shigella sonnei ProU transport system is transcriptionally up-regulated in vitro under hyperosmotic conditions.…”

Pathway of Glycine Betaine Biosynthesis in Aspergillus fumigatus

“…The antistress properties of GB have led to the production of transgenic plants that are able to resist abiotic stress and especially to become tolerant to salt and drought (2). It has also been suggested that the same mechanisms would be responsible for the capacity of many human-pathogenic bacteria, including Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Mycobacterium tuberculosis, to survive and grow in their human host (3)(4)(5)(6)(7). In the majority of biological systems, GB is synthesized by a two-step oxidation reaction: choline is first oxidized to betaine aldehyde (BA), which is later oxidized to yield GB.…”