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Mycobacterial phosphodiesterase Rv0805 is a virulence determinant and its cyclic nucleotide hydrolytic activity is

James R McDowell1,2, Guangchun Bai1,3, Erica Lasek-Nesselquist1,2

  • 1Wadsworth Center, New York State Department of Health, Albany, New York, USA.

Molecular Microbiology
|February 10, 2023
PubMed

Insights

Mycobacterium tuberculosis phosphodiesterases Rv0805 and Rv1339 impact cyclic AMP (cAMP) levels and bacterial growth. Rv0805 is crucial for growth on specific carbon sources, suggesting a specialized role in propionate metabolism.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclic AMP (cAMP) signaling is vital for Mycobacterium tuberculosis (Mtb) pathogenesis.
  • The specific roles of phosphodiesterases (PDEs) Rv0805 and Rv1339 in cAMP homeostasis and Mtb biology remain largely unknown.

Purpose of the Study:

  • To investigate the functions of Rv0805 and Rv1339 in regulating cAMP levels and influencing Mtb growth and metabolism.
  • To elucidate the distinct roles of Rv0805 and Rv1339 in Mtb pathogenesis.

Main Methods:

  • Growth assays of Mtb and Mycobacterium bovis BCG under various conditions, including different carbon sources.
  • Analysis of intracellular cAMP levels in response to PDE activity.
  • Genetic manipulation of Rv0805 and Rv1339, including gene deletion and ectopic expression.
  • Investigating the impact of mutations in the pta-ackA operon and vitamin B12 supplementation.

Main Results:

  • Rv0805 modulates Mtb growth in vivo, in macrophages, and on host-associated carbon sources.
  • Growth on propionate and glycerol led to high cAMP levels and a dependency on Rv0805 activity.
  • Vitamin B12 or pta-ackA operon mutations restored growth of BCG lacking Rv0805 and normalized cAMP levels.
  • Rv1339 reduced total cAMP but only partially restored growth, whereas Rv0805 complementation fully restored growth.
  • Deletion of an Rv0805 localization domain impaired BCG growth on propionate and glycerol.

Conclusions:

  • Rv0805 likely plays a localized role in hydrolyzing cAMP to regulate a specific pathway involved in propionate metabolism.
  • Rv1339 appears to have a broader function in maintaining overall cellular cAMP homeostasis.
  • Further research is needed to fully understand the biological significance of Rv0805 and Rv1339 in Mtb metabolism, cAMP signaling, and pathogenesis.
Keywords:
TB complex bacteriacAMP signalingcarbon metabolismcyclic nucleotide phosphodiesterase

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