Document Type

Article

Publication Date

2017

DOI

10.1128/IAI.00347-17

Publication Title

Infection and Immunity

Volume

85

Issue

9 (Article e 00347)

Pages

1-17

Abstract

The signaling molecule cyclic diguanylate (c-di-GMP) mediates physiological adaptation to extracellular stimuli in a wide range of bacteria. The complex metabolic pathways governing c-di-GMP synthesis and degradation are highly regulated, but the specific cues that impact c-di-GMP signaling are largely unknown. In the intestinal pathogen Clostridium difficile, c-di-GMP inhibits flagellar motility and toxin production and promotes pilus-dependent biofilm formation, but no specific biological functions have been ascribed to any of the individual c-di-GMP synthases or phosphodiesterases (PDEs). Here, we report the functional and biochemical characterization of a c-di-GMP PDE, PdcA, 1 of 37 confirmed or putative c-di-GMP metabolism proteins in C. difficile 630. Our studies reveal that pdcA transcription is controlled by the nutrient-regulated transcriptional regulator CodY and accordingly increases during stationary phase. In addition, PdcA PDE activity is allosterically regulated by GTP, further linking c-di-GMP levels to nutrient availability. Mutation of pdcA increased biofilm formation and reduced toxin biosynthesis without affecting swimming motility or global intracellular c-di-GMP. Analysis of the transcriptional response to pdcA mutation indicates that PdcA-dependent phenotypes manifest during stationary phase, consistent with regulation by CodY. These results demonstrate that inactivation of this single PDE gene is sufficient to impact multiple c-di-GMP-dependent phenotypes, including the production of major virulence factors, and suggest a link between c-di-GMP signaling and nutrient availability.

Comments

"ASM grants authors the right to post their accepted manuscripts in publicly accessible electronic repositories maintained by funding agencies, as well as appropriate institutional or subject-based open repositories established by a government or non-commercial entity."

Original Publication Citation

Purcell, E. B., McKee, R. W., Courson, D. S., Garrett, E. M., McBride, S. M., Cheney, R. E., & Tamayo, R. (2017). A nutrient-regulated cyclic diguanylate phosphodiesterase controls Clostridium difficile biofilm and toxin production during stationary phase. Infection and Immunity, 85(9 (Article e00347)), 1-17. doi:10.1128/IAI.00347-17

ORCID

0000-0002-3745-3316 (Rita Tamayo)

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