Roles of cyclic diguanylate in the regulation of bacterial pathogenesis

Abstract

Cyclic diguanylate (c-di-GMP) is a bacterial second messenger of growing recognition involved in the regulation of a number of complex physiological processes. This review describes the biosynthesis and hydrolysis of c-di-GMP and several mechanisms of regulation of c-di-GMP metabolism. The contribution of c-di-GMP to regulating biofilm formation and motility, processes that affect pathogenesis of many bacteria, is described, as is c-di-GMP regulation of virulence gene expression. Finally, ways in which c-di-GMP may mediate these regulatory effects are proposed.

Figure 1

c-di-GMP regulatory pathway. c-di-GMP is synthesized from two GTPs by GGDEF domain DGCs. c-di-GMP is hydrolyzed by EAL domain PDEAs into the linear pGpG before being hydrolyzed by other PDEs into two GMPs. HD-GYP domain PDEs hydrolyze c-di-GMP completely into two GMPs. Numerous studies have shown that c-di-GMP activates EPS production and biofilm formation but inhibits motility and virulence. These processes are regulated by c-di-GMP through a variety of pathways, as discussed in the text. PilZ domain proteins are one class of c-di-GMP sensor, although others likely exist. The mechanism(s) by which PilZ domain proteins transduce changes in c-di-GMP into downstream physiological effects is unknown.

Figure 2

(a) Model of the role of c-di-GMP in the transition of V. cholerae from persistence in aquatic reservoirs to survival in the human host. c-di-GMP is predicted to be high in V. cholerae existing in biofilms attached to biotic and abiotic surfaces in the pond environment. Upon entry into the human host, induction of PDE and/or repression of DGC activities can lower c-di-GMP and allow dispersion from the biofilm and maximal expression of virulence genes. Conversely, c-di-GMP must be elevated once again through activation of DGC and/or repression of PDE to resume the biofilm lifestyle. There is evidence that c-di-GMP may begin to be elevated during the later stage of V. cholerae infection, potentially giving the bacteria an advantage once they have exited the host. (b) The VieSA signal transduction system provides one mechanism by which V. cholerae can lower c-di-GMP concentration in the small intestine. An unknown extracellular signal present in the small intestine activates the VieS sensor, leading to autophosphorylation of VieS and phosphotransfer to the dual-function protein VieA. The phosphorylated, activated VieA autoactivates vieSA transcription, resulting in higher VieA PDEA in the cell, reduced c-di-GMP, and full expression of virulence factors.