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Infect. Immun. doi:10.1128/IAI.01337-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of Cyclic Di-GMP During El Tor biotype Vibrio cholerae Infection: Characterization of the In Vivo Induced Cyclic Di-GMP Phosphodiesterase CdpA

Howard Hughes Medical Institute and the Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, U.S.A.

^* To whom correspondence should be addressed. Email: andrew.camilli{at}tufts.edu.

	Abstract

In Vibrio cholerae, the second messenger cyclic di-GMP (c-di-GMP) positively regulates biofilm formation and negatively regulates virulence and is proposed to play an important role in the transition from persistence in the environment to survival in the host. Herein we describe a characterization of the infection-induced gene cdpA, which encodes both GGDEF and EAL domains known to mediate diguanylate cyclase (DGC) and c-di-GMP phosphodiesterase (PDE) activities, respectively. CdpA is shown to possess PDE activity, and this activity is regulated by its inactive degenerate GGDEF domain. CdpA inhibits biofilm formation but has no effect on colonization of the infant mouse small intestine. Consistent with these observations, cdpA is expressed during in vitro growth in a biofilm but is not expressed in vivo until the late stage of infection, after colonization has occurred. To test for a role of c-di-GMP in the early stages of infection, we artificially increased c-di-GMP and observed reduced colonization. This was attributed to a significant reduction in toxT transcription during infection. Cumulatively, these results support a model of the V. cholerae lifecycle in which c-di-GMP must be down-regulated early after entering the small intestine and maintained at a low level to allow virulence gene expression, colonization and motility at appropriate stages of infection.