IAI Accepts, published online ahead of print on 29 June 2009

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Infect. Immun. doi:10.1128/IAI.00409-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Bicarbonate induces Vibrio cholerae virulence gene expression by enhancing ToxT activity

Basel H. Abuaita and Jeffrey H. Withey^*

Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201

^* To whom correspondence should be addressed. Email: jwithey{at}med.wayne.edu.

Vibrio cholerae is a gram negative bacterium that is the causative agent of cholera, a severe diarrheal illness. The two biotypes of V. cholerae O1 capable of causing cholera, classical and El Tor, require different in vitro growth conditions to induce virulence gene expression. Growth under these inducing conditions or infection of a host initiates a complex regulatory cascade that results in production of ToxT, a regulatory protein that directly activates transcription of the genes encoding cholera toxin (CT), toxin co-regulated pilus (TCP), and other virulence genes. Previous studies have shown that sodium bicarbonate induces CT expression in the V. cholerae El Tor biotype. However, the mechanism for bicarbonate-mediated CT induction has not been defined. In this study, we demonstrate that bicarbonate stimulates virulence gene expression by enhancing ToxT activity. Both classical and El Tor biotypes produce inactive ToxT protein when cultured statically in the absence of bicarbonate. Addition of bicarbonate to culture medium does not affect ToxT production but causes a significant increase in CT and TCP expression in both biotypes. Ethoxyzolamide, a potent carbonic anhydrase inhibitor, inhibits bicarbonate- mediated virulence induction, suggesting that conversion of CO₂ into bicarbonate by carbonic anhydrase plays a role in virulence induction. Thus, bicarbonate is the first positive effector for ToxT activity to be identified. Given that bicarbonate is present at high concentration in the upper small intestine where V. cholerae colonizes, bicarbonate is likely an important chemical stimulus that V. cholerae senses to induce virulence during the natural course of infection.

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