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Infection and Immunity, March 2005, p. 1432-1440, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1432-1440.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

IpaD of Shigella flexneri Is Independently Required for Regulation of Ipa Protein Secretion and Efficient Insertion of IpaB and IpaC into Host Membranes

Wendy L. Picking,1 Hiroaki Nishioka,2 Patricia D. Hearn,1 M. Aaron Baxter,1 Amanda T. Harrington,1 Ariel Blocker,2 and William D. Picking1*

Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas,1 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom2

Received 19 August 2004/ Returned for modification 4 October 2004/ Accepted 19 November 2004

Shigella flexneri causes human dysentery after invading the cells of the colonic epithelium. The best-studied effectors of Shigella entry into colonocytes are the invasion plasmid antigens IpaC and IpaB. These proteins are exported via a type III secretion system (TTSS) to form a pore in the host membrane that may allow the translocation of other effectors into the host cytoplasm. TTSS-mediated secretion of IpaD is also required for translocation pore formation, bacterial invasion, and virulence, but the mechanistic role of this protein is unclear. IpaD is also known to be involved in controlling Ipa protein secretion, but here it is shown that this activity can be separated from its requirement for cellular invasion. Amino acids 40 to 120 of IpaD are not essential for IpaD-dependent invasion; however, deletions in this region still lead to constitutive IpaB/IpaC secretion. Meanwhile, a central deletion causes only a partial loss of control of Ipa secretion but completely eliminates IpaD's invasion function, indicating that IpaD's role in invasion is not a direct outcome of its ability to control Ipa secretion. As shigellae expressing ipaD N-terminal deletion mutations have reduced contact-mediated hemolysis activity and are less efficient at introducing IpaB and IpaC into erythrocyte membranes, it is possible that IpaD is responsible for insertion of IpaB/IpaC pores into target cell membranes. While efficient insertion of IpaB/IpaC pores is needed for optimal invasion efficiency, it may be especially important for Ipa-dependent membrane disruption and thus for efficient vacuolar escape and intercellular spread.

* Corresponding author. Mailing address: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence, KS 66045. Phone: (785) 864-3299. Fax: (785) 864-5294. E-mail: picking{at}ku.edu.

Editor: J. T. Barbieri

Infection and Immunity, March 2005, p. 1432-1440, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1432-1440.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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