ironjustice

Infection and Immunity, July 2007, p. 3478-3489, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.00023-07
Copyright © 2007, American Society for Microbiology. All Rights
Reserved.

Reversal of the Antichlamydial Activity of Putative Type III Secretion
Inhibitors by Iron
Anatoly Slepenkin,1 Per-Anders Enquist,2 Ulrik Hägglund,3 Luis M. de
la Maza,1 Mikael Elofsson,2 and Ellena M. Peterson1*
Department of Pathology and Laboratory Medicine, University of
California, Irvine, California,1 Department of Chemistry, Umea
University, SE-90187 Umea, Sweden,2 Innate Pharmaceuticals AB, Umestan
Foretagspark, SE-90347 Umea, Sweden3

Received 5 January 2007/ Returned for modification 30 January 2007/
Accepted 12 April 2007

INPs, which are chemically synthesized compounds belonging to a class
of acylated hydrazones of salicylaldehydes, can inhibit the growth of
Chlamydiaceae. Evidence has been presented that in Yersinia and
Chlamydia INPs may affect the type III secretion (T3S) system. In the
present study 25 INPs were screened for antichlamydial activity at a
concentration of 50 µM, and 14 were able to completely inhibit the
growth of Chlamydia trachomatis serovar D in McCoy and HeLa 229 cells.
The antichlamydial activities of two of these INPs, INPs 0341 and
0400, were further characterized due to their low cytotoxicity. These
compounds were found to inhibit C. trachomatis in a dose-dependent
manner; were not toxic to elementary bodies; were cidal at a
concentration of 20 µM; inhibited all Chlamydiaceae tested; and could
inhibit the development of C. trachomatis as determined by the yield
of progeny when they were added up to 24 h postinfection. INP 0341 was
able to affect the expression of several T3S genes. Compared to the
expression in control cultures, lcrH-1, copB, and incA, all middle- to
late-expressed T3S genes, were not expressed in the INP 0341-treated
cultures 24 to 36 h postinfection. Iron, supplied as ferrous sulfate,
as ferric chloride, or as holo-transferrin, was able to negate the
antichlamydial properties of the INPs. In contrast, apo-transferrin
and other divalent metal ions tested were not able to reverse the
inhibitory effect of the INPs. In conclusion, the potent
antichlamydial activity of INPs is directly or indirectly linked with
iron, and this inhibition of Chlamydia has an effect on the T3S system
of this intracellular pathogen.

--------------------------------------------------------------------------------
* Corresponding author. Mailing address: Department of Pathology and
Laboratory Medicine, Medical Science Building, Room D-440, University
of California, Irvine, Irvine, CA 92697-4800. Phone: (949) 824-4169.
Fax: (949) 824-2160. E-mail: epeterso@uci.edu

Published ahead of print on 30 April 2007.

Editor: R. P. Morrison

--------------------------------------------------------------------------------
Infection and Immunity, July 2007, p. 3478-3489, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.00023-07
Copyright © 2007, American Society for Microbiology. All Rights
Reserved.

Infection and Immunity, July 2007, p. 3220-3232, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.00072-07
Copyright © 2007, American Society for Microbiology. All Rights
Reserved.

Identification of Transferrin-Binding Domains in TbpB Expressed by
Neisseria gonorrhoeae
Amanda J. DeRocco and Cynthia Nau Cornelissen*
Department of Microbiology and Immunology, Virginia Commonwealth
University Medical Center, Richmond, Virginia 23298-0678

Received 12 January 2007/ Returned for modification 7 March 2007/
Accepted 9 April 2007

The transferrin iron acquisition system of Neisseria gonorrhoeae is
necessary for iron uptake from transferrin in the human host and
requires the participation of two distinct proteins: TbpA and TbpB.
TbpA is a TonB-dependent outer membrane transporter responsible for
the transport of iron into the cell. TbpB is a lipid-modified protein,
for which a precise role in receptor function has not yet been
elucidated. These receptor complex proteins show promise as vaccine
candidates; therefore, it is important to identify surface-exposed
regions of the proteins required for wild-type functions. In this
study we examined TbpB, which has been reported to be surface exposed
in its entirety; however, this hypothesis has never been tested
experimentally. We placed the hemagglutinin (HA) epitope into TbpB
with the dual purpose of examining the surface exposure of particular
epitopes as well as their impact on receptor function. Nine insertion
mutants were created, placing the epitope downstream of the signal
peptidase II cleavage site. We report that the HA epitope is surface
accessible in all mutants, indicating that the full-length TbpB is
completely surface exposed. By expressing the TbpB-HA fusion proteins
in N. gonorrhoeae, we were able to examine the impact of each
insertion on the function of TbpB and the transferrin acquisition
process. We propose that TbpB is comprised of two transferrin-binding-
competent lobes, both of which are critical for efficient iron uptake
from human transferrin.

--------------------------------------------------------------------------------
* Corresponding author. Mailing address: Department of Microbiology
and Immunology, Virginia Commonwealth University Medical Center, P.O.
Box 980678, Richmond, VA 23298-0678. Phone: (804) 827-1754. Fax: (804)
828-9946. E-mail: cncornel@vcu.edu

Published ahead of print on 16 April 2007.

Editor: D. L. Burns

--------------------------------------------------------------------------------
Infection and Immunity, July 2007, p. 3220-3232, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.00072-07
Copyright © 2007, American Society for Microbiology. All Rights
Reserved.

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