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Antimicrobial Agents and Chemotherapy, May 1999, p. 1242-1251, Vol. 43, No. 5
Unité de Pharmacologie Cellulaire et
Moléculaire,1 and Unité de
Médecine Expérimentale,
Received 26 May 1998/Returned for modification 10 December
1998/Accepted 18 February 1999
Listeria monocytogenes, a facultative intracellular
pathogen, readily enters cells and multiplies in the cytosol after
escaping from phagosomal vacuoles. Macrophages exposed to gamma
interferon, one of the main cellular host defenses against
Listeria, become nonpermissive for bacterial growth while
containing Listeria in the phagosomes. Using the human
myelomonocytic cell line THP-1, we show that the combination of
L-monomethyl arginine and catalase restores bacterial
growth without affecting the phagosomal containment of
Listeria. A previous report (B. Scorneaux, Y. Ouadrhiri, G. Anzalone, and P. M. Tulkens, Antimicrob. Agents Chemother.
40:1225-1230, 1996) showed that intracellular Listeria was
almost equally sensitive to ampicillin, azithromycin, and sparfloxacin
in control cells but became insensitive to ampicillin and more
sensitive to azithromycin and sparfloxacin in gamma interferon-treated
cells. We show here that these modulations of antibiotic activity are
largely counteracted by L-monomethyl arginine and catalase.
In parallel, we show that gamma interferon enhances the cellular
accumulation of azithromycin and sparfloxacin, an effect which is not
reversed by addition of L-monomethyl arginine and catalase
and which therefore cannot account for the increased activity of these
antibiotics in gamma interferon-treated cells. We conclude that (i) the
control exerted by gamma interferon on intracellular multiplication of
Listeria in THP-1 macrophages is dependent on the
production of nitric oxide and hydrogen peroxide; (ii) intracellular
Listeria may become insensitive to ampicillin in
macrophages exposed to gamma interferon because the increase in
reactive oxygen and nitrogen intermediates already controls bacterial
growth; and (iii) azithromycin and still more sparfloxacin cooperate
efficiently with gamma interferon, one of the main cellular host
defenses in Listeria infection.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Mechanism of the Intracellular Killing and Modulation of
Antibiotic Susceptibility of Listeria monocytogenes in THP-1
Macrophages Activated by Gamma Interferon

*
Corresponding author. Mailing address: Unité de
Pharmacologie Cellulaire et Moléculaire, Université
Catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200
Brussels, Belgium. Phone: 32-2-764.73.76. Fax: 32-2-764.73.73. E-mail:
ouadrhiri{at}facm.ucl.ac.be.
Present address: IDEA GmbH, Munich, Germany.
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