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Infection and Immunity, August 2007, p. 3791-3801, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.01779-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cytolysin-Dependent Escape of the Bacterium from the Phagosome Is Required but Not Sufficient for Induction of the Th1 Immune Response against Listeria monocytogenes Infection: Distinct Role of Listeriolysin O Determined by Cytolysin Gene Replacement{triangledown}

Hideki Hara, Ikuo Kawamura, Takamasa Nomura, Takanari Tominaga,{dagger} Kohsuke Tsuchiya, and Masao Mitsuyama*

Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan

Received 7 November 2006/ Returned for modification 4 January 2007/ Accepted 11 May 2007

Listeria monocytogenes evades the antimicrobial mechanisms of macrophages by escaping from the phagosome into the cytosolic space via a unique cytolysin that targets the phagosomal membrane, listeriolysin O (LLO), encoded by hly. Gamma interferon (IFN-{gamma}), which is known to play a pivotal role in the induction of Th1-dependent protective immunity in mice, appears to be produced, depending on the bacterial virulence factor. To determine whether the LLO molecule (the major virulence factor of L. monocytogenes) is indispensable or the escape of bacteria from the phagosome is sufficient to induce IFN-{gamma} production, we first constructed an hly-deleted mutant of L. monocytogenes and then established isogenic L. monocytogenes mutants expressing LLO or ivanolysin O (ILO), encoded by ilo from Listeria ivanovii. LLO-expressing L. monocytogenes was highly capable of inducing IFN-{gamma} production and Listeria-specific protective immunity, while the hly-deleted mutant was not. In contrast, the level of IFN-{gamma} induced by ILO-expressing L. monocytogenes was significantly lower both in vitro and in vivo, despite the ability of this strain to escape the phagosome and the intracellular multiplication at a level equivalent to that of LLO-expressing L. monocytogenes. Only a negligible level of protective immunity was induced in mice against challenge with LLO- and ILO-expressing L. monocytogenes. These results clearly show that escape of the bacterium from the phagosome is a prerequisite but is not sufficient for the IFN-{gamma}-dependent Th1 response against L. monocytogenes, and some distinct molecular nature of LLO is indispensable for the final induction of IFN-{gamma} that is essentially required to generate a Th1-dependent immune response.

* Corresponding author. Mailing address: Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshida-konoecho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81 (75) 753-4441. Fax: 81 (75) 753-4446. E-mail: mituyama{at}mb.med.kyoto-u.ac.jp

{triangledown} Published ahead of print on 21 May 2007.

Editor: J. L. Flynn

{dagger} Present address: TK Bio Research Laboratory, Nakakoma, Yamanashi 409-3866, Japan.

Infection and Immunity, August 2007, p. 3791-3801, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.01779-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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