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* Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan;
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan; and
¶ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan
Live attenuated Shigella vaccines elicit protective immune responses, but involve a potential risk of inducing a strong inflammatory reaction. The bacterial invasiveness that is crucial for Ag delivery causes inflammatory destruction of infected epithelial cells and proinflammatory cell death of infected macrophages. In this study, the noninvasive Shigella mutant 
ipaB was equipped with Yersinia invasin protein, which has been shown to mediate bacterial invasion and targeting to M cells located in follicle-associated epithelium. Invasin-expressing ipaB (ipaB/inv) was internalized into epithelial cells and retained in the intraphagosomal space. ipaB/inv did not induce necrotic cell death of infected macrophages nor cause symptomatic damage after intranasal vaccination of mice. ipaB/inv was safer and more effective than the conventional live vaccine, virG. Infection by ipaB/inv caused polymorphonuclear neutrophil infiltration in the lung, but did not induce production of large amounts of proinflammatory cytokines. We concluded that the low experimental morbidity and high vaccine efficacy of ipaB/inv are primarily based on high protective immune responses, which may be enhanced by the polymorphonuclear neutrophil infiltration unaccompanied by tissue injury.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Japan Science and Technology Agency, and Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, and Technology.
2 Address correspondence and reprint requests to Dr. Toshihiko Suzuki, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; E-mail address: t-suzuki{at}ims.u-tokyo.ac.jp or Dr. Chihiro Sasakawa, Department of Microbiology and Immunology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; E-mail address: sasakawa{at}ims.u-tokyo.ac.jp
3 Current address: Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
4 Current address: Department of Infectious Diseases, Research Institute, International Medical Center of Japan, Tokyo, Japan.
5 Current address: Chiba University Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba, Japan.
6 Abbreviations used in this paper: ipaB/inv, invasin-expressing ipaB; BAL, bronchoalveolar lavage; i.n., intranasal; LDH, lactate dehydrogenase; MPO, myeloperoxidase; PMN, polymorphonuclear neutrophil.
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