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Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV¹

Fumihiko Yasui^*, Chieko Kai, Masahiro Kitabatake^2,*, Shingo Inoue^||, Misako Yoneda, Shoji Yokochi^*,, Ryoichi Kase^*, Satoshi Sekiguchi^*, Kouichi Morita, Tsunekazu Hishima^¶, Hidenori Suzuki, Katsuo Karamatsu^#, Yasuhiro Yasutomi^#, Hisatoshi Shida^**, Minoru Kidokoro, Kyosuke Mizuno^*, Kouji Matsushima and Michinori Kohara^3,*

^* Department of Microbiology and Cell Biology, Laboratory of Electron Microscopy, The Tokyo Metropolitan Institute of Medical Science, Laboratory Animal Research Center, The Institute of Medical Science, Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, and ^¶ Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ^|| Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan; ^# Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan; ^** Division of Molecular Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Third Department of Virology, National Institute of Infectious Diseases, Musashimurayama, Japan; and ^* The Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan

The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7–8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-β), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.

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 study was supported in part by a Grant for Research on Emerging and Re-emerging Infectious Diseases from the Ministry of Health, Labor and Welfare, Japan, by the 21st Century Centers of Excellence program on Global Strategies for Control of Tropical and Emerging Infectious Diseases at Nagasaki University, and by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Strategic cooperation to control emerging and re-emerging infections is funded by the Special Co-ordination Fund for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology.

² Current address: Department of Immunology, Graduate School of Medicine, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.

³ Address correspondence and reprint requests to Dr. Michinori Kohara, Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. E-mail address: kohara-mc{at}igakuken.or.jp

⁴ Abbreviations used in this paper: SARS, severe acute respiratory syndrome; CoV, coronavirus; VV, vaccinia virus; HA, hemagglutinin; MOI, multiplicity of infection; VLP, virus-like particle; TCID₅₀, tissue culture ID₅₀.