Cross-protective potential of anti-nucleoprotein human monoclonal antibodies against lethal influenza A virus infection.
The nucleoprotein (NP) possesses regions that are highly conserved among influenza A viruses, and has therefore been one of the target viral proteins for development of a universal influenza vaccine. It has been expected that human or humanized antibodies will be made available for the prophylaxis, pre-emptive and acute treatment of viral infection. However, it is still unclear whether anti-NP human antibody can confer protection against influenza virus infection. In this study, we generated transgenic mice expressing anti-NP human mAbs derived from lymphocytes of a patient infected with H5N1 highly pathogenic avian influenza (HPAI) virus, and experimental infections were conducted to examine antiviral effects of the anti-NP antibodies against H5N1 HPAI viral infections with a high fatality rate in mammals. Transgenic mouse lines expressing the anti-NP human mAbs at more than 1 mg ml-1 showed marked resistance to H5N1 virus infections. In addition, resistance to infection with an H1N1 subtype that shows strong pathogenicity to mice was also confirmed. Although the anti-NP mAbs expressed in the transgenic mice did not neutralize the virus, the mAbs could bind to NP located on the surface of infected cells. These results suggested a possibility that the non-neutralizing anti-NP human mAbs could induce indirect antiviral effects, such as antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Taken together, these results demonstrated that anti-NP human mAbs play an important role in heterosubtypic protection against lethal influenza virus infections in vivo.
Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Yoshikazu
Y
Fujimoto
Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
Yukiko
Y
Tomioka
Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Hiroki
H
Takakuwa
Institute of Tropical Medicine, Nagasaki University, Nagasaki 851-2125, Japan.
Gen-Ichiro
GI
Uechi
Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Toshiyo
T
Yabuta
Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Kinuyo
K
Ozaki
Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Haruka
H
Suyama
Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Sayo
S
Yamamoto
Laboratory of Experimental Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Masami
M
Morimatsu
Department of Virology, National Institute of Hygiene and Epidemiology, No. 1 Yersin Street, Hanoi, Vietnam.
Le Quynh
LQ
Mai
Institute of Tropical Medicine, Nagasaki University, Nagasaki 851-2125, Japan.
Tetsu
T
Yamashiro
Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
Toshihiro
T
Ito
Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.|Avian Influenza Research Center, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Koichi
K
Otsuki
Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.|Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Etsuro
E
Ono
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D060467:Disease Resistance; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007155:Immunologic Factors; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins