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Int J Clin Exp Pathol 2012;5(8):787-795

Original Article
Emergence of HA mutants during influenza virus pneumonia

Maria Eugenia Vázquez Manríquez, Akiko Makino, Motoko Tanaka, Yasuhisa Abe, Hiroyuki Yoshida, Ichiro Morioka, Soichi Arakawa, Yasuhiro
Takeshima, Kentaro Iwata, Jin Takasaki, Toshie Manabe, Takaaki Nakaya, Shota Nakamura, Anjarath Lorena Higuera Iglesias, Rosa Maria
Rivera Rossales, Erika Pena Mirabal, Tateki Ito, Toshio Kitazawa, Teruaki Oka, Makoto Yamashita, Koichiro Kudo, Kyoko Shinya

National Institute of Respiratory Diseases, Mexico City, Mexico; Division of Zoonosis, Kobe University, Japan; Department of Infection Control
and Prevention, Kobe University Hospital, Japan; Department of Pediatrics, Kobe University Hospital, Japan; Division of Infectious Diseases,
Kobe University Hospital, Japan; National Center for Global Health and Medicine, Tokyo, Japan; Research Institute for Microbial Diseases,
Osaka University, Japan; Kanto Central Hospital, Tokyo, Japan; Biological Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan

Received August 1, 2012; Accepted September 5, 2012; Epub October 1, 2012; Published October 15, 2012

Abstract: During the influenza pandemic of 2009, the number of viral pneumonia cases showed a marked increase in comparison with
seasonal influenza viruses. Mutations at amino acid 222 (D222G mutations) in the virus hemagglutinin (HA) molecule, known to alter the
receptor-recognition properties of the virus, were detected in a number of the more severely-affected patients in the early phases of the
pandemic. To understand the background for the emergence of the mutant amino acid D222G in human lungs, we conducted histological
examinations on lung specimens of patients from Mexico who had succumbed in the pandemic. Prominent regenerative and hyperplastic
changes in the alveolar type II pneumocytes, which express avian-type sialoglycan receptors in the respiratory tract of severely affected
individuals, were observed in the Mexican patients. An infection model utilizing guinea pigs, which was chosen in order to best simulate the
sialic acid distribution of severe pneumonia in human patients, demonstrated an increase of D222G mutants and a delay in the diminution of
mutants in the lower respiratory tract in comparison to the upper respiratory tract. Our data suggests that the predominance of avian-type
sialoglycan receptors in the pneumonic lungs may contribute to the emergence of viral HA mutants. This data comprehensively illustrates the
mechanisms for the emergence of mutants in the clinical samples. (IJCEP1208001).

Keywords: Influenza, mutant, hemagglutinin, pneumonia, hyperplastic pneumocytes, syaloglycan receptor

Address all correspondence to:
Dr. Kyoko Shinya, Division of Zoonosis, Kobe University, Japan. Tel: +81-78-382-5701; Fax: +81-78-382-5701; E-mail: