title: Avian Influenza Virus Infection of Immortalized Human Respiratory Epithelial Cells Depends upon a Delicate Balance between Hemagglutinin Acid Stability and Endosomal pH.
abstract: The highly pathogenic avian influenza (AI) virus, H5N1, is a serious threat to public health worldwide. Both the currently circulating H5N1 and previously circulating AI viruses recognize avian-type receptors; however, only the H5N1 is highly infectious and virulent in humans. The mechanism(s) underlying this difference in infectivity remains unclear. The aim of this study was to clarify the mechanisms responsible for the difference in infectivity between the current and previously circulating strains. Primary human small airway epithelial cells (SAECs) were transformed with the SV40 large T-antigen to establish a series of clones (SAEC-Ts). These clones were then used to test the infectivity of AI strains. Human SAEC-Ts could be broadly categorized into two different types based on their susceptibility (high or low) to the viruses. SAEC-T clones were poorly susceptible to previously circulating AI but were completely susceptible to the currently circulating H5N1. The hemagglutinin (HA) of the current H5N1 virus showed greater membrane fusion activity at higher pH levels than that of previous AI viruses, resulting in broader cell tropism. Moreover, the endosomal pH was lower in high susceptibility SAEC-T clones than that in low susceptibility SAEC-T clones. Taken together, the results of this study suggest that the infectivity of AI viruses, including H5N1, depends upon a delicate balance between the acid sensitivity of the viral HA and the pH within the endosomes of the target cell. Thus, one of the mechanisms underlying H5N1 pathogenesis in humans relies on its ability to fuse efficiently with the endosomes in human airway epithelial cells.
authors: From the Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Tomo
authors: T
authors: Daidoji
authors: the Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Yohei
authors: Y
authors: Watanabe
authors: the Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan, the Department of Microbiology, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22111, Egypt.
authors: Madiha S
authors: MS
authors: Ibrahim
authors: the Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan, the Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka, 598-8531, Japan.
authors: Mayo
authors: M
authors: Yasugi
authors: the Department of Micro-Nano Systems Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan, and.
authors: Hisataka
authors: H
authors: Maruyama
authors: the Department of Micro-Nano Systems Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan, and.
authors: Taisuke
authors: T
authors: Masuda
authors: the Department of Micro-Nano Systems Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan, and.
authors: Fumihito
authors: F
authors: Arai
authors: the Department of Frontier Bioscience, Hosei University, Koganei, Tokyo 184-8584, Japan.
authors: Tomoyuki
authors: T
authors: Ohba
authors: the Department of Frontier Bioscience, Hosei University, Koganei, Tokyo 184-8584, Japan.
authors: Ayae
authors: A
authors: Honda
authors: the Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Kazuyoshi
authors: K
authors: Ikuta
authors: From the Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan, tnakaya@koto.kpu-m.ac.jp.
authors: Takaaki
authors: T
authors: Nakaya
mesh_terms: D000818:Animals; D001717:Birds; D002460:Cell Line; D002999:Clone Cells; D004285:Dogs; D011992:Endosomes / Q000378:metabolism / Q000821:virology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity* / Q000502:physiology*; D005585:Influenza in Birds / Q000378:metabolism / Q000635:transmission / Q000821:virology; D007251:Influenza, Human / Q000378:metabolism / Q000635:transmission / Q000821:virology; D055550:Protein Stability; D011956:Receptors, Cell Surface / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014774:Virulence / Q000502:physiology; D053586:Virus Internalization
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011956:Receptors, Cell Surface; C092488:sialic acid receptor
keywords: Avian Influenza Virus; Endosomal pH; Endosome; Epithelial Cell; Hemagglutinin; Membrane Fusion; Tropism; Viral Protein; Virus Entry