Infection of Human Tracheal Epithelial Cells by H5 Avian Influenza Virus Is Regulated by the Acid Stability of Hemagglutinin and the pH of Target Cell Endosomes.

Tomo Daidoji,Junichi Kajikawa,Yohei Watanabe,Takaaki Nakaya,Ryohei Hirose,Yasuha Arai

doi:10.3390/v12010082

Tomo Daidoji, Junichi Kajikawa + Show 4 more

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Journal: Viruses	Publication Date: Jan 9, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Kyoto Prefectural University of Medicine

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Despite the possible relationships between tracheal infection and concomitant infection of the terminal part of the lower respiratory tract (bronchioles/alveoli), the behavior of avian influenza viruses (AIVs), such as H5N1, in the conducting airways is unclear. To examine the tropism of AIVs for cells lining the conducting airways of humans, we established human tracheal epithelial cell clones (HTEpC-Ts) and examined their susceptibility to infection by AIVs. The HTEpC-Ts showed differing susceptibility to H5N1 and non-zoonotic AIVs. Viral receptors expressed by HTEpC-Ts bound all viruses; however, the endosomal pH was associated with the overall susceptibility to infection by AIVs. Moreover, H5N1 hemagglutinin broadened viral tropism to include HTEpC-Ts, because it had a higher pH threshold for viral–cell membrane fusion. Thus, H5N1 viruses infect human tracheal epithelial cells as a result of their higher pH threshold for membrane fusion which may be one mechanism underlying H5N1 pathogenesis in human airway epithelia. Efficient replication of H5N1 in the conducting airways of humans may facilitate infection of the lower respiratory tract.

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Because the infection of cells requires viral–cell membrane fusion, which is induced by a pH-dependent HA conformational change, we investigated whether the acid stability of the HA molecule affects the susceptibility of human tracheal epithelial cells (HTEpCs)-Ts to viral infection
Both small airway epithelial cell (SAEC)-T clone 21E5 and HTEpC-Ts were highly susceptible to infection by human influenza and H5N1) (Thailand (H5N1) viruses, but they were less susceptible to infection by non-zoonotic avian influenza viruses (AIVs), such as H5N3 and H5N9, regardless of the presence of multiple basic amino acids in the HA cleavage site (Figure 1)
HTEpC-T (LA-9) and SAEC-T (1A5) cells which are marginally and adequately susceptible, respectively, to infection by AIVs. These results suggest that an event(s) arising after viral internalization by endocytosis is responsible for differences in the susceptibility of LA-9 and 1A5 cells to infection by AIVs

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Introduction

Since the first case of human infection in Hong Kong in 1997, H5N1 viruses have remained a serious threat to public health worldwide, even though recent reports show that other subtypes of avian influenza viruses (AIVs), such as H5N6, H6N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7, and H10N8, can infect humans [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Infectious viruses have been isolated from the tracheal aspirates of patients infected with H5N1 [21,25]. These studies suggest that cells lining the human conducting airways (e.g., trachea) are susceptible to infection by H5N1. They suggest a possible relationship between tracheal. Viruses 2020, 12, 82 infection and concomitant infection of the terminal part of the lower respiratory tract (LRT). The behavior of AIVs, such as H5N1, in the conducting airways is unclear

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