Research Article: An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism

Date Published: January 27, 2016

Publisher: Public Library of Science

Author(s): Hao Song, Jianxun Qi, Zahra Khedri, Sandra Diaz, Hai Yu, Xi Chen, Ajit Varki, Yi Shi, George F. Gao, Félix A. Rey.


Influenza viruses cause seasonal flu each year and pandemics or epidemic sporadically, posing a major threat to public health. Recently, a new influenza D virus (IDV) was isolated from pigs and cattle. Here, we reveal that the IDV utilizes 9-O-acetylated sialic acids as its receptor for virus entry. Then, we determined the crystal structures of hemagglutinin-esterase-fusion glycoprotein (HEF) of IDV both in its free form and in complex with the receptor and enzymatic substrate analogs. The IDV HEF shows an extremely similar structural fold as the human-infecting influenza C virus (ICV) HEF. However, IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. This structural difference provides an explanation for the phenomenon that the IDV has a broad cell tropism. As IDV HEF is structurally and functionally similar to ICV HEF, our findings highlight the potential threat of the virus to public health.

Partial Text

Influenza viruses are enveloped, segmented, single-stranded, negative-sense RNA viruses and belong to the family Orthomyxoviridae [1]. The genomes of influenza A virus (IAV) and influenza B virus (IBV) consist of eight RNA segments, whereas influenza C viruses (ICV) only have seven segments. Both IAV and IBV contain two major surface glycoproteins: the hemagglutinin (HA), which binds to sialylated host cell receptors and mediates membrane fusion; and the neuraminidase (NA), which destroys the receptor by cleaving sialic acid from host cell membranes, thereby releasing newly assembled virus particles [1], and likely assisting initial invasion by destroying sialylated mucin decoys [2]. ICV, however, has only one major surface glycoprotein, the hemagglutinin-esterase-fusion (HEF) protein, which possesses all-in-one of receptor binding, receptor destroying and membrane fusion activities [3, 4]. While IAV infects avian, human, swine, and many other mammalian species including dogs, horses, tigers and seals, IBV and ICV are found principally in humans and rarely infect other species [3].

Since the first ICV strain (C/Taylor/1233/47) was isolated in 1947 during an epidemic of respiratory illness, hundreds of viruses have been isolated in clinical specimens [48–50], due to its inconspicuous or mild symptoms and lack of suitable cell lines for virus isolation [51]. Recently, a dozen of novel IDV strains have been isolated from both pigs and cattle, strains that are distantly related to human ICV [20, 21, 23, 25, 26, 52]. Ferrets, guinea pigs and small ruminants (sheep and goats) have also been found to be susceptible to the virus [20, 24, 29]. Clearly, the viral traits necessary for host switching are different between ICV and IDV.




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