An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism.
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ABSTRACT:
SUBMITTER: Song H
PROVIDER: S-EPMC4729479 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Influenza D virus (IDV) is unique among four types of influenza viruses in that it utilizes cattle as a primary reservoir. The thermal and acid stability of IDV were examined and directly compared with those of influenza A virus (IAV), influenza B virus (IBV), and influenza C virus (ICV). The results of our experiments demonstrated that only IDV had a high residual infectivity (~2.5 log units of 50% tissue culture infective dose [TCID50]/ml) after a 60-min exposure to 53°C in solution at a neutral pH, and remarkably, IDV retained this infectivity even after exposure to 53°C for 120 min. Furthermore, the data showed that IDV was extremely resistant to inactivation by low pH. After being treated at pH 3.0 for 30 min, IDV lost only approximately 20% of its original infectiousness, while all other types of influenza viruses were completely inactivated. Finally, replacement of the hemagglutinin (HA) and neuraminidase (NA) proteins of a temperature- and acid-sensitive IAV with the hemagglutinin-esterase fusion (HEF) protein of a stable IDV through a reverse genetic system largely rendered the recombinant IAVs resistant to high-temperature and low-pH treatments. Together, these results indicated that the HEF glycoprotein is a primary determinant of the exceptional temperature and acid tolerance of IDV. Further investigation into the viral entry and fusion mechanism mediated by the intrinsically stable HEF protein of IDV may offer novel insights into how the fusion machinery of influenza viruses evolve to achieve acid and thermal stability, which as a result promotes the potential to transmit across mammal species. IMPORTANCE Influenza D virus (IDV) utilizes cattle as a primary reservoir. Increased outbreaks in pigs and serological evidence of human infection have raised a concern about the potential of IDV adapting to humans. Here, we directly compared IDV's stability to that of other influenza types (A, B, and C) following prolonged incubation at high temperatures or in a low-pH environment. We found that IDV is the most stable of the four types of influenza viruses. Importantly, we demonstrated that the hemagglutinin-esterase fusion (HEF) protein, which drives the fusion between viral and host cell membranes, is the primary determinant for the high thermal and acid stability of IDV. Considering that there is a link between the acid stability of the hemagglutinin protein of influenza A virus and its cross-species transmission, further investigation of the mechanism of HEF-directed viral tolerance may offer novel insights into tissue tropism and cross-species transmission of influenza viruses.
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Project description:The spike glycoproteins of the lipid-enveloped orthomyxoviruses and paramyxoviruses have three functions: to recognize the receptor on the cell surface, to mediate viral fusion with the cell membrane, and to destroy the receptor. In influenza C virus, a single glycoprotein, the haemagglutinin-esterase-fusion (HEF) protein, possesses all three functions. In influenza A and B, the first two activities are mediated by haemagglutinin and the third by a second glycoprotein, neuraminidase. Here we report the crystal structure of the HEF envelope glycoprotein of influenza C virus. We have identified the receptor-binding site and the receptor-destroying enzyme (9-O-acetylesterase) sites, by using receptor analogues. The receptor-binding domain is structurally similar to the sialic acid-binding domain of influenza A haemagglutinin, but binds 9-O-acetylsialic acid. The esterase domain has a structure similar to the esterase from Streptomyces scabies and a brain acetylhydrolase. The receptor domain is inserted into a surface loop of the esterase domain and the esterase domain is inserted into a surface loop of the stem. The stem domain is similar to that of influenza A haemagglutinin, except that the triple-stranded, alpha-helical bundle diverges at both of its ends, and the amino terminus of HEF2, the fusion peptide, is partially exposed. The segregation of HEF's three functions into structurally distinct domains suggests that the entire stem region, including sequences at the amino and carboxy termini of HEF1 which precede the post-translational cleavage site between HEF1 and HEF2, forms an independent fusion domain which is probably derived from an ancestral membrane fusion protein.
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