Duck and Human Pandemic Influenza A Viruses Retain Sialidase Activity under Low pH Conditions

Takahashi, Toshifumi; Suzuki, Yasuo; Nishinaka, Daisuke; Kawase, Nana; Kobayashi, Yukiko; Hidari, Kazuya I.-R Jwa; Miyamoto, Daisei; Guo, Chan-Tan; Shortridge, K. F.; Suzuki, Takashi

doi:10.1093/oxfordjournals.jbchem.a002983

Cited by 35 publications

(49 citation statements)

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“…On day 3 p.i., tracheal shedding was generally observed more often and at higher titers than cloacal shedding, consistent with previous work (48). The H24 1 Q and K58 2 I mutations did not appear to increase cloacal virus shedding; thus, small decreases in the pH of activation (and inactivation) of the HA protein may be insufficient to enhance virus replication in the low-pH environment of the duck digestive tract (49). We also investigated shedding of the recombinant viruses by titrating virus in the ducks' water dishes.…”

Section: Resultssupporting

confidence: 89%

The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks

Reed

Bridges

Seiler

et al. 2010

J Virol

133

187

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While the molecular mechanism of membrane fusion by the influenza virus hemagglutinin (HA) protein has been studied extensively in vitro, the role of acid-dependent HA protein activation in virus replication, pathogenesis, and transmission in vivo has not been characterized. To investigate the biological significance of the pH of activation of the HA protein, we compared the properties of four recombinant viruses with altered HA protein acid stability to those of wild-type influenza virus A/chicken/Vietnam/C58/04 (H5N1) in vitro and in mallards. Membrane fusion by wild-type virus was activated at pH 5.9. Wild-type virus had a calculated environmental persistence of 62 days and caused extensive morbidity, mortality, shedding, and transmission in mallards. An N114K mutation that increased the pH of HA activation by 0.5 unit resulted in decreased replication, genetic stability, and environmental stability. Changes of ؉0.4 and ؊0.5 unit in the pH of activation by Y23H and K58I mutations, respectively, reduced weight loss, mortality, shedding, and transmission in mallards. An H24Q mutation that decreased the pH of activation by 0.3 unit resulted in weight loss, mortality, clinical symptoms, and shedding similar to those of the wild type. However, the HA-H24 1 Q virus was shed more extensively into drinking water and persisted longer in the environment. The pH of activation of the H5 HA protein plays a key role in the propagation of H5N1 influenza viruses in ducks and may be a novel molecular factor in the ecology of influenza viruses. The data also demonstrate that H5N1 neuraminidase activity increases the pH of activation of the HA protein in vitro.

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Section: Resultssupporting

confidence: 89%

The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks

Reed

Bridges

Seiler

et al. 2010

J Virol

133

187

View full text Add to dashboard Cite

show abstract

“…This interpretation is consistent with our observations that Dk-rec6 NA protein with proline at position 431 showed low-pH resistance, whereas the Dk78/Eng62N2 and Dk-rec1 NA proteins with glutamine at this position did not. Ten amino acid residues, including proline at position 431, may be associated with the low-pH stability of NA (18). Our present finding that proline at position 431 plays a critical role in the low-pH resistance of the N2 NA protein of influenza A viruses supports the results of this earlier study.…”

Section: Resultssupporting

confidence: 90%

The Low-pH Resistance of Neuraminidase Is Essential for the Replication of Influenza A Virus in Duck Intestine following Infection via the Oral Route

Fujimoto

Ito

Ono

et al. 2016

J Virol

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Influenza A viruses are known to primarily replicate in duck intestine following infection via the oral route, but the specific role of neuraminidase (NA) for the intestinal tropism of influenza A viruses has been unclear. A reassortant virus (Dk78/Eng62N2) did not propagate in ducks infected via the oral route. To generate variant viruses that grow well in ducks via the oral route, we isolated viruses that effectively replicate in intestinal mucosal cells by passaging Dk78/Eng62N2 in duck via rectal-route infection. This procedure led to the isolation of a variant virus from the duck intestine. This virus was propagated using embryonated chicken eggs and inoculated into a duck via the oral route, which led to the isolation of Dk-rec6 from the duck intestine. Experimental infections with mutant viruses generated by using reverse genetics indicated that the paired mutation of residues 356 and 431 in NA was necessary for the viral replication in duck intestine. The NA assay revealed that the activity of Dk78/Eng62N2 almost disappeared after pH 3 treatment, whereas that of Dk-rec6 was maintained. Furthermore, to identify the amino acid residues associated with the low-pH resistance, we measured the activities of mutant NA proteins transiently expressed in 293 cells after pH 3 treatment. All mutant NA proteins that possessed proline at position 431 showed higher activities than NA proteins that possessed glutamine at this position. These findings indicate that the low-pH resistance of NA plays an important role in the ability of influenza A virus to replicate in duck intestine. IMPORTANCENeuraminidase (NA) activity facilitates the release of viruses from cells and, as such, is important for the replicative efficiency of influenza A virus. Ducks are believed to serve as the principal natural reservoir for influenza A virus; however, the key properties of NA for viral infection in duck are not well understood. In this study, we identify amino acid residues in NA that contribute to viral replication in ducks via the natural route of infection and demonstrate that maintenance of NA activity under low-pH conditions is associated with the biological properties of the virus. These findings provide insights into the mechanisms of replication of influenza A virus in ducks.

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“…Part of human IAV strains maintains avianlike low-pH stability of sialidase activity. 32,33) The low-pH stability of IAV sialidase is functionally linked to virus entry via the endocytic pathway and contributes to the ability of virus replication. 31) The difference of GH effects between A/Aichi/2/68 (H3N2) and other strains may depend on the low-pH stability of their sialidase activities.…”

Section: Resultsmentioning

confidence: 99%

Glucosyl Hesperidin Prevents Influenza A Virus Replication <i>in Vitro</i> by Inhibition of Viral Sialidase

Saha

Takahashi

Suzuki

2009

Biological & Pharmaceutical Bulletin

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Hesperidin, a flavonoid obtained from citrus fruits, is known to have multiple biological activities and antimicrobial activities for human viruses; however, hesperidin has very low solubility in water and the target molecule of hesperidin for influenza virus remains unknown. A water-soluble derivative of hesperidin, glucosyl hesperidin (GH), which was synthesized by regioselective transglycosylation with cyclodextrin glucanotransferase, has been reported to have biological activities that are as or stronger than those of hesperidin. To determine the inhibitory effect of GH on influenza A virus (IAV) infection, Madin-Darby canine kidney (MDCK) cells were treated with GH before, at the same time as, and after IAV inoculation. GH treatment before IAV inoculation had no effect on virus replication, whereas, treatment with GH at the same time as or after IAV inoculation induced distinct reduction in IAV replication. Inhibition analysis of GH against two surface glycoprotein spikes of IAV revealed that GH prevents IAV replication by inhibition of viral sialidase activity that is involved in the entry and release stages on IAV infection but not by receptor binding inhibition. GH had no cytotoxic effects on MDCK cells in a dose range of 0-25 mM. Our results provide useful information for the development of novel sialidase inhibitors for influenza prevention.

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Duck and Human Pandemic Influenza A Viruses Retain Sialidase Activity under Low pH Conditions

Cited by 35 publications

References 0 publications

The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks

The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks

The Low-pH Resistance of Neuraminidase Is Essential for the Replication of Influenza A Virus in Duck Intestine following Infection via the Oral Route

Glucosyl Hesperidin Prevents Influenza A Virus Replication <i>in Vitro</i> by Inhibition of Viral Sialidase

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